1. − If Approved, Vutrisiran will Provide a New, Subcutaneously Administered, Once-Quarterly Treatment Option for Patients with hATTR Amyloidosis −

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced the submission of a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for vutrisiran, an investigational RNAi therapeutic for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis in adult patients with polyneuropathy.

    "hATTR amyloidosis is a rare, rapidly progressive, debilitating and fatal condition and we are delighted that the EMA has agreed to review the regulatory submission for vutrisiran based on the positive 9-month data from the HELIOS-A Phase…

    − If Approved, Vutrisiran will Provide a New, Subcutaneously Administered, Once-Quarterly Treatment Option for Patients with hATTR Amyloidosis −

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced the submission of a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for vutrisiran, an investigational RNAi therapeutic for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis in adult patients with polyneuropathy.

    "hATTR amyloidosis is a rare, rapidly progressive, debilitating and fatal condition and we are delighted that the EMA has agreed to review the regulatory submission for vutrisiran based on the positive 9-month data from the HELIOS-A Phase 3 study," said Rena Denoncourt, Vice President, TTR Franchise Lead. "If approved, we believe that vutrisiran will provide an important new subcutaneously administered, once-quarterly treatment option for patients, with the potential to reverse manifestations of the disease in hATTR amyloidosis patients with polyneuropathy. We look forward to working closely with the EMA to bring vutrisiran to the hATTR amyloidosis community in Europe."

    Positive 9-month results from the HELIOS-A Phase 3 study of vutrisiran were presented in April 2021 at the American Academy of Neurology (AAN) Virtual Annual Meeting. At 9 months, vutrisiran met the primary and all secondary endpoints, with statistically significant improvements in neuropathy, quality of life, and gait speed, and demonstrated an encouraging safety profile, relative to the external placebo group of the APOLLO study of patisiran. As aligned with the EMA, the results of the 18-month analysis from the HELIOS-A study will be provided to the Agency during its evaluation of the MAA.

    Vutrisiran has been granted Orphan Drug Designation in the European Union (EU) and U.S. for the treatment of ATTR amyloidosis. In June 2021, the U.S. Food and Drug Administration (FDA) accepted the Company's New Drug Application (NDA) submission for review for vutrisiran, with an action date set for April 14, 2022 under the Prescription Drug User Fee Act (PDUFA). The Company also plans to submit regulatory filings in Brazil and Japan in 2021.

    About Vutrisiran

    Vutrisiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hereditary ATTR (hATTR) and wild-type ATTR (wtATTR) amyloidosis. It is designed to target and silence specific messenger RNA, blocking the production of wild-type and variant transthyretin (TTR) protein before it is made. Quarterly, and potentially biannual, administration of vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues. Vutrisiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability that may allow for infrequent subcutaneous injections. The safety and efficacy of vutrisiran have not been evaluated by the European Medicines Agency, the U.S. Food and Drug Administration, or any other health authority.

    About the HELIOS-A Phase 3 Study

    HELIOS-A (NCT03759379) is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran. The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries. Patients were randomized 3:1 to receive either 25mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (as a reference comparator) for 18 months. The efficacy results of vutrisiran in HELIOS-A are compared to the placebo group from the landmark APOLLO Phase 3 study, which evaluated the efficacy and safety of patisiran in a patient population similar to that studied in HELIOS-A. The primary endpoint is the change from baseline in mNIS+7 score at nine months. Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at nine months. Additional secondary endpoints at 18 months will be evaluated in the HELIOS-A study, including change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum transthyretin (TTR) levels. Additional exploratory cardiac endpoint data at the 18-month time point will be evaluated, including NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging. Following the 18-month treatment period, all patients are eligible to receive vutrisiran for an additional 18 months as part of the randomized treatment extension where they will receive either 25mg vutrisiran once quarterly or 50mg vutrisiran once every six months.

    About hATTR Amyloidosis

    Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, and fatal disease caused by variants (i.e., mutations) in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis, represents a major unmet medical need with significant morbidity and mortality affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the potential treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran) and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's expectations, plans, aspirations, and goals, including those related to the investigational therapeutic vutrisiran and its potential as a low-dose, once quarterly, subcutaneously administered treatment option with encouraging safety profile for patients with hATTR amyloidosis with polyneuropathy that has the potential to reverse polyneuropathy manifestations of disease, the expected timing for FDA review of the NDA for vutrisiran, plans for additional regulatory filings for vutrisiran, and Alnylam's aspiration to become a leading biotech company, and the planned achievement of its "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO (or vutrisiran, if approved) in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

    This release is not intended to convey conclusions about efficacy or safety as to any investigational uses or dosing regimens of any investigational RNAi therapeutics. There is no guarantee that any investigational therapeutics or dosing regimens for such therapeutics will successfully complete clinical development or gain health authority approval.

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  2. - Subgroup Analyses and Exploratory Endpoints Demonstrated that Vutrisiran Improved Important Areas of Patient Health and Function Compared with Placebo at 9 Months –

    - Additional Analyses Showed Similar Improvements in Progression of Neuropathy and Quality of Life Measures with Vutrisiran Treatment Compared with Placebo, Regardless of Prior TTR Stabilizer Use –

    - Company Remains On Track to Announce Topline 18-Month Results, Including Additional Exploratory Cardiac Endpoint Data, in Late 2021 –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced additional positive results from subgroup analyses and exploratory endpoints of the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi…

    - Subgroup Analyses and Exploratory Endpoints Demonstrated that Vutrisiran Improved Important Areas of Patient Health and Function Compared with Placebo at 9 Months –

    - Additional Analyses Showed Similar Improvements in Progression of Neuropathy and Quality of Life Measures with Vutrisiran Treatment Compared with Placebo, Regardless of Prior TTR Stabilizer Use –

    - Company Remains On Track to Announce Topline 18-Month Results, Including Additional Exploratory Cardiac Endpoint Data, in Late 2021 –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced additional positive results from subgroup analyses and exploratory endpoints of the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis. Data presented at the 3rd European ATTR Amyloidosis Meeting further supports and builds on the previously reported primary and secondary endpoint results of the HELIOS-A study in hereditary ATTR amyloidosis patients with polyneuropathy, with improvements observed across important areas of patient health and function, including neuropathy impairment, Quality of Life (QoL), ability to perform daily activities and social engagement, nutritional status, and cardiac stress.

    "Hereditary ATTR amyloidosis is a multisystem, rapidly progressive disease with significant impact on the daily lives of patients, and which worsens over time without appropriate management," said Pushkal Garg, M.D., Chief Medical Officer of Alnylam. "These additional data from the HELIOS-A study show the potential of vutrisiran in treating a broad group of patients with hATTR amyloidosis with polyneuropathy, with encouraging improvements seen across a range of important health and functional measures. Additionally, patients experienced improvements in neuropathy impairment and quality of life scores regardless of prior TTR stabilizer use. We look forward to sharing additional results at the 18-month readout, expected later this year. With the recent NDA submission accepted for review by the U.S. FDA and planned regulatory submission in Europe ahead of schedule, we are continuing our progress to bring vutrisiran forward as a potential new treatment option for hATTR amyloidosis patients with polyneuropathy, with subcutaneous administration and quarterly dosing."

    The HELIOS-A study included 164 hATTR amyloidosis patients with polyneuropathy. At 9 months, vutrisiran met the primary and all secondary endpoints, with statistically significant improvements in neuropathy impairment, QoL, and gait speed, relative to external placebo. The subgroup analyses and exploratory efficacy data from HELIOS-A provide additional insights on the potential benefits of vutrisiran across important aspects of patients' health and wellbeing, specifically:

    • the modified Neuropathy Impairment Score (mNIS+7) and Norfolk Quality of Life-Diabetic Neuropathy Score (Norfolk QOL-DN) were consistently improved with vutrisiran treatment compared with external placebo across all pre-specified patient subgroups at month 9, including age, sex, race, geographic region, baseline neuropathy impairment, genotype, prior TTR stabilizer use, baseline Familial Amyloid Polyneuropathy (FAP) stage, and in a pre-specified cardiac subpopulation
    • improvements were observed in the Rasch-built Overall Disability Scale (R-ODS), a comprehensive patient-ranked 24-item scale which assesses activity and social participation limitations on a linearly weighted scale, compared with external placebo. Activity measures increase in intensity and include ability to perform activities of daily living and social engagement. [LS mean difference vs. placebo 4.3 (2.7, 6.0) p=3.26x10-7]
    • modified body mass index (mBMI) levels increased in patients receiving vutrisiran treatment compared with external placebo, indicating improvements in nutritional status over 9 months [LS mean difference vs. placebo 67.8 (43.0, 92.6) p=8.46×10−8]
    • QoL (EuroQol Visual Analog Scale, EQ-VAS, self-rated health score) and neuropathy impairment (NIS), assessing patients' muscle strength, sensation and reflexes, also improved in patients receiving vutrisiran versus external placebo at 9 months. [EQ-VAS LS mean difference vs. placebo 9.8 (4.8, 14.9) p=0.0001; NIS LS mean difference vs. placebo −13.7 (− 17.3, −10.1) p=1.08 x 10−13]
    • improvement in the exploratory endpoint of the cardiac biomarker, NT-proBNP, a measure of cardiac stress, was observed in the vutrisiran arm in both the prespecified cardiac subpopulation [adjusted geometric fold change ratio: 0.60 (0.43, 0.82) p=0.0016] and the modified intent-to-treat (mITT) population [adjusted geometric fold change ratio: 0.63 (0.52, 0.75) p=9.2×10−7], relative to external placebo.

    Patients with Prior TTR Stabilizer Use Receiving Vutrisiran

    A second analysis presented from the HELIOS-A study showed that similar improvements in mNIS+7 and Norfolk QOL-DN were seen for vutrisiran-treated patients regardless of prior TTR stabilizer use. While TTR stabilizer use was not permitted at study entry, two-thirds of patients in HELIOS-A had previously used a TTR stabilizer. The most common reasons for discontinuing the stabilizer were to participate in the HELIOS-A study and disease progression. For improvements in mNIS+7 relative to external placebo, LS mean values were -14.49 (-22.69, -6.29) for patients with no previous stabilizer use and -18.96 (-24.77, -13.16) for patients with previous stabilizer use. In the case of Norfolk QOL-DN, the LS mean difference vs. external placebo was -23.0 (− 32.1, −14.0) for patients with no previous stabilizer use and -14.9 (-22.1, -7.6) for previous stabilizer use.

    In the study, vutrisiran demonstrated an encouraging safety and tolerability profile relative to external placebo with 9 months of dosing regardless of prior stabilizer use. The majority of adverse events were mild to moderate in severity in all groups and there were no drug-related discontinuations or deaths.

    The U.S. Food and Drug Administration (FDA) recently accepted the New Drug Application (NDA) submission for review for vutrisiran and has set an action date of April 14, 2022 under the Prescription Drug User Fee Act (PDUFA). Additionally, it was recently announced that based on discussions with the European Medicines Agency (EMA), the Company now plans to file, ahead of schedule, a Marketing Authorization Application (MAA) for vutrisiran based on 9-month results from the HELIOS-A study.

    About Vutrisiran

    Vutrisiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hereditary ATTR (hATTR) and wild-type ATTR (wtATTR) amyloidosis. It is designed to target and silence specific messenger RNA, blocking the production of wild-type and variant transthyretin (TTR) protein before it is made. Quarterly, and potentially biannual, administration of vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues. Vutrisiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability that may allow for infrequent subcutaneous injections. The safety and efficacy of vutrisiran have not been evaluated by the European Medicines Agency, the U.S. Food and Drug Administration, or any other health authority.

    About the HELIOS-A Phase 3 Study

    HELIOS-A (NCT03759379) is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran. The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries. Patients were randomized 3:1 to receive either 25mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (as a reference comparator) for 18 months. The efficacy results of vutrisiran in HELIOS-A are compared to the placebo group from the landmark APOLLO Phase 3 study, which evaluated the efficacy and safety of patisiran in a patient population similar to that studied in HELIOS-A. The primary endpoint is the change from baseline in mNIS+7 at nine months. Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at nine months. Additional secondary endpoints at 18 months will be evaluated in the HELIOS-A study, including change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum transthyretin (TTR) levels. Additional exploratory cardiac endpoint data at the 18-month time point will be evaluated, including NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging. Following the 18-month treatment period, all patients are eligible to receive vutrisiran for an additional 18 months as part of the randomized treatment extension where they will receive either 25mg vutrisiran once quarterly or 50mg vutrisiran once every six months.

    About hATTR Amyloidosis

    Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, and fatal disease caused by variants (i.e., mutations) in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis, represents a major unmet medical need with significant morbidity and mortality affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the potential treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran) and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's expectations, plans, aspirations, and goals, including those related to the investigational therapeutic vutrisiran and its potential as a low-dose, once quarterly, subcutaneously administered treatment option with encouraging safety profile for a broad range of patients with hATTR amyloidosis, the timing of additional results from the ongoing HELIOS-A Phase 3 study of vutrisiran, the expected timing for FDA review of the NDA for vutrisiran and the accelerated timing for the filing of a MAA for vutrisiran with the EMA, Alnylam's aspiration to become a leading biotech company, and the planned achievement of its "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO (or vutrisiran, if approved) in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements. This release is not intended to convey conclusions about efficacy or safety as to any investigational uses or dosing regimens of any investigational RNAi therapeutics. There is no guarantee that any investigational therapeutics or dosing regimens for such therapeutics will successfully complete clinical development or gain health authority approval.

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  3. Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that management will present company overviews at the following conferences being held virtually:

    • Morgan Stanley 19th Annual Global Healthcare Conference on Thursday, September 9, 2021 at 3:30 pm ET
    • H.C. Wainwright 23rd Annual Global Investment Conference on Monday, September 13, 2021 at 7:00 am ET
    • BofA Global Healthcare Conference on Thursday, September 16, 2021 at 10:05 am ET
    • Cantor Virtual Global Healthcare Conference on Tuesday, September 28, 2021 at 10:40 am ET

    A live audio webcast of each presentation will be available on the Investors section of the Company's website at www.alnylam.com/events. A replay will be available on the…

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that management will present company overviews at the following conferences being held virtually:

    • Morgan Stanley 19th Annual Global Healthcare Conference on Thursday, September 9, 2021 at 3:30 pm ET
    • H.C. Wainwright 23rd Annual Global Investment Conference on Monday, September 13, 2021 at 7:00 am ET
    • BofA Global Healthcare Conference on Thursday, September 16, 2021 at 10:05 am ET
    • Cantor Virtual Global Healthcare Conference on Tuesday, September 28, 2021 at 10:40 am ET

    A live audio webcast of each presentation will be available on the Investors section of the Company's website at www.alnylam.com/events. A replay will be available on the Alnylam website within 48 hours after each event.

    About Alnylam

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the potential treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

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  4. − Full Study Enrollment Completed Well Ahead of Schedule

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that it has achieved full patient enrollment in its HELIOS-B Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of cardiomyopathy in patients with transthyretin-mediated (ATTR) amyloidosis. Enrollment was completed, significantly ahead of schedule, with more than 600 ATTR amyloidosis patients across 123 activated sites in 32 countries.

    The HELIOS-B study was designed to evaluate the safety and efficacy of investigational vutrisiran, an RNAi therapeutic subcutaneously administered once every three months for the potential treatment of cardiomyopathy…

    − Full Study Enrollment Completed Well Ahead of Schedule

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that it has achieved full patient enrollment in its HELIOS-B Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of cardiomyopathy in patients with transthyretin-mediated (ATTR) amyloidosis. Enrollment was completed, significantly ahead of schedule, with more than 600 ATTR amyloidosis patients across 123 activated sites in 32 countries.

    The HELIOS-B study was designed to evaluate the safety and efficacy of investigational vutrisiran, an RNAi therapeutic subcutaneously administered once every three months for the potential treatment of cardiomyopathy in ATTR amyloidosis patients. The primary endpoint will evaluate the efficacy of vutrisiran versus placebo on the composite endpoint of all-cause mortality and recurrent cardiovascular (CV) events (CV hospitalizations and urgent heart failure visits) at 30 months in ATTR amyloidosis patients with cardiomyopathy.

    "Today's milestone represents another exciting step forward as we advance the investigation of RNAi therapeutics like vutrisiran in ATTR amyloidosis patients with cardiomyopathy. We reached full study enrollment for HELIOS-B, our largest clinical trial to date, approximately 20 months from study initiation, reflecting the high interest from patients and physicians in a potential treatment option with subcutaneous administration, quarterly dosing, and potent and reversible serum TTR reduction," said Rena Denoncourt, Vice President, TTR Franchise Lead. "If positive, the HELIOS-B study would support our efforts to advance the development of an industry leading franchise of RNAi therapeutics for the treatment of ATTR amyloidosis."

    Topline full results from HELIOS-B are expected in early 2024. The HELIOS-B protocol includes an optional interim analysis which, if pursued, would be conducted following the data readout from Alnylam's APOLLO-B Phase 3 clinical study of patisiran in patients with ATTR amyloidosis with cardiomyopathy. The APOLLO-B study completed enrollment in June 2021 and is expected to have topline data available in mid-2022. Based on those data and subsequent regulatory interactions, the potential path forward for a HELIOS-B interim analysis will be further refined, including potential for an earlier readout of topline results.

    About the HELIOS-B Phase 3 Study

    HELIOS-B is a global, Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy, which enrolled more than 600 adult patients with ATTR amyloidosis (including both hATTR and wtATTR amyloidosis) with cardiomyopathy. Patients were randomized on a 1:1 basis to receive either 25 mg of vutrisiran or placebo administered as a subcutaneous injection once every three months for up to 36 months. The primary endpoint will evaluate the efficacy of vutrisiran versus placebo on the composite endpoint of all-cause mortality and recurrent cardiovascular (CV) events (CV hospitalizations and urgent heart failure (HF) visits) at 30 months. For more information on HELIOS-B (NCT04153149) please visit www.clinicaltrials.gov.

    About Vutrisiran

    Vutrisiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hereditary ATTR (hATTR) and wild-type ATTR (wtATTR) amyloidosis. It is designed to target and silence specific messenger RNA, with the goal of blocking the production of wild-type and variant transthyretin (TTR) protein before it is made. Quarterly, and potentially biannual, administration of vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues. Vutrisiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability that may allow for infrequent subcutaneous injections. The U.S. Food and Drug Administration is currently evaluating the New Drug Application (NDA) for vutrisiran for the treatment of the polyneuropathy of hATTR amyloidosis. The safety and efficacy of vutrisiran for this indication or for the treatment of cardiomyopathy of ATTR amyloidosis have not been evaluated by the U.S. Food and Drug Administration, European Medicines Agency, or any other health authority.

    About ATTR Amyloidosis

    Transthyretin-mediated (ATTR) amyloidosis is a rare, rapidly progressive, debilitating disease caused by misfolded transthyretin (TTR) proteins which accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal (GI) tract. There are two different types of ATTR amyloidosis – Hereditary ATTR (hATTR) amyloidosis, caused by a TTR gene variant, and wild-type ATTR (wtATTR) amyloidosis, which occurs without a TTR gene variant. hATTR amyloidosis affects approximately 50,000 people worldwide, while wtATTR amyloidosis is estimated to impact 200,000 – 300,000 people worldwide.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the potential treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's expectations, plans, aspirations, and goals, including those related to the investigational therapeutic vutrisiran and its potential as a low-dose, once quarterly, subcutaneously administered treatment option with reversible serum TTR reduction for patients with hATTR amyloidosis with cardiomyopathy, the expected timing for topline results from the HELIOS-B Phase 3 study of vutrisiran and the APOLLO-B Phase 3 study of patisiran, the potential for an optional interim analysis in HELIOS-B following the data readout from the APOLLO-B study, progress toward building an industry leading franchise of RNAi therapeutics for the treatment of ATTR amyloidosis, our aspiration to become a leading biotech company, and the planned achievement of our "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO (or vutrisiran, if approved) in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

    This release is not intended to convey conclusions about efficacy or safety as to any investigational uses or dosing regimens of any investigational RNAi therapeutics. There is no guarantee that any investigational therapeutics or dosing regimens for such therapeutics will successfully complete clinical development or gain health authority approval.

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  5. − Achieved Second Quarter 2021 Combined Net Product Revenues of $161 Million for ONPATTRO®, GIVLAARI®, and OXLUMO®

    − Advanced Vutrisiran with New Drug Application (NDA) Submission to the U.S. Food and Drug Administration (FDA) for the Treatment of the Polyneuropathy of Hereditary ATTR Amyloidosis (hATTR-PN); Received FDA Acceptance of NDA with Prescription Drug User Fee Act (PDUFA) Date Set for April 14, 2022 –

    – Completed Enrollment in APOLLO-B Phase 3 Study of Patisiran in Transthyretin-Mediated (ATTR) Amyloidosis Patients with Cardiomyopathy (ATTR-CM) –

    – Initiated KARDIA Phase 2 Program with Zilebesiran (ALN-AGT) in Patients with Mild-to-Moderate Hypertension –

    – Increased 2021 Guidance Range for Combined Net Product Revenues from

    − Achieved Second Quarter 2021 Combined Net Product Revenues of $161 Million for ONPATTRO®, GIVLAARI®, and OXLUMO®

    − Advanced Vutrisiran with New Drug Application (NDA) Submission to the U.S. Food and Drug Administration (FDA) for the Treatment of the Polyneuropathy of Hereditary ATTR Amyloidosis (hATTR-PN); Received FDA Acceptance of NDA with Prescription Drug User Fee Act (PDUFA) Date Set for April 14, 2022 –

    – Completed Enrollment in APOLLO-B Phase 3 Study of Patisiran in Transthyretin-Mediated (ATTR) Amyloidosis Patients with Cardiomyopathy (ATTR-CM) –

    – Initiated KARDIA Phase 2 Program with Zilebesiran (ALN-AGT) in Patients with Mild-to-Moderate Hypertension –

    – Increased 2021 Guidance Range for Combined Net Product Revenues from $610-$660 Million to $640-$665 Million –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today reported its consolidated financial results for the second quarter ended June 30, 2021 and reviewed recent business highlights.

    "Our commercial performance in the second quarter continued to demonstrate steady and continued growth across our three wholly owned marketed products. The second quarter also marked significant progress for our TTR franchise overall, including NDA submission and acceptance for vutrisiran based on positive HELIOS-A results, initiation of a biannual dosing study for vutrisiran, completion of enrollment in the APOLLO-B Phase 3 trial and imminent enrollment completion for HELIOS-B, and introduction of ALN-TTRsc04 for a potential annual dosing regimen. Together, these efforts highlight our commitment to ATTR amyloidosis for years to come," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "With sights set on our ‘Alnylam P5x25' five-year vision announced earlier this year, we believe we are well positioned and on our way to achieving these ambitious goals. With this strategy we intend to deliver transformative medicines for rare and prevalent diseases to patients around the world, advancing a robust and high-yielding clinical pipeline of first and/or best-in-class product candidates stemming from our organic product engine, while delivering exceptional financial performance."

    Second Quarter 2021 and Recent Significant Corporate Highlights

    Commercial Performance

    ONPATTRO®

    • Achieved global net product revenues for the second quarter of 2021 of $114 million, representing 12% growth compared to Q1 2021.
    • Attained over 1,725 patients worldwide on commercial ONPATTRO treatment as of June 30, 2021.

    GIVLAARI®

    • Achieved global net product revenues for the second quarter of 2021 of $31 million, representing 24% growth compared to Q1 2021.
    • Attained over 270 patients worldwide on commercial GIVLAARI treatment as of June 30, 2021.
    • Received marketing authorization approval for GIVLAARI in Japan for the treatment of acute hepatic porphyria in adults and adolescents.

    OXLUMO®

    • Achieved global net product revenues for the second quarter of 2021 of $16 million, representing 79% growth compared to Q1 2021.
    • Attained approximately 100 patients worldwide on commercial OXLUMO treatment as of June 30, 2021.
    • Received marketing authorization approval for OXLUMO in Brazil for the treatment of primary hyperoxaluria type 1 (PH1).

    Leqvio®

    • Alnylam earned royalty revenues of $0.3 million from Novartis based on Leqvio global net product revenues through the second quarter of 2021.
    • Novartis announced that the resubmission to the FDA for the inclisiran NDA to address the Complete Response Letter (CRL) was filed with an action date of January 1, 2022.

    R&D Highlights

    Patisiran (the non-proprietary name for ONPATTRO), in development for the treatment of the cardiomyopathy of both hereditary and wild-type ATTR amyloidosis

    • Completed enrollment in the APOLLO-B Phase 3 study in ATTR-CM, with topline results expected in mid-2022.
    • Presented positive results from the Phase 3b open-label study in hATTR-PN patients with disease progression after receiving an orthotopic liver transplant.
    • Completed enrollment in the Phase 4 study in hATTR-PN patients with V122I or T60A variant.

    Vutrisiran, a subcutaneously administered investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis

    • Submitted NDA to the FDA for hATTR-PN, and received FDA acceptance of the NDA with a PDUFA date set for April 14, 2022.
    • Presented positive 9-month results from the HELIOS-A Phase 3 study.
    • Based on discussions with the European Medicines Agency (EMA), the Company now plans to file, ahead of schedule, a Marketing Authorisation Application (MAA) for vutrisiran for the treatment of hATTR amyloidosis in adult patients with polyneuropathy based on 9-month results from the HELIOS-A Phase 3 study.
    • Initiated a clinical study of a biannual dosing regimen in hATTR-PN patients, with data expected in 2022 potentially supporting regulatory submissions.
    • Continued enrollment in the HELIOS-B Phase 3 study in ATTR-CM. The Company announces today that, due to high interest from patients and physicians, it now expects to complete enrollment within the next two weeks, significantly ahead of schedule.

    Lumasiran (the non-proprietary name for OXLUMO), for the treatment of primary hyperoxaluria type 1 (PH1)

    • Achieved positive topline results from the ILLUMINATE-C Phase 3 study in PH1 patients with advanced renal disease.
    • Presented positive early results on clinical outcome measures after 12 months of treatment in the ILLUMINATE-A Phase 3 study.

    Inclisiran (the non-proprietary name for Leqvio) for the treatment of hypercholesterolemia or mixed dyslipidemia, in collaboration with Novartis

    • Resubmission to the FDA for the inclisiran NDA to address the CRL was filed with an action date of January 1, 2022.

    Fitusiran, in development for the treatment of hemophilia A or B with and without inhibitors, in collaboration with Sanofi

    • Sanofi announced substantial progress with fitusiran, and now expects to present data from the Phase 3 ATLAS program as early as the beginning of next year, with a potential regulatory submission later in 2022.

    Early- and mid-stage RNAi therapeutic pipeline programs

    • Presented positive interim results from the Phase 1 study of zilebesiran (ALN-AGT), in development for the treatment of hypertension and initiated KARDIA-1 monotherapy Phase 2 study in patients with mild-to-moderate hypertension.
    • Alnylam's partner Vir Biotechnology presented new clinical data from ongoing Phase 2 clinical trials of ALN-HBV02 (VIR-2218), alone and in combination with pegylated interferon-alpha (PEG-IFN-α), in patients with chronic hepatitis B virus infection.
    • Continued progress with investigational RNAi therapeutics for CNS and ocular diseases, including advancement of ALN-APP, in development for the treatment of autosomal dominant Alzheimer's Disease (ADAD) and cerebral amyloid angiopathy (CAA), with a CTA filing now planned for late 2021, in collaboration with Regeneron.
    • Company announces today plans to advance ALN-XDH, in development for the treatment of gout, with a CTA filing planned for late 2021.
    • Company announces today a portfolio prioritization decision to discontinue ALN-COV, in development for the treatment of COVID-19, based on availability of highly effective vaccines and alternative treatment options.
    • Introduced IKARIA extended duration platform, aimed at highly potent (>90%) target mRNA silencing with a potential annual dosing regimen, and a new ATTR amyloidosis program ALN-TTRsc04, with expected IND filing at or around year-end 2022.

    Additional Business Updates

    • Entered into a strategic collaboration with PeptiDream Inc. to discover and develop peptide-siRNA conjugates for targeted delivery of investigational RNAi therapeutics to tissues outside the liver.
    • The Company announces today that its Board of Directors has appointed Michael Bonney as Executive Chair of Alnylam. In what is expected to be a temporary expansion of his role, Mr. Bonney will be focused on further enhancing the Company's ethics and compliance function and its integration with the business, in addition to his more historic role as Chair and its associated responsibilities.

    Upcoming Events

    In mid- and late 2021, Alnylam intends to:

    • Complete enrollment in the HELIOS-B Phase 3 study of vutrisiran
    • Present topline results for 18-month endpoints and safety from the HELIOS-A Phase 3 study of vutrisiran
    • Present additional data from the Phase 1 study of zilebesiran
    • Initiate KARDIA-2 Phase 2 combination therapy study of zilebesiran
    • Report initial clinical results in healthy volunteers from the Phase 1 study of ALN-HSD
    • Alnylam's partner Regeneron plans to initiate a Phase 3 study of cemdisiran and pozelimab combination in myasthenia gravis, in addition to multiple Phase 2 studies in paroxysmal nocturnal hemoglobinuria (PNH)
    • Initiate Phase 2 study of lumasiran in patients with recurrent renal stones
    • File a CTA for ALN-APP, in development for the treatment of ADAD and CAA
    • File a CTA for ALN-XDH, in development for the treatment of gout

    Financial Results for the Quarter Ended June 30, 2021

    "Based on the strong commercial performance of our products in the first half of the year, with growth in combined net product revenues nearly double the same period in 2020, we are increasing our revenue guidance for 2021, and now expect to achieve between $640 million and $665 million in combined net product revenues across our three wholly owned commercial brands for the full year 2021. We're also pleased to now recognize royalty revenue from Novartis' sales of Leqvio, and believe that commercial success of this important medicine could be a meaningful contributor to our growth in the future," said Jeff Poulton, Chief Financial Officer of Alnylam. "We remain focused on delivering strong topline growth while continuing to demonstrate disciplined investment in our operations, and believe this will transition us toward a self-sustainable financial profile, aligned with our Alnylam P5x25 strategy."

    Financial highlights

    (in thousands, except per share amounts)

     

     

    Three Months Ended

    June 30,

     

    Six Months Ended

    June 30,

     

    2021

     

    2020

     

    2021

     

    2020

     

     

     

     

     

     

     

     

    ONPATTRO net product revenues

    $

    113,839

     

     

     

    $

    66,535

     

     

     

    $

    215,790

     

     

     

    $

    133,199

     

     

    GIVLAARI net product revenues

    30,630

     

     

     

    10,998

     

     

     

    55,303

     

     

     

    16,272

     

     

    OXLUMO net product revenues

    16,342

     

     

     

     

     

     

    25,487

     

     

     

     

     

    Total net product revenues

    $

    160,811

     

     

     

    $

    77,533

     

     

     

    $

    296,580

     

     

     

    $

    149,471

     

     

     

     

     

     

     

     

     

     

    Net revenue from collaborations

    $

    59,395

     

     

     

    $

    26,429

     

     

     

    $

    101,192

     

     

     

    $

    53,967

     

     

     

     

     

     

     

     

     

     

    Royalty revenue

    $

    347

     

     

     

    $

     

     

     

    $

    347

     

     

     

    $

     

     

     

     

     

     

     

     

     

     

    GAAP operating loss

    $

    (146,160

    )

     

     

    $

    (198,859

    )

     

     

    $

    (332,414

    )

     

     

    $

    (409,017

    )

     

    Non-GAAP operating loss

    $

    (114,082

    )

     

     

    $

    (164,784

    )

     

     

    $

    (244,646

    )

     

     

    $

    (340,364

    )

     

     

     

     

     

     

     

     

     

    GAAP net loss

    $

    (189,559

    )

     

     

    $

    (179,229

    )

     

     

    $

    (389,850

    )

     

     

    $

    (361,450

    )

     

    Non-GAAP net loss

    $

    (153,047

    )

     

     

    $

    (191,328

    )

     

     

    $

    (344,664

    )

     

     

    $

    (363,082

    )

     

     

     

     

     

     

     

     

     

    GAAP net loss per common share - basic and diluted

    $

    (1.61

    )

     

     

    $

    (1.56

    )

     

     

    $

    (3.32

    )

     

     

    $

    (3.18

    )

     

    Non-GAAP net loss per common share - basic and diluted

    $

    (1.30

    )

     

     

    $

    (1.67

    )

     

     

    $

    (2.93

    )

     

     

    $

    (3.19

    )

     

    Net Product Revenues

    • Net product revenues increased 107% and 98% during the three and six months ended June 30, 2021, as compared to the same periods in 2020, respectively, primarily due to increased ONPATTRO and GIVLAARI demand in the U.S. and Europe, and the ongoing launch of OXLUMO since the first quarter of 2021.

    Net Revenues from Collaborations

    • Net revenues from collaborations increased 125% and 88% during the three and six months ended June 30, 2021, as compared to the same periods in 2020, respectively, primarily due to an increase in revenue from our collaborations with Regeneron and Novartis.

    Royalty Revenue

    • We recognized initial royalty revenue from net global sales of Leqvio from our partner, Novartis.

    Second Quarter and Year-to-Date 2021 Expenses

     

     

    Three Months Ended

    June 30,

     

    Six Months Ended

    June 30,

     

    2021

     

    2020

     

    2021

     

    2020

     

     

     

     

     

     

     

     

    GAAP research and development expenses

    $

    182,635

     

     

    $

    154,996

     

     

    $

    368,534

     

     

    $

    324,567

     

    Non-GAAP research and development expenses

    $

    169,549

     

     

    $

    139,206

     

     

    $

    331,073

     

     

    $

    292,728

     

     

     

     

     

     

     

     

     

    GAAP selling, general and administrative expenses

    $

    145,323

     

     

    $

    127,896

     

     

    $

    292,182

     

     

    $

    254,657

     

    Non-GAAP selling, general and administrative expenses

    $

    126,331

     

     

    $

    109,611

     

     

    $

    241,875

     

     

    $

    217,843

     

    Research & Development (R&D) Expenses

    • GAAP and Non-GAAP R&D expenses increased during the three and six months ended June 30, 2021, as compared to the same periods in 2020, primarily due to continued investment in our early- and late-stage clinical programs.

    Selling, General & Administrative (SG&A) Expenses

    • GAAP and Non-GAAP SG&A expenses increased during the three and six months ended June 30, 2021, as compared to the same periods in 2020, primarily due to increased investment to support the global growth of our three commercialized products. GAAP SG&A also increased during the six months ended June 30, 2021, as compared to the same period in 2020, due to increased stock-based compensation expense primarily due to the accounting for certain performance-based stock awards.

    Other Financial Highlights

    Other (Expense) Income

    • For the three months ended June 30, 2021, interest expense was $33.4 million, which included $28.9 million associated with the sale of future royalties and $4.5 million associated with the drawdown of our credit facility beginning in December 2020. For the six months ended June 30, 2021, interest expense was $65.9 million, which included $57.1 million associated with the sale of future royalties and $8.9 million associated with the drawdown of our credit facility beginning in December 2020.
    • For the six months ended June 30, 2021, the change in the fair value of the development derivative liability was a loss of $22.8 million.

    Cash and Investments

    • Cash, cash equivalents, and marketable securities were $1.90 billion as of June 30, 2021 compared to $1.87 billion as of December 31, 2020 with the increase primarily due to the second drawdown on our credit facility and cash received from the exercise of employee equity awards and purchases of shares under our employee stock purchase plans, offset by cash used in our operations to support overall growth.

    A reconciliation of our GAAP to non-GAAP results for the current quarter is included in the tables of this press release.

    2021 Updated Financial Guidance

    Full year 2021 financial guidance consists of the following:

     

     

     

    Provided 2/11/2021

     

    Updated 8/3/2021

     

     

    ($ millions)

     

    ($ millions)

    Combined net product revenues for ONPATTRO, GIVLAARI and OXLUMO

     

    $610 - $660

     

    $640 - $665

    Net revenues from collaborations and royalties

     

    $150 - $200

     

    Unchanged

    GAAP R&D and SG&A expenses

     

    $1,335 - $1,455

     

    Unchanged

    Non-GAAP R&D and SG&A expenses*

     

    $1,175 - $1,275

     

    Unchanged

     

     

     

     

     

    *Excludes $160-$180 million of stock-based from estimated GAAP R&D and SG&A expenses.

    Use of Non-GAAP Financial Measures

    This press release contains non-GAAP financial measures, including expenses adjusted to exclude certain non-cash expenses and non-recurring gains outside the ordinary course of the Company's business. These measures are not in accordance with, or an alternative to, GAAP, and may be different from non-GAAP financial measures used by other companies.

    The items included in GAAP presentations but excluded for purposes of determining non-GAAP financial measures for the periods presented in this press release are stock-based compensation expenses, unrealized losses (gains) on marketable equity securities, costs associated with our strategic financing collaboration, and gain on contractual settlement. The Company has excluded the impact of stock-based compensation expense, which may fluctuate from period to period based on factors including the variability associated with performance-based grants for stock options and restricted stock units and changes in the Company's stock price, which impacts the fair value of these awards. The Company has excluded the impact of the unrealized losses (gains) on marketable equity securities because the Company does not believe these adjustments accurately reflect the performance of the Company's ongoing operations for the period in which such gains or losses are reported, as their sole purpose is to adjust amounts on the balance sheet. The Company has excluded the impact of the costs associated with our strategic financing collaboration and gain on settlement because the Company believes these items are non-recurring transactions outside the ordinary course of the Company's business.

    The Company believes the presentation of non-GAAP financial measures provides useful information to management and investors regarding the Company's financial condition and results of operations. When GAAP financial measures are viewed in conjunction with non-GAAP financial measures, investors are provided with a more meaningful understanding of the Company's ongoing operating performance and are better able to compare the Company's performance between periods. In addition, these non-GAAP financial measures are among those indicators the Company uses as a basis for evaluating performance, allocating resources and planning and forecasting future periods. Non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation of selected GAAP and non-GAAP measures is provided later in this press release.

    Conference Call Information

    Management will provide an update on the Company and discuss second quarter 2021 results as well as expectations for the future via conference call on Tuesday, August 3, 2021 at 8:30 am ET. To access the call, please dial 877-312-7507 (domestic) or +1-631-813-4828 (international) five minutes prior to the start time and refer to conference ID 8870516. A replay of the call will be available beginning at 11:30 am ET on the day of the call. To access the replay, please dial 855-859-2056 (domestic) or +1-404-537-3406 (international) and refer to conference ID 8870516.

    A live audio webcast of the call will be available on the Investors section of the Company's website at www.alnylam.com/events. An archived webcast will be available on the Alnylam website approximately two hours after the event.

    About ONPATTRO® (patisiran)

    ONPATTRO is an RNAi therapeutic that was approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby blocking the production of TTR protein before it is made. ONPATTRO blocks the production of TTR in the liver, reducing its accumulation in the body's tissues in order to halt or slow down the progression of the polyneuropathy associated with the disease. For more information about ONPATTRO, visit ONPATTRO.com.

    ONPATTRO Important Safety Information

    Infusion-Related Reactions

    Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO® (patisiran). In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache.

    To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.

    Reduced Serum Vitamin A Levels and Recommended Supplementation

    ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body.

    Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness).

    Adverse Reactions

    The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory tract infections (29%) and infusion-related reactions (19%).

    For additional information about ONPATTRO, please see the full Prescribing Information.

    About GIVLAARI® (givosiran)

    GIVLAARI is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) approved in the United States and Brazil for the treatment of adults with acute hepatic porphyria (AHP). GIVLAARI is also approved in the European Union for the treatment of AHP in adults and adolescents aged 12 years and older. In the pivotal study, givosiran was shown to significantly reduce the rate of porphyria attacks that required hospitalizations, urgent healthcare visits or intravenous hemin administration at home compared to placebo. GIVLAARI is Alnylam's first commercially available therapeutic based on its Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology to increase potency and durability. GIVLAARI is administered via subcutaneous injection once monthly at a dose based on actual body weight and should be administered by a healthcare professional. GIVLAARI works by specifically reducing elevated levels of aminolevulinic acid synthase 1 (ALAS1) messenger RNA (mRNA), leading to reduction of toxins associated with attacks and other disease manifestations of AHP. For more information about GIVLAARI, visit GIVLAARI.com.

    GIVLAARI Important Safety Information

    Contraindications

    GIVLAARI is contraindicated in patients with known severe hypersensitivity to givosiran. Reactions have included anaphylaxis.

    Anaphylactic Reaction

    Anaphylaxis has occurred with GIVLAARI treatment (<1% of patients in clinical trials). Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms of anaphylaxis. If anaphylaxis occurs, immediately discontinue administration of GIVLAARI and institute appropriate medical treatment.

    Hepatic Toxicity

    Transaminase elevations (ALT) of at least 3 times the upper limit of normal (ULN) were observed in 15% of patients receiving GIVLAARI in the placebo-controlled trial. Transaminase elevations primarily occurred between 3 to 5 months following initiation of treatment.

    Measure liver function tests prior to initiating treatment with GIVLAARI, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter. Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations. In patients who have dose interruption and subsequent improvement, reduce the dose to 1.25 mg/kg once monthly. The dose may be increased to the recommended dose of 2.5 mg/kg once monthly if there is no recurrence of severe or clinically significant transaminase elevations at the 1.25 mg/kg dose.

    Renal Toxicity

    Increases in serum creatinine levels and decreases in estimated glomerular filtration rate (eGFR) have been reported during treatment with GIVLAARI. In the placebo-controlled study, 15% of patients receiving GIVLAARI experienced a renally-related adverse reaction. The median increase in creatinine at Month 3 was 0.07 mg/dL. Monitor renal function during treatment with GIVLAARI as clinically indicated.

    Injection Site Reactions

    Injection site reactions were reported in 25% of patients receiving GIVLAARI in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. One (2%) patient experienced a single, transient, recall reaction of erythema at a prior injection site with a subsequent dose administration.

    Drug Interactions

    Concomitant use of GIVLAARI increases the concentration of CYP1A2 or CYP2D6 substrates, which may increase adverse reactions of these substrates. Avoid concomitant use of GIVLAARI with CYP1A2 or CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP1A2 or CYP2D6 substrate dosage in accordance with approved product labeling.

    Adverse Reactions

    The most common adverse reactions that occurred in patients receiving GIVLAARI were nausea (27%) and injection site reactions (25%).

    For additional information about GIVLAARI, please see full Prescribing Information.

    About OXLUMO® (lumasiran)

    OXLUMO is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients. HAO1 encodes glycolate oxidase (GO), an enzyme upstream of the disease-causing defect in PH1. OXLUMO works by degrading HAO1 messenger RNA and reducing the synthesis of GO, which inhibits hepatic production of oxalate – the toxic metabolite responsible for the clinical manifestations of PH1. In the pivotal ILLUMINATE-A study, OXLUMO was shown to significantly reduce levels of urinary oxalate relative to placebo, with the majority of patients reaching normal or near-normal levels. Injection site reactions (ISRs) were the most common drug-related adverse reaction. In the ILLUMINATE-B pediatric Phase 3 study, OXLUMO demonstrated an efficacy and safety profile consistent to that observed in ILLUMINATE-A. OXLUMO utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc conjugate technology designed to increase potency and durability. OXLUMO is administered via subcutaneous injection once monthly for three months, then once quarterly thereafter at a dose based on actual body weight. For patients who weigh less than 10 kg, ongoing dosing remains monthly. OXLUMO should be administered by a healthcare professional. For more information about OXLUMO, visit OXLUMO.com.

    OXLUMO Important Safety Information

    Adverse Reactions

    The most common adverse reaction that occurred in patients treated with OXLUMO was injection site reaction (38%). Symptoms included erythema, pain, pruritus, and swelling.

    Pregnancy and Lactation

    No data are available on the use of OXLUMO in pregnant women. No data are available on the presence of OXLUMO in human milk or its effects on breastfed infants or milk production. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for OXLUMO and any potential adverse effects on the breastfed child from OXLUMO or the underlying maternal condition.

    For additional information about OXLUMO, please see the full Prescribing Information.

    About LNP Technology

    Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), and OXLUMO® (lumasiran), as well as Leqvio® (inclisiran), which is being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's expectations, plans and prospects, including, without limitation, its plans for additional global regulatory filings and the continuing product launches of its approved products, its commitment to ATTR amyloidosis for years to come, FDA review of the vutrisiran NDA, including the expected PDUFA date, and the inclisiran NDA, the achievement of additional pipeline milestones and data, including relating to ongoing clinical studies of patisiran, vutrisiran, lumasiran, zilebesiran and ALN-HSD, the expected timing for filing an MAA for vutrisiran, and a CTA for each of ALN-APP and ALN-XDH, the potential impact of the commercial success of Leqvio on its future growth, continued revenue growth for its approved products and updates to the expected range of net product revenues for 2021, net revenues from collaborations and royalties for 2021, the expected range of aggregate annual GAAP and non-GAAP R&D and SG&A expenses, and its aspiration to become a leading biotech company, and the planned achievement of its "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO and vutrisiran in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the potential impact of a current government investigation and the risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

    This release discusses investigational RNAi therapeutics and uses of previously approved RNAi therapeutics in development and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics or uses. There is no guarantee that any investigational therapeutics or expanded uses of commercial products will successfully complete clinical development or gain health authority approval.

    ALNYLAM PHARMACEUTICALS, INC.

    CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS

    (In thousands, except per share amounts)

    (Unaudited)

     

     

    Three Months Ended

     

    Six Months Ended

     

    June 30,

    2021

     

    June 30,

    2020

     

    June 30,

    2021

     

    June 30,

    2020

    Statements of Operations

     

     

     

     

     

     

     

    Revenues:

     

     

     

     

     

     

     

    Net product revenues

    $

    160,811

     

     

     

    $

    77,533

     

     

     

    $

    296,580

     

     

     

    $

    149,471

     

     

    Net revenues from collaborations

    59,395

     

     

     

    26,429

     

     

     

    101,192

     

     

     

    53,967

     

     

    Royalty revenue

    347

     

     

     

     

     

     

    347

     

     

     

     

     

    Total revenues

    220,553

     

     

     

    103,962

     

     

     

    398,119

     

     

     

    203,438

     

     

     

     

     

     

     

     

     

     

    Operating costs and expenses:

     

     

     

     

     

     

     

    Cost of goods sold

    30,256

     

     

     

    18,265

     

     

     

    53,279

     

     

     

    31,567

     

     

    Cost of collaborations and royalties

    8,499

     

     

     

    1,664

     

     

     

    16,538

     

     

     

    1,664

     

     

    Research and development

    182,635

     

     

     

    154,996

     

     

     

    368,534

     

     

     

    324,567

     

     

    Selling, general and administrative

    145,323

     

     

     

    127,896

     

     

     

    292,182

     

     

     

    254,657

     

     

    Total operating costs and expenses

    366,713

     

     

     

    302,821

     

     

     

    730,533

     

     

     

    612,455

     

     

    Loss from operations

    (146,160

    )

     

     

    (198,859

    )

     

     

    (332,414

    )

     

     

    (409,017

    )

     

    Other (expense) income:

     

     

     

     

     

     

     

    Interest expense

    (33,416

    )

     

     

    (27,248

    )

     

     

    (65,931

    )

     

     

    (27,248

    )

     

    Interest income

    409

     

     

     

    3,165

     

     

     

    859

     

     

     

    8,645

     

     

    Other (expense) income, net

    (9,164

    )

     

     

    45,039

     

     

     

    9,880

     

     

     

    68,071

     

     

    Total other (expense) income, net

    (42,171

    )

     

     

    20,956

     

     

     

    (55,192

    )

     

     

    49,468

     

     

    Loss before income taxes

    (188,331

    )

     

     

    (177,903

    )

     

     

    (387,606

    )

     

     

    (359,549

    )

     

    Provision for income taxes

    (1,228

    )

     

     

    (1,326

    )

     

     

    (2,244

    )

     

     

    (1,901

    )

     

    Net loss

    $

    (189,559

    )

     

     

    $

    (179,229

    )

     

     

    $

    (389,850

    )

     

     

    $

    (361,450

    )

     

    Net loss per common share - basic and diluted

    $

    (1.61

    )

     

     

    $

    (1.56

    )

     

     

    $

    (3.32

    )

     

     

    $

    (3.18

    )

     

    Weighted-average common shares used to compute basic and diluted net loss per common share

    117,772

     

     

     

    114,911

     

     

     

    117,428

     

     

     

    113,830

     

     

    ALNYLAM PHARMACEUTICALS, INC.

    RECONCILIATION OF SELECTED GAAP MEASURES TO NON-GAAP MEASURES

    (In thousands, except per share amounts)

     

     

    Three Months Ended

     

    Six Months Ended

     

    June 30,

    2021

     

    June 30,

    2020

     

    June 30,

    2021

     

    June 30,

    2020

    Reconciliation of GAAP to Non-GAAP research and development:

     

     

     

     

     

     

     

    GAAP Research and development

    $

    182,635

     

     

     

    $

    154,996

     

     

     

    368,534

     

     

     

    324,567

     

     

    Less: Stock-based compensation expenses

    (13,086

    )

     

     

    (15,790

    )

     

     

    (37,461

    )

     

     

    (31,839

    )

     

    Non-GAAP Research and development

    $

    169,549

     

     

     

    $

    139,206

     

     

     

    331,073

     

     

     

    292,728

     

     

     

     

     

     

     

     

     

     

    Reconciliation of GAAP to Non-GAAP selling, general and administrative:

     

     

     

     

     

     

     

    GAAP Selling, general and administrative

    $

    145,323

     

     

     

    $

    127,896

     

     

     

    292,182

     

     

     

    254,657

     

     

    Less: Stock-based compensation expenses

    (18,992

    )

     

     

    (17,965

    )

     

     

    (50,307

    )

     

     

    (36,494

    )

     

    Less: Costs associated with the strategic financing collaboration

     

     

     

    (320

    )

     

     

     

     

     

    (320

    )

     

    Non-GAAP Selling, general and administrative

    $

    126,331

     

     

     

    $

    109,611

     

     

     

    241,875

     

     

     

    217,843

     

     

     

     

     

     

     

     

     

     

    Reconciliation of GAAP to Non-GAAP operating loss:

     

     

     

     

     

     

     

    GAAP operating loss

    $

    (146,160

    )

     

     

    $

    (198,859

    )

     

     

    (332,414

    )

     

     

    (409,017

    )

     

    Add: Stock-based compensation expenses

    32,078

     

     

     

    33,755

     

     

     

    87,768

     

     

     

    68,333

     

     

    Add: Costs associated with the strategic financing collaboration

     

     

     

    320

     

     

     

     

     

     

    320

     

     

    Non-GAAP operating loss

    $

    (114,082

    )

     

     

    $

    (164,784

    )

     

     

    (244,646

    )

     

     

    (340,364

    )

     

     

     

     

     

     

     

     

     

    Reconciliation of GAAP to Non-GAAP net loss:

     

     

     

     

     

     

     

    GAAP net loss

    $

    (189,559

    )

     

     

    $

    (179,229

    )

     

     

    (389,850

    )

     

     

    (361,450

    )

     

    Add: Stock-based compensation expenses

    32,078

     

     

     

    33,755

     

     

     

    87,768

     

     

     

    68,333

     

     

    Add: Costs associated with the strategic financing collaboration

     

     

     

    320

     

     

     

     

     

     

    320

     

     

    Less: Unrealized loss (gain) on marketable equity securities

    4,434

     

     

     

    (45,532

    )

     

     

    (42,582

    )

     

     

    (69,643

    )

     

    Less: Gain on contractual settlement

     

     

     

    (642

    )

     

     

     

     

     

    (642

    )

     

    Non-GAAP net loss

    $

    (153,047

    )

     

     

    $

    (191,328

    )

     

     

    (344,664

    )

     

     

    (363,082

    )

     

     

     

     

     

     

     

     

     

    Reconciliation of GAAP to Non-GAAP net loss per common share-basic and diluted:

     

     

     

     

     

     

     

    GAAP net loss per common share - basic and diluted

    $

    (1.61

    )

     

     

    $

    (1.56

    )

     

     

    (3.32

    )

     

     

    (3.18

    )

     

    Add: Stock-based compensation expenses

    0.27

     

     

     

    0.29

     

     

     

    0.75

     

     

     

    0.59

     

     

    Add: Costs associated with the strategic financing collaboration

     

     

     

     

     

     

     

     

     

     

     

    Less: Unrealized loss (gain) on marketable equity securities

    0.04

     

     

     

    (0.39

    )

     

     

    (0.36

    )

     

     

    (0.60

    )

     

    Less: Gain on contractual settlement

     

     

     

    (0.01

    )

     

     

     

     

     

    (0.01

    )

     

    Non-GAAP net loss per common share - basic and diluted

    $

    (1.30

    )

     

     

    $

    (1.67

    )

     

     

    (2.93

    )

     

     

    (3.19

    )

     

    Please note that the figures presented above may not sum exactly due to rounding

    ALNYLAM PHARMACEUTICALS, INC.

    CONDENSED CONSOLIDATED BALANCE SHEETS

    (In thousands, except share amounts)

    (Unaudited)

     

     

    June 30, 2021

    December 31, 2020

    Cash, cash equivalents, and marketable debt and equity securities

    $

    1,900,082

     

    $

    1,874,395

     

    Restricted investments

    40,890

     

    40,725

     

    Accounts receivable, net

    146,587

     

    102,413

     

    Inventory

    96,108

     

    92,302

     

    Prepaid expenses and other assets

    116,973

     

    90,712

     

    Property, plant and equipment, net

    470,700

     

    465,029

     

    Operating lease right-of-use lease assets

    238,089

     

    241,485

     

    Receivable related to the sale of future royalties

    500,000

     

    500,000

     

    Total assets

    $

    3,509,429

     

    $

    3,407,061

     

    Accounts payable, accrued expenses and other liabilities

    $

    465,899

     

    $

    445,783

     

    Total deferred revenue

    300,535

     

    352,301

     

    Operating lease liability

    327,921

     

    329,911

     

    Liability related to the sale of future royalties

    1,128,561

     

    1,071,541

     

    Long-term debt

    433,151

     

    191,278

     

    Total stockholders' equity (118.6 million shares issued and outstanding at June 30, 2021; 116.4 million shares issued and outstanding at December 31, 2020)

    853,362

     

    1,016,247

     

    Total liabilities and stockholders' equity

    $

    3,509,429

     

    $

    3,407,061

     

    This selected financial information should be read in conjunction with the consolidated financial statements and notes thereto included in Alnylam's Annual Report on Form 10-K which includes the audited financial statements for the year ended December 31, 2020.

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  6. − Agreement Combines PeptiDream's Peptide Discovery Platform to Identify High Affinity Peptide Ligands with Alnylam's Expertise in siRNA-Conjugate-Based Delivery and in Developing and Commercializing RNAi Therapeutics

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, and PeptiDream, Inc. (Tokyo Stock Exchange: 4587), the leading peptide-based drug discovery company with its proprietary Peptide Discovery Platform System (PDPS), announced today a license and collaboration agreement to discover and develop peptide-siRNA conjugates to create multiple opportunities to deliver RNAi therapeutics to tissues outside the liver. Through this collaboration, the companies will collaborate to select and optimize peptides…

    − Agreement Combines PeptiDream's Peptide Discovery Platform to Identify High Affinity Peptide Ligands with Alnylam's Expertise in siRNA-Conjugate-Based Delivery and in Developing and Commercializing RNAi Therapeutics

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, and PeptiDream, Inc. (Tokyo Stock Exchange: 4587), the leading peptide-based drug discovery company with its proprietary Peptide Discovery Platform System (PDPS), announced today a license and collaboration agreement to discover and develop peptide-siRNA conjugates to create multiple opportunities to deliver RNAi therapeutics to tissues outside the liver. Through this collaboration, the companies will collaborate to select and optimize peptides for targeted delivery of small interfering RNA (siRNA) molecules to a wide range of cell types and tissues via specific interactions with receptors expressed on the target cells.

    Under the terms of the alliance, Alnylam will select a set of receptors for PeptiDream's peptide discovery platform. PeptiDream will select, optimize, and synthesize peptides for each receptor. Alnylam will then generate peptide-siRNA conjugates and perform in vitro and in vivo studies to support final peptide selection. The collaboration has the potential to yield multiple treatment opportunities by targeting disease causing mRNA transcripts in a wide variety of tissue types.

    "Having solved delivery of RNAi therapeutics to the liver and made substantial preclinical progress on in vivo delivery to the CNS, eye, and lung, we are now adding to our suite of delivery technologies that have the potential to enable efficient delivery of siRNA to even broader tissue types throughout the human body," said Kevin Fitzgerald, Ph.D., Chief Scientific Officer of Alnylam. "We are excited to enter into this collaborative research agreement with PeptiDream, an industry leader in the discovery and optimization of peptide ligands against a wide variety of receptors. Through this collaboration, we hope to identify robust ligand-receptor pairs for extrahepatic tissue delivery, similar to the GalNAc-ASGPR pair that we have pioneered for effective liver delivery."

    "We look forward to partnering with Alnylam to leverage our PDPS technology and peptide discovery capabilities to identify novel ligands against Alnylam selected target receptors that can facilitate delivery of drug payloads to a broad range of extrahepatic tissues," said Patrick C. Reid Ph.D., President and Representative Director of PeptiDream. "This deal further expands on our strategy of using peptides to deliver a variety of therapeutic payloads (as peptide drug-conjugates) to disease cells/tissues in a targeted fashion. We hope this partnership will enable the creation of innovative peptide-siRNA conjugates in a variety of diseases and unlock many new therapeutic opportunities."

    Under the terms of the agreement, PeptiDream will receive an upfront payment from Alnylam as well as R&D funding over the term of the research collaboration, as provided in the agreement. PeptiDream may also receive payments based on the achievement of specified development, regulatory, and commercial milestones potentially totaling up to $2.2 billion (¥244 billion*1). In addition, PeptiDream is eligible to receive low-to-mid single digit royalties on sales on any such Alnylam products.

    *1: USD/ JPY currency conversion rate: 110.9

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

    About PeptiDream, Inc.

    PeptiDream Inc. is a public (TSE: 4587) biopharmaceutical company founded in 2006 employing its proprietary Peptide Discovery Platform System (PDPS), a state-of-the-art highly versatile discovery platform which enables the production of highly diverse (trillions) non-standard peptide libraries with high efficiency, for the identification of highly potent and selective hit candidates, which then can be developed into peptide-based, small molecule-based or peptide-drug conjugate therapeutics. PeptiDream aspires to be a world leader in drug discovery and development to address unmet medical needs and improve the quality of life of patients worldwide. For further information, please visit https://www.peptidream.com.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's expectations, plans, aspirations, and goals, including those related to the license and collaboration agreement with PeptiDream and the opportunity to discover and develop robust peptide-siRNA conjugates to create multiple opportunities to deliver RNAi therapeutics to a wide variety of tissue types outside the liver, the potential for payment of milestones and royalties to PeptiDream in the future, and the planned achievement of our "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO (or vutrisiran, if approved) in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

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  7. - Results Showed Substantial Reductions in Plasma Oxalate Relative to Baseline in PH1 Patients with Severe Renal Impairment, Including Those on Dialysis, and an Encouraging Safety and Tolerability Profile -

    - Alnylam Intends to File Supplemental Regulatory Applications with the U.S. Food and Drug Administration and the European Medicines Agency Based on ILLUMINATE-C Results in Late 2021 -

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today positive topline results from the ILLUMINATE-C Phase 3 open-label study of lumasiran in patients of all ages with advanced primary hyperoxaluria type 1 (PH1) associated with progressive decline in renal function. Lumasiran is an RNAi therapeutic targeting…

    - Results Showed Substantial Reductions in Plasma Oxalate Relative to Baseline in PH1 Patients with Severe Renal Impairment, Including Those on Dialysis, and an Encouraging Safety and Tolerability Profile -

    - Alnylam Intends to File Supplemental Regulatory Applications with the U.S. Food and Drug Administration and the European Medicines Agency Based on ILLUMINATE-C Results in Late 2021 -

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today positive topline results from the ILLUMINATE-C Phase 3 open-label study of lumasiran in patients of all ages with advanced primary hyperoxaluria type 1 (PH1) associated with progressive decline in renal function. Lumasiran is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) – the gene encoding glycolate oxidase (GO) – that is being investigated for the treatment of adult and pediatric patients with advanced PH1. Results of the primary analysis at six months demonstrated substantial reduction in plasma oxalate from baseline in patients (N=21) with advanced disease, including those on hemodialysis. Elevated plasma oxalate is directly related to the pathophysiology of oxalosis and results in systemic deposition of oxalate in extra-renal tissues, potentially leading to bone fractures, cardiomyopathy, impaired erythropoiesis, vision loss, skin ulcers, and other serious manifestations1. The safety and tolerability profile of lumasiran following six months of treatment is encouraging across all ages, with no drug related serious adverse events (SAEs) and injection site reactions (ISRs) as the most common adverse event (AE).

    "People with advanced PH1 suffer from severely impaired kidney function and may require an intensive dialysis regimen as a bridge to receiving a combined liver/kidney transplant – a procedure associated with high morbidity and lifelong immunosuppression. In ILLUMINATE-C, lumasiran reduced elevated levels of plasma oxalate that can lead to the morbidity and mortality associated with systemic oxalosis in this particularly vulnerable patient population," said Jeroen Valkenburg, General Manager, Lumasiran program at Alnylam. "Through the ILLUMINATE clinical program, we are hoping to establish that lumasiran may be a therapeutic option for PH1 patients regardless of age or disease severity, including patients on hemodialysis. We look forward to reporting complete data from the ILLUMINATE-C study at a medical congress later this year."

    "Patients with PH1 face devastating health challenges, especially those approaching or experiencing kidney failure, and these new results from the ILLUMINATE clinical development program signal hope to some of the sickest and most severely impacted individuals in this patient community," said Kim Hollander, Executive Director of the Oxalosis and Hyperoxaluria Foundation. "We're thankful that Alnylam continues to drive forth research that may benefit the PH1 community and for conducting a study that has the potential to help those who have the most severe form of the disease."

    Results

    ILLUMINATE-C (NCT04152200) is a single arm, open-label, multinational Phase 3 study evaluating the safety and efficacy of lumasiran in PH1 patients of all ages with severe renal impairment (eGFR ≤ 45 mL/min/1.73m2 or elevated serum creatinine for patients <12 months of age), and conducted at 13 study sites across 10 countries around the world. Cohort A enrolled six patients with advanced PH1 who do not yet require dialysis, and Cohort B enrolled 15 patients who are hemodialysis-dependent. The dosing regimen is based on weight with three monthly starting doses followed by ongoing monthly or quarterly doses. The primary efficacy endpoint for Cohort A was the percent change in plasma oxalate from baseline to month six, and the primary endpoint for Cohort B was the percent change in pre-dialysis plasma oxalate from baseline to month six. Key secondary endpoints are designed to evaluate additional measures of plasma oxalate and changes in urinary oxalate. Renal function, frequency and mode of dialysis, frequency of renal stone events, and measures of systemic oxalosis, including clinical manifestations, will also be evaluated in the extension period of the study.

    At six months, treatment with lumasiran resulted in a substantial reduction in plasma oxalate from baseline in both dialysis-independent and -dependent patients. Lumasiran also demonstrated positive results across key secondary endpoints, including measures of urinary oxalate (for patients in Cohort A) and additional measures of plasma oxalate. There were no deaths and no drug related SAEs among enrolled patients. There were two treatment discontinuations due to adverse events in the extension period of the study, neither of which was drug related. The most common drug related AEs (occurring in 10 percent or more of patients) were ISRs reported in five patients (23.8 percent), all of which were mild.

    Based on these results, the Company plans to submit a Supplemental New Drug Application (sNDA) for lumasiran with the U.S. Food and Drug Administration (FDA) and a Type II Variation with the European Medicines Agency (EMA) in late 2021. In November 2020, lumasiran was approved by the FDA for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients and by the EMA for the treatment of PH1 in all age groups. Lumasiran is marketed in the U.S. and EU as OXLUMO®. ILLUMINATE-C topline results will be discussed during Alnylam's Second Quarter Earnings Conference Call on August 3rd at 8:30 am ET, and full results are expected to be presented at a medical meeting later this year.

    About Lumasiran

    Lumasiran is a subcutaneously administered RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) in development for the treatment of primary hyperoxaluria type 1 (PH1). HAO1 encodes glycolate oxidase (GO). Thus, by silencing HAO1 and depleting the GO enzyme, lumasiran inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology of PH1. Lumasiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. Lumasiran has received regulatory approvals from the U.S. Food and Drug Administration (FDA) for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients and from the European Medicines Agency (EMA) for the treatment of PH1 in all age groups under the brand name OXLUMO®.

    IMPORTANT SAFETY INFORMATION for OXLUMO (lumasiran)

    Adverse Reactions

    The most common adverse reaction that occurred in patients treated with OXLUMO was injection site reaction (38%). Symptoms included erythema, pain, pruritus, and swelling.

    Pregnancy and Lactation

    No data are available on the use of OXLUMO in pregnant women. No data are available on the presence of OXLUMO in human milk or its effects on breastfed infants or milk production. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for OXLUMO and any potential adverse effects on the breastfed child from OXLUMO or the underlying maternal condition.

    For additional information about OXLUMO, please see the full Prescribing Information.

    About Primary Hyperoxaluria Type 1 (PH1)

    PH1 is an ultra-rare genetic disease that affects an estimated one to three individuals per million in the United States and Europe. PH1 is characterized by oxalate overproduction in the liver. The excess oxalate results in the deposition of calcium oxalate crystals in the kidneys and urinary tract and can lead to the formation of painful and recurrent kidney stones and nephrocalcinosis. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium oxalate deposition in the kidneys, and urinary obstruction by calcium oxalate stones. PH1 is associated with a progressive decline in kidney function, which exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and deposition of oxalate in bones, eyes, skin, and heart, leading to severe illness and death.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's future expectations, plans and prospects, including, without limitation, Alnylam's views with respect to the safety and efficacy of lumasiran as demonstrated in the ILLUMINATE-C Phase 3 study and the potential for lumasiran to be a therapeutic option for PH1 regardless of age or disease severity, including for patients on hemodialysis, expectations regarding the timing of the presentation of full results from the ILLUMINATE-C Phase 3 study, and the timing and planned filing of supplemental applications with FDA and EMA based on the ILLUMINATE-C results, and Alnylam's aspiration to become a leading biotech company, and the planned achievement of its "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the potential impact of current and the risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

    This release discusses the use of a previously approved RNAi therapeutic in continued development and is not intended to convey conclusions about efficacy or safety as to these uses. There is no guarantee that the data described in this release will result in expanded use of this commercial product, will successfully complete clinical development or will gain health authority approval.

    Footnote:

    1 Milliner et al., End Points for Clinical Trials in Primary Hyperoxaluria. Clin J Am Soc Nephrol. 2020; 15(7):1056-1065.

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  8. Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that it will report financial results for the second quarter ending June 30, 2021 on Tuesday, August 3, 2021, before the U.S. financial markets open.

    Management will provide an update on the Company and discuss second quarter 2021 results as well as expectations for the future via conference call on Tuesday, August 3, 2021 at 8:30 am ET. To access the call, please dial 877-312-7507 (domestic) or +1-631-813-4828 (international) five minutes prior to the start time and refer to conference ID 8870516. A replay of the call will be available beginning at 11:30 am ET on the day of the call. To access the replay, please dial 855-859-2056 (domestic…

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that it will report financial results for the second quarter ending June 30, 2021 on Tuesday, August 3, 2021, before the U.S. financial markets open.

    Management will provide an update on the Company and discuss second quarter 2021 results as well as expectations for the future via conference call on Tuesday, August 3, 2021 at 8:30 am ET. To access the call, please dial 877-312-7507 (domestic) or +1-631-813-4828 (international) five minutes prior to the start time and refer to conference ID 8870516. A replay of the call will be available beginning at 11:30 am ET on the day of the call. To access the replay, please dial 855-859-2056 (domestic) or +1-404-537-3406 (international) and refer to conference ID 8870516.

    A live audio webcast of the call will be available on the Investors section of the Company's website at www.alnylam.com/events. An archived webcast will be available on the Alnylam website approximately two hours after the event.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

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  9. – KARDIA-1 will Evaluate Efficacy and Safety of Quarterly and Biannual Regimens of Zilebesiran as Monotherapy –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced initiation of KARDIA-1, a global Phase 2 study evaluating the efficacy and safety of zilebesiran (pronounced "zile-BEE-siran" and formerly known as ALN-AGT), an investigational subcutaneous RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension. KARDIA-1 will evaluate zilebesiran as monotherapy across different doses administered quarterly and biannually. The Company will host an "RNAi Roundtable" webinar today at 10:00 a.m. ET to discuss the zilebesiran program.

    The primary…

    – KARDIA-1 will Evaluate Efficacy and Safety of Quarterly and Biannual Regimens of Zilebesiran as Monotherapy –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced initiation of KARDIA-1, a global Phase 2 study evaluating the efficacy and safety of zilebesiran (pronounced "zile-BEE-siran" and formerly known as ALN-AGT), an investigational subcutaneous RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension. KARDIA-1 will evaluate zilebesiran as monotherapy across different doses administered quarterly and biannually. The Company will host an "RNAi Roundtable" webinar today at 10:00 a.m. ET to discuss the zilebesiran program.

    The primary endpoint of KARDIA-1 is the change from baseline in systolic blood pressure as measured by 24-hour ambulatory blood pressure monitoring after three months of treatment. Additional endpoints will include change from baseline in blood pressure at six months, time-averaged reduction of blood pressure as a measure of tonic control, and safety. The study initiation is based on encouraging Phase 1 data, including results presented earlier this year at the 2021 Joint Meeting of the European Society of Hypertension (ESH) and the International Society of Hypertension (ISH). KARDIA-1 has been activated at clinical sites in the U.S. and will also be conducted at sites in Europe.

    "According to the World Health Organization, hypertension is the largest modifiable risk factor for cardiovascular morbidity and mortality. Despite the availability of numerous anti-hypertensive medications, tonic control of blood pressure remains elusive and represents a major unmet need, elevating the risk of fatal and nonfatal cardiovascular events, primarily stroke and heart attack. In addition, lack of patient adherence to therapy with daily oral medications further contributes to the challenges of inadequate blood pressure control," said Weinong Guo, M.D., Ph.D., Senior Vice President of Clinical Development at Alnylam. "The initiation of KARDIA-1, along with the planned start of the KARDIA-2 Phase 2 study later this year, signifies Alnylam's commitment to advance zilebesiran as a potential treatment to help address the worldwide burden of uncontrolled hypertension."

    Additional details about the RNAi Roundtable can be found on the Capella section of the Company's website here.

    About KARDIA-1 Phase 2 Study

    The KARDIA-1 Phase 2 trial is a randomized, double-blind (DB), placebo-controlled, dose-ranging study to evaluate the efficacy and safety of zilebesiran as monotherapy in adults with mild-to-moderate hypertension. This global, multicenter trial will enroll approximately 375 adults with untreated hypertension or who are on stable therapy with one or more anti-hypertensive medications. Any patients taking prior anti-hypertensive medications will complete at least a four-week wash-out before randomization. Study participants will be randomized to one of five treatment arms during a 12-month DB period and DB extension period: 1) 150 mg zilebesiran subcutaneously once every six months; 2) 300 mg zilebesiran subcutaneously once every six months; 3) 300 mg zilebesiran subcutaneously once every three months; 4) 600 mg zilebesiran subcutaneously once every six months; or 5) placebo. Patients who receive placebo will be randomized to one of the four initial zilebesiran dose regimens beginning at month six. The study's primary efficacy endpoint is the change from baseline in systolic blood pressure, assessed by 24-hour ambulatory blood pressure monitoring, after three months of treatment. In addition to the evaluation of the safety of zilebesiran, key secondary and exploratory endpoints in this study include additional measures of blood pressure reduction at six months, time-adjusted change in blood pressure, and change in daytime average and night-time average blood pressure. For more information on KARDIA-1 (NCT04936035), please visit clinicaltrials.gov, email clinicaltrials@alnylam.com or call 877-256-9526 in North America and +31 20 369 7861 in Europe.

    About Zilebesiran

    Formerly known as ALN-AGT, zilebesiran (pronounced "zile-BEE-siran") is an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen (AGT) in development for the treatment of hypertension in high unmet need populations. AGT is the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS), a cascade which has a demonstrated role in blood pressure regulation and its inhibition has well-established anti-hypertensive effects. Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin (Ang) II. Zilebesiran utilizes Alnylam's Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, which enables subcutaneous dosing with increased selectivity and a wide therapeutic index. The safety and efficacy of zilebesiran have not been established or evaluated by the FDA, EMA or any other health authority.

    About Hypertension

    Hypertension is a complex multifactorial disease clinically defined by most major guidelines as a systolic blood pressure (SBP) of above 140 mm Hg and/or a diastolic blood pressure (DBP) greater than 90 mm Hg, though AHA/ACC guidelines have a lower threshold of a SBP above 130 mm Hg and/or a DBP greater than 80 mm Hg. More than one billion people worldwide live with hypertension.i In the U.S. alone, approximately 47 percent of adults live with hypertension, with more than half of patients on medication remaining above the blood pressure target level. Despite the availability of anti-hypertensive medications, there remains a significant unmet medical need, especially given the poor rates of adherence to existing daily oral medications and daily peak and trough effects, resulting in inconsistent blood pressure control and an increased risk for stroke, heart attack and premature death.ii In particular, there are a number of high unmet need settings where novel approaches to hypertension warrant additional development focus, including patients with poor medication adherence, difficult-to-treat and resistant hypertension, and in patients with high cardiovascular risk.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's expectations, plans, aspirations, and goals, including those related to encouraging results from our Phase 1 study of zilebesiran (formerly known as ALN-AGT), the design and conduct of our KARDIA-1 Phase 2 study of zilebesiran and the planned activation of the study at sites in Europe following U.S. initiation, our commitment to advancing zilebesiran as a potential [treatment to help] address the worldwide burden of uncontrolled hypertension, our aspiration to become a leading biotech company, and the planned achievement of our "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO (or vutrisiran, if approved) in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

    This release is not intended to convey conclusions about efficacy or safety as to any investigational uses or dosing regimens of any investigational RNAi therapeutics. There is no guarantee that any investigational therapeutics or dosing regimens for such therapeutics will successfully complete clinical development or gain health authority approval.

    __________________________________

    i Hypertension. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/hypertension. Published September 2019. Accessed June 2021.

    ii Carey, R. M., Muntner, P., Bosworth, H. B., & Whelton, P. K. (2018). Prevention and Control of Hypertension: JACC Health Promotion Series. Journal of the American College of Cardiology, 72(11), 1278–1293. https://doi.org/10.1016/j.jacc.2018.07.008

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  10. – PDUFA Date Set for April 14, 2022 –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that the U.S. Food and Drug Administration (FDA) has accepted the Company's New Drug Application (NDA) for vutrisiran, an investigational RNAi therapeutic for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. The FDA has set an action date of April 14, 2022 under the Prescription Drug User Fee Act (PDUFA), and the Agency has indicated that they are not currently planning an advisory committee meeting as part of the NDA review.

    "We are excited that the FDA has accepted our NDA for vutrisiran, which was based on 9-month results from the HELIOS-A study…

    – PDUFA Date Set for April 14, 2022 –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that the U.S. Food and Drug Administration (FDA) has accepted the Company's New Drug Application (NDA) for vutrisiran, an investigational RNAi therapeutic for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. The FDA has set an action date of April 14, 2022 under the Prescription Drug User Fee Act (PDUFA), and the Agency has indicated that they are not currently planning an advisory committee meeting as part of the NDA review.

    "We are excited that the FDA has accepted our NDA for vutrisiran, which was based on 9-month results from the HELIOS-A study. Today's announcement marks another important milestone as we work to make vutrisiran available to hATTR amyloidosis patients with polyneuropathy," said Rena Denoncourt, Vice President, TTR Franchise Lead. "If approved, once-quarterly, subcutaneously administered vutrisiran may represent a new treatment option that potentially reverses polyneuropathy manifestations of disease."

    Vutrisiran has been granted Orphan Drug Designation in the U.S. and the European Union (EU) for the treatment of ATTR amyloidosis. Vutrisiran has also been granted a Fast-Track designation in the U.S. for the treatment of the polyneuropathy of hATTR amyloidosis in adults. The Company plans to also submit regulatory filings in the EU, Brazil, and Japan in 2021 based on the HELIOS-A results.

    About Vutrisiran

    Vutrisiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hereditary (hATTR) and wild-type (wtATTR) amyloidosis. It is designed to target and silence specific messenger RNA, blocking the production of wild-type and variant transthyretin (TTR) protein before it is made. Quarterly administration of vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues. Vutrisiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability that may allow for infrequent subcutaneous injections. The safety and efficacy of vutrisiran have not been evaluated by the U.S. Food and Drug Administration, European Medicines Agency or any other health authority.

    About the HELIOS-A Phase 3 Study

    HELIOS-A (NCT03759379) is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran. The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries. Patients were randomized 3:1 to receive either 25mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (as a reference comparator) for 18 months. The efficacy results of vutrisiran in HELIOS-A are compared to the placebo group from the landmark APOLLO Phase 3 study, which evaluated the efficacy and safety of patisiran in a patient population similar to that studied in HELIOS-A. The primary endpoint is the change from baseline in mNIS+7 score at nine months. Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at nine months. Additional secondary endpoints at 18 months will be evaluated in the HELIOS-A study, including change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum transthyretin (TTR) levels. Additional exploratory cardiac endpoint data at the 18-month time point will be evaluated, including NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging. Following the 18-month treatment period, all patients are eligible to receive vutrisiran for an additional 18 months as part of the randomized treatment extension where they will receive either 25mg vutrisiran once quarterly or 50mg vutrisiran once every six months.

    About hATTR Amyloidosis

    Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, and fatal disease caused by variants (i.e., mutations) in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis, represents a major unmet medical need with significant morbidity and mortality affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's expectations, plans, aspirations, and goals, including those related to the investigational therapeutic vutrisiran and its potential as a low-dose, once quarterly, subcutaneously administered treatment option with encouraging safety profile for patients with hATTR amyloidosis with polyneuropathy that has the potential to reverse polyneuropathy manifestations of disease, the expected timing for FDA review of the NDA for vutrisiran, our progress toward building in the future a franchise of medicines for the treatment of ATTR amyloidosis, our aspiration to become a leading biotech company, and the planned achievement of our "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO (or vutrisiran, if approved) in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

    This release is not intended to convey conclusions about efficacy or safety as to any investigational uses or dosing regimens of any investigational RNAi therapeutics. There is no guarantee that any investigational therapeutics or dosing regimens for such therapeutics will successfully complete clinical development or gain health authority approval.

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  11. Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that it plans to host its 8th annual series of "RNAi Roundtable" webinars over the coming weeks. The series will offer a range of presentations from Alnylam scientists and program leaders who will review recent progress in many of the Company's pipeline programs and platform innovations, as well as medical thought leaders who will provide their perspectives on clinical developments and unmet needs in various therapeutic areas. Each event will be webcast live on the Investors section of the Company's website at www.alnylam.com/events, and a replay will be posted on the Alnylam website approximately three hours after each event.

    The 2021 RNAi…

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that it plans to host its 8th annual series of "RNAi Roundtable" webinars over the coming weeks. The series will offer a range of presentations from Alnylam scientists and program leaders who will review recent progress in many of the Company's pipeline programs and platform innovations, as well as medical thought leaders who will provide their perspectives on clinical developments and unmet needs in various therapeutic areas. Each event will be webcast live on the Investors section of the Company's website at www.alnylam.com/events, and a replay will be posted on the Alnylam website approximately three hours after each event.

    The 2021 RNAi Roundtable schedule is as follows:

    • ALN-AGT, in Development for the Treatment of Hypertension

      Wednesday, June 30, 10:00 am ET
    • Patisiran and Vutrisiran, in Development for the Treatment of ATTR Amyloidosis

      Friday, July 16, 11:00 am ET
    • Givosiran, for the Treatment of Acute Hepatic Porphyria

      Wednesday, August 4, 1:30 pm ET
    • Lumasiran, for the Treatment of Primary Hyperoxaluria Type 1

      Thursday, August 19, 9:30 am ET (tentative)
    • Liver-Directed RNAi Pipeline Programs

      Monday, September 20, 11:00 am ET
    • CNS & Extrahepatic RNAi Pipeline Programs

      Friday, October 1, 1:30 pm ET

    Please visit the Capella section of our website for the latest information regarding webcast dates.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

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  12. − Phase 3b Open-Label Study Showed Treatment with Patisiran Achieved Rapid and Sustained Reduction in Serum TTR Levels in hATTR Amyloidosis Patients with Polyneuropathy Progression Following Orthotopic Liver Transplant –

    − Additional Results from Pre-specified Patient Subgroups Analysis Included with Encore Presentation of HELIOS-A Phase 3 Study of Investigational Vutrisiran −

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced positive results from a Phase 3b open-label study conducted to evaluate the safety, efficacy and pharmacokinetics (PK) of patisiran in hereditary ATTR (hATTR) amyloidosis patients with polyneuropathy progression after receiving an orthotopic liver transplant (OLT). In…

    − Phase 3b Open-Label Study Showed Treatment with Patisiran Achieved Rapid and Sustained Reduction in Serum TTR Levels in hATTR Amyloidosis Patients with Polyneuropathy Progression Following Orthotopic Liver Transplant –

    − Additional Results from Pre-specified Patient Subgroups Analysis Included with Encore Presentation of HELIOS-A Phase 3 Study of Investigational Vutrisiran −

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced positive results from a Phase 3b open-label study conducted to evaluate the safety, efficacy and pharmacokinetics (PK) of patisiran in hereditary ATTR (hATTR) amyloidosis patients with polyneuropathy progression after receiving an orthotopic liver transplant (OLT). In patients treated with patisiran, the median reduction in serum TTR levels compared to baseline was 91 percent, measured as an average of the month six and month 12 reduction. In addition, the safety profile of patisiran was consistent with the previously reported safety results observed in the APOLLO Phase 3 study. Patisiran is the established name for ONPATTRO®, which is approved in the United States, Canada and Japan for the treatment of the polyneuropathy of hATTR amyloidosis in adults, and in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy. These data will form the basis of post-approval supplements which have the potential to change labeling for ONPATTRO where approved, including in the European Union.

    In addition, positive results from the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis, were presented today with additional data from pre-specified patient subgroups. Improvement in the modified Neuropathy Impairment Score (mNIS+7) and Norfolk Quality of Life-Diabetic Neuropathy score (Norfolk QOL-DN) from vutrisiran treatment was consistently observed across all pre-specified patient subgroups, including age, sex, race, geographic region, baseline neuropathy impairment, genotype, prior TTR stabilizer use, baseline Familial Amyloid Polyneuropathy (FAP) stage, and in a pre-specified cardiac subpopulation. These data were presented as posters during the 2021 Peripheral Nerve Society's Annual Meeting, and the HELIOS-A results will also be featured during the Richard A.C. Hughes - Clinical Science Highlights Presentation on Sunday, June 27th.

    "We are excited to share new data from our TTR clinical program at this year's PNS virtual conference, which help demonstrate the potential of patisiran and vutrisiran for a broad group of patients with hATTR amyloidosis with polyneuropathy. Patients with hATTR amyloidosis who experience polyneuropathy progression post-OLT have a significant treatment need and the results of the Phase 3b study of patisiran demonstrated robust TTR knockdown, improved neuropathy, and quality of life after 12 months of treatment," said John Vest, M.D., Vice President of Clinical Research at Alnylam. "In addition, results from our HELIOS-A study of investigational vutrisiran underscore the potential of vutrisiran as an attractive potential new treatment option for hATTR amyloidosis patients with polyneuropathy with subcutaneous administration and quarterly dosing."

    Results of Patisiran in Patients with hATTR Amyloidosis Post-OLT

    Historically, OLT has been used to slow disease progression in patients with early stages of hATTR amyloidosis; however, some patients experience disease progression after the transplant due to continued amyloid deposition of wild-type TTR on top of existing amyloid deposits in tissues. In the Phase 3b study conducted across several European countries, 23 patients who showed polyneuropathy progression post-OLT (based on an increase in polyneuropathy disability [PND] score) received patisiran infusion (0.3 mg/kg) every three weeks for 12 months.

    Results from the study show that at month 12, patisiran treatment resulted in an improvement in neuropathy, as demonstrated by a 3.7 point decrease in the mean total neurological impairment (NIS) score from baseline. Patisiran treatment also resulted in an improvement in quality of life with a 6.5 decrease in mean total Norfolk Quality of Life-Diabetic Neuropathy score (Norfolk QOL-DN) and autonomic symptoms with treatment resulting in a 5.0 decrease in the least squares (LS) mean total COMPASS-31 score from baseline. Patisiran treatment also demonstrated stabilization in other endpoints, including measures of disability like the Rasch-built Overall Disability Scale (R-ODS) and nutritional status with the modified body mass index (mBMI) which were both stable relative to baseline at month 12.

    Patisiran also demonstrated an encouraging safety and tolerability profile after 12 months of treatment and there were no drug-related study discontinuations or deaths. There was one serious adverse event (SAE) considered related to patisiran by the study investigator, consisting of an infusion reaction, which resolved without intervention and without change in patisiran treatment. Treatment emergent adverse events (AE) were consistent with those seen in the Phase 3 APOLLO study. The most common observed AE was diarrhea. There was one case of liver transplant rejection observed during the study which was deemed unrelated to patisiran by the study investigator. There were no safety signals regarding hematology, renal function or liver function tests (LFTs).

    About ONPATTRO® (Patisiran)

    ONPATTRO is an RNAi therapeutic that was approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby blocking the production of TTR protein before it is made. ONPATTRO blocks the production of TTR in the liver, reducing its accumulation in the body's tissues in order to halt or slow down the progression of the polyneuropathy associated with the disease. For more information about ONPATTRO, visit ONPATTRO.com.

    ONPATTRO Important Safety Information

    Infusion-Related Reactions

    Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. In a controlled clinical study, 19 percent of ONPATTRO-treated patients experienced IRRs, compared to 9 percent of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache.

    To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, paracetamol, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.

    Reduced Serum Vitamin A Levels and Recommended Supplementation

    ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body.

    Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness).

    Adverse Reactions

    The most common adverse reactions that occurred in patients treated with ONPATTRO were respiratory-tract infection (29 percent) and infusion-related reactions (19 percent).

    About Vutrisiran

    Vutrisiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hereditary (hATTR) and wild-type (wtATTR) amyloidosis. It is designed to target and silence specific messenger RNA, blocking the production of wild-type and variant transthyretin (TTR) protein before it is made. Quarterly administration of vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues. Vutrisiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability that may allow for infrequent subcutaneous injections. The safety and efficacy of vutrisiran have not been evaluated by the U.S. Food and Drug Administration, European Medicines Agency or any other health authority.

    About the HELIOS-A Phase 3 Study

    HELIOS-A (NCT03759379) is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran. The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries. Patients were randomized 3:1 to receive either 25mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (as a reference comparator) for 18 months. The efficacy results of vutrisiran in HELIOS-A are compared to the placebo group from the landmark APOLLO Phase 3 study, which evaluated the efficacy and safety of patisiran in a patient population similar to that studied in HELIOS-A. The primary endpoint is the change from baseline in mNIS+7 score at nine months. Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at nine months. Additional secondary endpoints at 18 months will be evaluated in the HELIOS-A study, including change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum transthyretin (TTR) levels. Additional exploratory cardiac endpoint data at the 18-month time point will be evaluated, including NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging. Following the 18-month treatment period, all patients are eligible to receive vutrisiran for an additional 18 months as part of the randomized treatment extension.

    About hATTR Amyloidosis

    Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, and fatal disease caused by variants (i.e., mutations) in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis, represents a major unmet medical need with significant morbidity and mortality affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

    Alnylam Forward-Looking Statements

    Various statements in this release concerning Alnylam's expectations, plans, aspirations, and goals, including those related to results from a Phase 3b open-label study of patisiran and the potential benefit of patisiran treatment for patients with polyneuropathy progression after receiving an OLT, the use of the Phase 3b data to support post-approval supplements which have the potential to change labeling for ONPATTRO where approved, including in the European Union, vutrisiran and its potential as an attractive new treatment option for hATTR amyloidosis patients with polyneuropathy with subcutaneous administration and quarterly dosing, and the achievement of its "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO (or vutrisiran, if approved) in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

    This release is not intended to convey conclusions about efficacy or safety as to any investigational uses or dosing regimens of any investigational RNAi therapeutics. There is no guarantee that any investigational therapeutics or dosing regimens for such therapeutics will successfully complete clinical development or gain health authority approval.

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  13. − APOLLO-B is the Industry's Furthest Progressed Randomized, Double-Blind, Placebo-Controlled Pivotal Study of an Investigational TTR Silencer in Hereditary and Wild-type ATTR Amyloidosis with Cardiomyopathy −

    − Topline Results Expected in Mid-2022 −

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that it has achieved full patient enrollment in its APOLLO-B Phase 3 study of patisiran, an investigational RNAi therapeutic in development for the treatment of cardiomyopathy in patients with transthyretin-mediated (ATTR) amyloidosis. Enrollment was completed with over 300 ATTR amyloidosis patients across 90 sites in more than 20 countries. ATTR amyloidosis is a rare, progressively debilitating…

    − APOLLO-B is the Industry's Furthest Progressed Randomized, Double-Blind, Placebo-Controlled Pivotal Study of an Investigational TTR Silencer in Hereditary and Wild-type ATTR Amyloidosis with Cardiomyopathy −

    − Topline Results Expected in Mid-2022 −

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that it has achieved full patient enrollment in its APOLLO-B Phase 3 study of patisiran, an investigational RNAi therapeutic in development for the treatment of cardiomyopathy in patients with transthyretin-mediated (ATTR) amyloidosis. Enrollment was completed with over 300 ATTR amyloidosis patients across 90 sites in more than 20 countries. ATTR amyloidosis is a rare, progressively debilitating, and fatal disease that is caused by misfolded transthyretin (TTR) proteins that accumulate as amyloid deposits in multiple tissues, including the nerves, heart and gastrointestinal (GI) tract and encompasses hereditary ATTR (hATTR) amyloidosis and wild-type ATTR (wtATTR) amyloidosis. hATTR amyloidosis is estimated to impact approximately 50,000 people worldwide and is a multisystem disease that can include sensory and motor, autonomic, and cardiac symptoms. wtATTR amyloidosis is estimated to impact between 200,000 and 300,000 people worldwide and primarily manifests as cardiomyopathy, which can lead to heart failure and mortality. APOLLO-B is the industry's furthest progressed randomized, double-blind, placebo-controlled study of a TTR silencer investigational medicine for the treatment of cardiomyopathy in hATTR and wtATTR amyloidosis patients.

    Patisiran is the established name for ONPATTRO®, which is approved in the United States, Canada and Japan for the treatment of the polyneuropathy of hATTR amyloidosis in adults and in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy.

    "The APOLLO-B trial was initiated based on encouraging data from previous studies that support further investigation of patisiran in ATTR amyloidosis patients with cardiomyopathy. Specifically, encouraging results were obtained from the landmark Phase 3 APOLLO study in hATTR amyloidosis patients with polyneuropathy on a number of exploratory cardiac endpoints. Today's milestone marks an important step forward as we continue to study the safety and efficacy of patisiran in the treatment of cardiovascular-related manifestations of ATTR amyloidosis, which can often be devastating for these patients," said Rena Denoncourt, Vice President, TTR Franchise Lead. "We look forward to announcing topline APOLLO-B results in mid-2022 and are excited about the potential of patisiran to treat multiple manifestations of this rapidly progressive disease and further advance our aspiration to build the industry leading franchise of RNAi therapeutics for the treatment of ATTR amyloidosis."

    About the APOLLO-B Phase 3 Study Design

    The APOLLO-B study is a Phase 3, randomized, double-blind, placebo-controlled multicenter global study designed to evaluate the efficacy and safety of patisiran in patients with transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy, which enrolled over 300 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy. Patients were randomized on a 1:1 basis to receive 0.3 mg/kg of patisiran or placebo intravenously administered every three weeks over a 12-month treatment period. After 12 months, all patients will receive patisiran in an open-label extension period. The primary outcome measure of APOLLO-B is the change from baseline in the 6-minute walk test at 12 months compared to placebo. Key secondary and exploratory endpoints will evaluate the efficacy of patisiran on health-related quality of life, mortality and cardiovascular events, cardiac biomarkers and additional manifestations of cardiac amyloid involvement. For more information on APOLLO-B (NCT03997383) please visit www.clinicaltrials.gov.

    About ONPATTRO® (Patisiran)

    ONPATTRO is an RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby blocking the production of TTR protein before it is made. ONPATTRO blocks the production of TTR in the liver, reducing its accumulation in the body's tissues in order to halt or slow down the progression of the polyneuropathy associated with the disease. For more information about ONPATTRO, including full Prescribing Information and Important Safety Information, visit ONPATTRO.com.

    ONPATTRO Indication and Important Safety Information

    Indication

    ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

    Infusion-Related Reactions

    Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO® (patisiran). In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache.

    To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.

    Reduced Serum Vitamin A Levels and Recommended Supplementation

    ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).

    Adverse Reactions

    The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory tract infections (29%) and infusion-related reactions (19%).

    About ATTR Amyloidosis

    Transthyretin-mediated (ATTR) amyloidosis is a rare, rapidly progressive, debilitating disease caused by misfolded transthyretin (TTR) proteins which accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal (GI) tract. There are two different types of ATTR amyloidosis – Hereditary ATTR (hATTR) amyloidosis, caused by a TTR gene variant, and Wild-type ATTR amyloidosis (wtATTR), which occurs without a TTR gene variant. hATTR amyloidosis affects approximately 50,000 people worldwide, while wtATTR amyloidosis is estimated to impact 200,000 – 300,000 people worldwide.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's expectations, plans, aspirations, and goals, including those related to patisiran and its potential to treat cardiovascular-related manifestations of ATTR amyloidosis in both in hATTR and wtATTR amyloidosis patients, the expected timing for topline results from the APOLLO-B Phase 3 study, Alnylam's aspiration to build the industry leading franchise of RNAi therapeutics for the treatment of ATTR amyloidosis, and the achievement of its "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO (or vutrisiran, if approved) in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

    This release is not intended to convey conclusions about efficacy or safety as to any investigational uses or dosing regimens of any investigational RNAi therapeutics. There is no guarantee that any investigational therapeutics or dosing regimens for such therapeutics will successfully complete clinical development or gain health authority approval.

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  14. Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that management will present company overviews at the following conferences which are being held virtually:

    • Jefferies Virtual Healthcare Conference on Tuesday, June 1, 2021 at 2:30 pm ET
    • Bernstein 37th Annual Strategic Decisions Conference on Thursday, June 3, 2021 at 9:00 am ET
    • Goldman Sachs 42nd Annual Global Healthcare Conference on Tuesday, June 8, 2021 at 10:30 am ET
    • 44th Nasdaq Investor Conference on Tuesday, June 15, 2021 at 10:00 am ET

    A live audio webcast of each presentation will be available on the Investors section of the Company's website at www.alnylam.com/events. A replay will be available on the Alnylam website within…

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that management will present company overviews at the following conferences which are being held virtually:

    • Jefferies Virtual Healthcare Conference on Tuesday, June 1, 2021 at 2:30 pm ET
    • Bernstein 37th Annual Strategic Decisions Conference on Thursday, June 3, 2021 at 9:00 am ET
    • Goldman Sachs 42nd Annual Global Healthcare Conference on Tuesday, June 8, 2021 at 10:30 am ET
    • 44th Nasdaq Investor Conference on Tuesday, June 15, 2021 at 10:00 am ET

    A live audio webcast of each presentation will be available on the Investors section of the Company's website at www.alnylam.com/events. A replay will be available on the Alnylam website within 48 hours after each event.

    About Alnylam

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

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  15. Initiates Clinical Study of Biannual Dosing Regimen of Investigational Vutrisiran in hATTR Patients with Polyneuropathy, with Data Expected in 2022 Potentially Supporting sNDA Submission –

    Introduces New ATTR Program Aimed at Achieving Annual Dosing Regimen with Highly Potent and Reversible Effects; Expected IND Filing at or Around Year-end 2022 –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced that it has started a clinical study of a biannual dosing regimen of vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis. The study is being conducted during a randomized treatment extension (RTE) period in the HELIOS-A…

    Initiates Clinical Study of Biannual Dosing Regimen of Investigational Vutrisiran in hATTR Patients with Polyneuropathy, with Data Expected in 2022 Potentially Supporting sNDA Submission –

    Introduces New ATTR Program Aimed at Achieving Annual Dosing Regimen with Highly Potent and Reversible Effects; Expected IND Filing at or Around Year-end 2022 –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced that it has started a clinical study of a biannual dosing regimen of vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis. The study is being conducted during a randomized treatment extension (RTE) period in the HELIOS-A Phase 3 study, and will characterize the safety, efficacy, and TTR reduction of a 50 mg biannual dosing regimen of subcutaneously administered vutrisiran in patients with hereditary ATTR (hATTR) amyloidosis with polyneuropathy. In addition, the Company announces today advancement of a new pre-clinical ATTR amyloidosis program aimed at achieving highly potent and reversible TTR reduction of over 90 percent with an annual subcutaneous dosing regimen.

    "Alnylam has a long-standing commitment to continuous innovation aimed at providing breakthrough treatment options for patients with ATTR amyloidosis. We're pleased to have now initiated a clinical study of a biannual dosing regimen for vutrisiran. If shown to be safe and efficacious, the new dosing regimen may provide some patients with a treatment option that neatly aligns the frequency of administration with biannual visits to their doctor," said Rena Denoncourt, Vice President, Vutrisiran Program Leader. "In addition, based on continued discoveries from our RNAi therapeutics platform, we're also advancing a new pre-clinical program that could enable highly potent and reversible TTR reduction with an annual dosing regimen. We believe that once yearly dosing could provide a vaccine-like dosing schedule strategy for management of ATTR amyloidosis, providing meaningful life-cycle management for our ATTR franchise."

    As reported previously, positive results were achieved in HELIOS-A with a 25 mg quarterly dosing regimen of subcutaneously administered vutrisiran; a New Drug Application (NDA) for the approval of vutrisiran was filed with the U.S. Food and Drug Administration (FDA) in April 2021 for the treatment of the polyneuropathy of hATTR amyloidosis in adults1. The vutrisiran biannual dosing study is being conducted as part of the HELIOS-A randomized, open-label study. During the RTE period, which begins following completion of the 18-month HELIOS-A treatment period, patients are randomized 1:1 to receive 25 mg of vutrisiran quarterly or 50 mg of vutrisiran biannually for the remainder of the study. Patients will undergo periodic assessments for safety and TTR reduction, and efficacy assessments at months nine and 18 of the RTE. As previously disclosed in mid-2020, clinical pharmacology data indicate that a 50 mg biannual dose of vutrisiran is expected to achieve comparable TTR reduction – over 80 percent – to that demonstrated with the 25 mg quarterly dosing regimen of vutrisiran. Alnylam expects results from the RTE study in 2022; if positive, data would support a supplemental NDA (sNDA) submission to the FDA.

    The new ATTR program announced today stems from continued innovation from Alnylam's RNAi therapeutics platform efforts. Specifically, Alnylam scientists have developed an extended duration platform, called IKARIA™, that is aimed at highly potent (>90 percent) target mRNA silencing with an annual dosing regimen. Targeting mRNA with the IKARIA platform is expected to yield small interfering RNA (siRNA) with potentially long-acting and reversible effects and a proven RNAi mechanism of action. This new platform has yielded ALN-TTRsc04, which is planned to enter clinical development at or around year-end 2022 with an investigational new drug (IND) application filing. If successfully developed, ALN-TTRsc04 is expected to have minimal, if any, third-party royalty obligations. Alnylam plans to present data from its IKARIA platform and ALN-TTRsc04 program at a scientific meeting in mid-2021.

    "Our platform team continues to discover innovations for RNAi therapeutics that we believe can deliver meaningful advances for patients. Our new IKARIA platform represents an excellent example," said Kevin Fitzgerald, Ph.D., Senior Vice President, Chief Scientific Officer. "With IKARIA, we are confident we can design long-acting siRNA with all the proven pharmacological advantages and established human experience of RNAi therapeutics, including predictable dose-dependence and onset/offset kinetics, without permanent effects on the target or cell."

    About HELIOS-A Phase 3 Study

    HELIOS-A (NCT03759379) is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran. The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries. Patients were randomized 3:1 to receive either 25mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (as a reference comparator) for 18 months. The primary endpoint is the change from baseline in mNIS+7 score at nine months, relative to an external placebo group (APOLLO). Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT, relative to an external placebo group. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at nine months. The efficacy results of vutrisiran in HELIOS-A are compared to the placebo group from the landmark APOLLO Phase 3 study, which evaluated the efficacy and safety of patisiran in a patient population similar to that studied in HELIOS-A. Additional secondary endpoints at 18 months will be evaluated in the HELIOS-A study, including change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum transthyretin (TTR) levels. Additional exploratory cardiac endpoint data at the 18-month time point will be evaluated, including NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging. Following the 18-month treatment period, all patients are eligible to receive vutrisiran for an additional 18 months as part of the randomized treatment extension.

    About Vutrisiran

    Vutrisiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hereditary (hATTR) and wild-type (wtATTR) amyloidosis. It is designed to target and silence specific messenger RNA, blocking the production of wild-type and variant transthyretin (TTR) protein before it is made. Quarterly administration of vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues. Vutrisiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability that may allow for infrequent subcutaneous injections. The safety and efficacy of vutrisiran have not been evaluated by the U.S. Food and Drug Administration, European Medicines Agency or any other health authority.

    About hATTR Amyloidosis

    Hereditary transthyretin (TTR)-mediated amyloidosis (hATTR) is an inherited, progressively debilitating, and fatal disease caused by variants (i.e., mutations) in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis, represents a major unmet medical need with significant morbidity and mortality affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

    About IKARIA™ Platform

    Alnylam's IKARIA platform takes advantage of more than two decades of experience in developing RNAi therapeutics. IKARIA enables an extended duration of activity in preclinical studies, with potential for annual dosing in humans, and has design features which provide exquisite specificity, further widening the potential therapeutic index, with enhanced target reduction levels.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's expectations, plans, aspirations, and goals, including those related to vutrisiran and its potential as a low-dose, once quarterly, subcutaneously administered treatment option with an encouraging safety profile for patients with hATTR amyloidosis with polyneuropathy, the potential of a new biannual dosing regimen of vutrisiran for such patients, the expected timing of additional data on the biannual dosing regimen and potential additional regulatory filings for vutrisiran, including an sNDA with the FDA, if the data for such biannual dosing are positive, the potential of the IKARIA platform to enable highly potent (>90 percent) target mRNA silencing with an annual dosing regimen and the expected timing for the initiation of clinical studies for ALN-TTRsc04, that could enable highly potent and reversible TTR reduction with an annual dosing regimen and, if successful, could provide a vaccine-like strategy for management of ATTR amyloidosis, becoming a leading biotech company, and the achievement of its "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO (or vutrisiran, if approved) in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

    This release is not intended to convey conclusions about efficacy or safety as to any investigational uses or dosing regimens of any investigational RNAi therapeutics. There is no guarantee that any investigational therapeutics or dosing regimens for such therapeutics will successfully complete clinical development or gain health authority approval.

    1 The safety and efficacy of investigational vutrisiran have not been evaluated by the U.S. Food and Drug Administration, European Medicines Agency, or any other health authority. Regulatory authorities have not yet determined that vutrisiran is safe or effective for any indication.

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  16. Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that management will present company overviews at the following conferences which are being held virtually:

    • BofA Health Care Conference on Tuesday, May 11, 2021 at 2:45 pm ET
    • UBS Global Healthcare Virtual Conference on Tuesday, May 25, 2021 at 3:00 pm ET

    A live audio webcast of each presentation will be available on the Investors section of the Company's website at www.alnylam.com/events. A replay will be available on the Alnylam website within 48 hours after each event.

    About Alnylam

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform…

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that management will present company overviews at the following conferences which are being held virtually:

    • BofA Health Care Conference on Tuesday, May 11, 2021 at 2:45 pm ET
    • UBS Global Healthcare Virtual Conference on Tuesday, May 25, 2021 at 3:00 pm ET

    A live audio webcast of each presentation will be available on the Investors section of the Company's website at www.alnylam.com/events. A replay will be available on the Alnylam website within 48 hours after each event.

    About Alnylam

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

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  17. – OXLUMO Demonstrated Improvements in Nephrocalcinosis in Patients with Primary Hyperoxaluria Type 1 After 12 Months of Treatment –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today positive early results on clinical outcome measures from the 12-month analysis of ILLUMINATE-A Phase 3 study of OXLUMO® (lumasiran), an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) – the gene encoding glycolate oxidase (GO) – for the treatment of primary hyperoxaluria type 1 (PH1). These data were presented at the American Society of Pediatric Nephrology (ASPN)/Pediatric Academic Societies (PAS) virtual meeting being held on April 30–May 4, 2021.

    As previously reported, treatment with OXLUMO significantly…

    – OXLUMO Demonstrated Improvements in Nephrocalcinosis in Patients with Primary Hyperoxaluria Type 1 After 12 Months of Treatment –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today positive early results on clinical outcome measures from the 12-month analysis of ILLUMINATE-A Phase 3 study of OXLUMO® (lumasiran), an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) – the gene encoding glycolate oxidase (GO) – for the treatment of primary hyperoxaluria type 1 (PH1). These data were presented at the American Society of Pediatric Nephrology (ASPN)/Pediatric Academic Societies (PAS) virtual meeting being held on April 30–May 4, 2021.

    As previously reported, treatment with OXLUMO significantly reduced urinary oxalate levels in infants1, children1,2 and adults2 with PH1 in the ILLUMINATE-A and ILLUMINATE-B studies. OXLUMO also demonstrated an acceptable safety profile across age groups, with injection site reactions as the most common drug-related adverse reaction. New results from ILLUMINATE-A showed that treatment with OXLUMO for 12 months was associated with evidence of improvements in nephrocalcinosis in one or both kidneys, relative to baseline.

    "Nephrocalcinosis is a key indicator of disease severity in PH1," said Jeffrey M. Saland, M.D., Professor and Chief, Pediatric Nephrology and Hypertension, Jack and Lucy Clark Department of Pediatrics, Mount Sinai Kravis Children's Hospital, New York City and Investigator on the ILLUMINATE-A trial. "Thus, unilateral and bilateral improvements in nephrocalcinosis in some patients treated with OXLUMO are a welcome observation and are consistent with our expectation of the potential clinical impact of a sustained and substantial reduction in urinary oxalate levels."

    "We are thrilled to be presenting positive nephrocalcinosis data from our ILLUMINATE-A study," said Pushkal Garg, M.D., Chief Medical Officer at Alnylam. "These early data provide emerging evidence demonstrating improvements in nephrocalcinosis in some patients. Notably, the majority of patients with baseline nephrocalcinosis and available ultrasounds experienced improvement, often in both kidneys, after 12 months of treatment – an encouraging sign indicating the potential of OXLUMO to improve renal outcome measures in patients with PH1. We look forward to reporting additional data later in the year."

    Results

    Among 24 patients in ILLUMINATE-A who had been treated with lumasiran for 12 months and had valid renal ultrasounds at baseline, 46 percent (11/24) of patients experienced improvement in nephrocalcinosis grade relative to baseline, 17 percent (4/24) remained stable, and 13 percent (3/24) experienced worsening; 25 percent (6/24) did not have ultrasounds available at 12 months. Of 14 patients with baseline nephrocalcinosis and available ultrasounds, 79 percent (11/14) showed improvement relative to baseline, and of those who improved, 73 percent (8/11) improved in both kidneys. Additional data were presented regarding effects on estimated glomerular filtration rate (eGFR) and kidney stone events.

    To view the full results presented at the virtual ASPN congress, please visit www.alnylam.com/capella.

    IMPORTANT SAFETY INFORMATION

    Adverse Reactions

    The most common adverse reaction that occurred in patients treated with OXLUMO was injection site reaction (38%). Symptoms included erythema, pain, pruritus, and swelling.

    Pregnancy and Lactation

    No data are available on the use of OXLUMO in pregnant women. No data are available on the presence of OXLUMO in human milk or its effects on breastfed infants or milk production. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for OXLUMO and any potential adverse effects on the breastfed child from OXLUMO or the underlying maternal condition.

    For additional information about OXLUMO, please see the full Prescribing Information.

    About OXLUMO® (lumasiran)

    OXLUMO is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients. HAO1 encodes glycolate oxidase (GO), an enzyme upstream of the disease-causing defect in PH1. OXLUMO works by degrading HAO1 messenger RNA and reducing the synthesis of GO, which inhibits hepatic production of oxalate – the toxic metabolite responsible for the clinical manifestations of PH1. In the pivotal ILLUMINATE-A study, OXLUMO was shown to significantly reduce levels of urinary oxalate relative to placebo, with the majority of patients reaching normal or near-normal levels. Injection site reactions (ISRs) were the most common drug-related adverse reaction. In the ILLUMINATE-B pediatric Phase 3 study, OXLUMO demonstrated an efficacy and safety profile consistent with that observed in ILLUMINATE-A. OXLUMO utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc conjugate technology designed to increase potency and durability. OXLUMO is administered via subcutaneous injection once monthly for three months, then once quarterly thereafter at a dose based on actual body weight. For patients who weigh less than 10 kg, ongoing dosing remains monthly. OXLUMO should be administered by a healthcare professional. For more information about OXLUMO, visit OXLUMO.com.

    About ILLUMINATE-A Phase 3 Study

    ILLUMINATE-A (NCT03681184) is a six-month randomized, double-blind, placebo-controlled, global, multicenter Phase 3 study (with a 54-month extension period) to evaluate the efficacy and safety of lumasiran in 39 patients, age six and older, with a documented diagnosis of PH1. Patients were randomized 2:1 to receive three monthly doses of lumasiran or placebo followed by quarterly doses at 3 mg/kg. The primary endpoint was the percent change in 24-hour urinary oxalate excretion from baseline to the average of months 3 to 6 in the patients treated with lumasiran as compared to placebo. Treatment arms were stratified at randomization based upon mean 24-hour urinary oxalate during screening (≤1.7 or >1.7 mmol/24hr/1.73m2). Key secondary and exploratory endpoints were designed to evaluate additional measures of urinary oxalate, plasma oxalate, estimated glomerular filtration rate (eGFR), nephrocalcinosis, renal stone events, safety and tolerability.

    About ILLUMINATE-B Phase 3 Study

    ILLUMINATE-B (NCT03905694) is a single arm, open-label, multicenter Phase 3 trial to evaluate the efficacy and safety of lumasiran in 18 patients with PH1 under the age of six (range: 3-72 months), with an estimated glomerular filtration rate (eGFR) of greater than 45 mL/min/1.73 m2 or normal serum creatinine if less than 12 months old, at nine study sites, in five countries around the world. Lumasiran was administered according to a weight-based dosing regimen. The primary efficacy endpoint of the study was the percent change from baseline to Month 6 in spot urinary oxalate:creatinine ratio averaged across Months 3 to 6. At six months, relative to baseline, lumasiran demonstrated a clinically meaningful reduction in spot urinary oxalate:creatinine ratio. Reduction of urinary oxalate relative to baseline was consistent across all three body weight categories (less than 10 kg; 10 kg to less than 20 kg, and 20 kg or higher).

    About Primary Hyperoxaluria Type 1 (PH1)

    PH1 is an ultra-rare genetic disease that affects an estimated one to three individuals per million in the United States and Europe. PH1 is characterized by oxalate overproduction in the liver. The excess oxalate results in the deposition of calcium oxalate crystals in the kidneys and urinary tract and can lead to the formation of painful and recurrent kidney stones and nephrocalcinosis. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium oxalate deposition in the kidneys, and urinary obstruction by calcium oxalate stones. PH1 is associated with a progressive decline in kidney function, which exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and deposition of oxalate in bones, eyes, skin, and heart, leading to severe illness and death. Management options to date were limited to hyperhydration, crystallization inhibitors and, in a minority of patients with a specific genotype, pyridoxine (vitamin B6). These measures do not adequately address oxalate overproduction but instead help to delay inevitable progression to kidney failure and the need for intensive dialysis as a bridge to a dual or sequential liver/kidney transplant. Liver transplantation is the only intervention that addresses the underlying metabolic defect, but is associated with high morbidity and mortality, and life-long immunosuppression. Until today, there were no approved pharmaceutical therapies for PH1.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's future expectations, plans and prospects, including, without limitation, Alnylam's views with respect to the safety and efficacy of OXLUMO as demonstrated after 12-months of treatment in the ILLUMINATE-A Phase 3 study and expectations regarding the timing for reporting additional data on clinical outcomes measures, the potential clinical impact of treatment with OXLUMO as demonstrated by unilateral and bilateral improvements in nephrocalcinosis in some patients, and Alnylam's ability to achieve its "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the potential impact of current and the risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

    This release discusses the use of a previously approved RNAi therapeutic in continued development and is not intended to convey conclusions about efficacy or safety as to these uses. There is no guarantee that the data described in this release will result in expanded use of this commercial product, will successfully complete clinical development or will gain health authority approval.

    Footnotes:

    1See About ILLUMINATE-B for patient population and study endpoints

    2See About ILLUMINATE-A for patient population and study endpoints

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  18. − Achieved First Quarter 2021 Combined Net Product Revenues of $136 Million for ONPATTRO®, GIVLAARI®, and OXLUMO®

    − Advanced Vutrisiran toward Market with Positive Results from HELIOS-A Phase 3 Study and Submission of New Drug Application (NDA) with U.S. Food and Drug Administration (FDA) –

    – Launched "Alnylam P5x25" Strategy to Deliver Transformative Rare and Prevalent Disease Medicines for Patients Around the World Through Sustainable Innovation and Exceptional Financial Performance –

    – Provides Enrollment Update on HELIOS-B Phase 3 Study of Vutrisiran and Now Expects to Complete Enrollment in Late 2021, Ahead of Previous Expectations –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today reported…

    − Achieved First Quarter 2021 Combined Net Product Revenues of $136 Million for ONPATTRO®, GIVLAARI®, and OXLUMO®

    − Advanced Vutrisiran toward Market with Positive Results from HELIOS-A Phase 3 Study and Submission of New Drug Application (NDA) with U.S. Food and Drug Administration (FDA) –

    – Launched "Alnylam P5x25" Strategy to Deliver Transformative Rare and Prevalent Disease Medicines for Patients Around the World Through Sustainable Innovation and Exceptional Financial Performance –

    – Provides Enrollment Update on HELIOS-B Phase 3 Study of Vutrisiran and Now Expects to Complete Enrollment in Late 2021, Ahead of Previous Expectations –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today reported its consolidated financial results for the first quarter ended March 31, 2021 and reviewed recent business highlights.

    "We are extremely pleased with the commercial performance of our marketed products in the first quarter, reflecting strong execution by our global commercial teams. In particular, we achieved steady and continued growth for ONPATTRO with approximately 13% quarterly growth and we observed strong initial demand for OXLUMO in its first full quarter of launch. We also presented positive results from the HELIOS-A Phase 3 study of vutrisiran, and with our recent NDA filing we are one step closer to potentially bringing this transformative medicine to patients. Given the strong pace of enrollment in the HELIOS-B Phase 3 study of vutrisiran, we are announcing today that we expect to complete study enrollment in late 2021, earlier than previously anticipated," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "Finally, early in the quarter we launched our new five-year vision, ‘Alnylam P5x25,' marking our strategy for a planned transition to a top five biotech company in market capitalization by the end of 2025. With Alnylam P5x25, we aim to deliver transformative medicines for rare and prevalent diseases to patients around the world, while advancing a robust and high-yielding pipeline of first and/or best-in-class clinical programs from our organic product engine, while delivering strong topline growth and profitability within the period."

    First Quarter 2021 and Recent Significant Corporate Highlights

    Commercial Performance

    ONPATTRO®

    • Achieved global net product revenues for the first quarter of 2021 of $102 million, representing 13% growth compared to Q4 2020.
    • Attained over 1,500 patients worldwide on commercial ONPATTRO treatment as of March 31, 2021.
    • Secured additional market access with over 30 countries now selling ONPATTRO through direct reimbursement, named patient sales, or reimbursed expanded access.

    GIVLAARI®

    • Achieved global net product revenues for the first quarter of 2021 of $25 million, representing 11% growth compared to Q4 2020.
    • Attained approximately 225 patients worldwide on commercial GIVLAARI treatment as of March 31, 2021.
    • Received marketing authorization approval for GIVLAARI in Switzerland for the treatment of acute hepatic porphyria in adults and adolescents.
    • Continued strong progress toward establishing value-based agreements (VBAs), with over 10 VBAs finalized to date with commercial payers and confirmed access for over 98% of covered U.S. lives.
    • Maintained steady progress with market access efforts across the CEMEA region, with recent launch in Italy, ongoing launch in Germany, Temporary Authorization for Use (ATU) supply in France, and named patient sales in other countries.

    OXLUMO®

    • Achieved global net product revenues for the first quarter of 2021 of $9 million, representing strong initial demand in the first full quarter of the OXLUMO launch.
    • Received over 30 Start Forms in the U.S. and attained approximately 50 patients on commercial OXLUMO treatment in the U.S. and EU from launch through March 31, 2021.
    • Continued strong progress toward establishing VBAs, with over 5 VBAs finalized to date with commercial payers and confirmed access for about two thirds of covered U.S. lives.
    • Continued progress with market access efforts across the CEMEA region, with recent launch in Germany, ATU supply in France, and named patient sales in other countries.

    R&D Highlights

    Patisiran (the non-proprietary name for ONPATTRO), in development for the treatment of the cardiomyopathy of both hereditary and wild-type ATTR amyloidosis

    • Continued enrollment in the APOLLO-B Phase 3 study in ATTR amyloidosis patients with cardiomyopathy and remain on track to complete enrollment in early 2021.

    Vutrisiran, a subcutaneously administered investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis

    • Filed a NDA with the FDA.
    • Presented positive 9-month results from the HELIOS-A Phase 3 study.
    • Announces today that due to strong pace of enrollment in the HELIOS-B Phase 3 study, the Company now expects to complete study enrollment in late 2021, earlier than previously anticipated.

    Lumasiran (the non-proprietary name for OXLUMO), for the treatment of primary hyperoxaluria type 1 (PH1)

    • Continued dosing PH1 patients with advanced renal disease in the ILLUMINATE-C Phase 3 study, and remain on track to report topline results in mid-2021.

    Inclisiran (the non-proprietary name for Leqvio®) for the treatment of hypercholesterolemia or mixed dyslipidemia, in collaboration with Novartis

    • Response to U.S. Complete Response Letter to be submitted Q2-Q3 2021.
    • ORION-4 readout expected 2026 due to COVID-19.

    Fitusiran, in development for the treatment of hemophilia A or B with and without inhibitors, in collaboration with Sanofi

    • The amended protocol for all ongoing adult and adolescent fitusiran clinical studies, aimed at further enhancing the benefit-risk profile, was presented at the 14th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD).

    Early- and mid-stage RNAi therapeutic pipeline programs

    • Continued enrollment and dosing in the Phase 2 study of cemdisiran monotherapy in IgA nephropathy, and continued dosing in a Phase 1 study of combination therapy with pozelimab, an anti-C5 monoclonal antibody, in collaboration with Regeneron.
    • Alnylam's partner Vir Biotechnology continued enrollment and dosing in a Phase 2 combination trial of ALN-HBV02 (VIR-2218) with pegylated interferon-alpha (PEG-IFN-α).
    • Presented updated positive interim results from the Phase 1 study of ALN-AGT, in development for the treatment of hypertension.
    • Continued enrollment and dosing in the Phase 1 study of ALN-HSD, in development for the treatment of non-alcoholic steatohepatits (NASH) , in collaboration with Regeneron.
    • Continued progress with investigational RNAi therapeutics for CNS and ocular diseases, including advancement of ALN-APP, in development for the treatment of autosomal dominant Alzheimer's Disease (ADAD) and cerebral amyloid angiopathy (CAA), with an expected CTA filing in mid-2021, in collaboration with Regeneron.

    Additional Business Updates

    Upcoming Events

    In mid-2021, Alnylam intends to:

    • Complete enrollment in the APOLLO-B Phase 3 study of patisiran
    • Initiate a study of vutrisiran administered biannually
    • File a CTA for ALN-APP
    • Achieve marketing authorization for GIVLAARI in Japan
    • Achieve marketing authorization for OXLUMO in Brazil
    • Report topline results from the ILLUMINATE-C Phase 3 study of lumasiran
    • Initiate KARDIA Phase 2 studies of ALN-AGT

    Financial Results for the Quarter Ended March 31, 2021

    "We continued to see strong performance from our commercial products in the first quarter of 2021, and are pleased with the impact that our three wholly owned products are having on patients around the world," said Jeff Poulton, Chief Financial Officer of Alnylam. "We are reiterating our guidance that we expect to achieve between $610 million and $660 million in combined net product revenues across our three wholly owned commercial brands for the full year 2021. Through strong topline growth, and by continuing to demonstrate disciplined investment in our operations, we believe that we are effectively transitioning toward achieving a self-sustainable financial profile in line with our Alnylam P5x25 strategy."

    Financial highlights

    (in thousands, except per share amounts)

     

     

    Three Months Ended March 31,

     

     

    2021

     

    2020

     

     

     

     

     

    Net product revenues

     

    $

    135,769

     

     

    $

    71,938

     

    ONPATTRO net product revenues

     

    $

    101,951

     

     

    $

    66,664

     

    GIVLAARI net product revenues

     

    $

    24,673

     

     

    $

    5,274

     

    OXLUMO net product revenues

     

    $

    9,145

     

     

    $

     

     

     

     

     

     

    Net revenue from collaborations

     

    $

    41,797

     

     

    $

    27,538

     

     

     

     

     

     

    GAAP operating loss

     

    $

    (186,254)

     

     

    $

    (210,158)

     

    Non-GAAP operating loss

     

    $

    (130,564)

     

     

    $

    (175,580)

     

     

     

     

     

     

    GAAP net loss

     

    $

    (200,291)

     

     

    $

    (182,221)

     

    Non-GAAP net loss

     

    $

    (191,617)

     

     

    $

    (171,754)

     

     

     

     

     

     

    GAAP net loss per common share - basic and diluted

     

    $

    (1.71)

     

     

    $

    (1.62)

     

    Non-GAAP net loss per common share - basic and diluted

     

    $

    (1.64)

     

     

    $

    (1.52)

     

    Net Product Revenues

    • Combined net product revenues increased 89% compared to the first quarter of 2020, primarily due to increased ONPATTRO demand in the U.S. and Europe, the ongoing launch of GIVLAARI, and the initial launch of OXLUMO in the first quarter of 2021.

    Net Revenues from Collaborations

    • Net revenues from collaborations increased 52% compared to the first quarter of 2020, primarily due to an increase in revenue from our collaborations with Regeneron and Novartis.

    First Quarter 2021 Expenses

     

     

    Three Months Ended March 31,

     

     

    2021

     

    2020

     

     

     

     

     

    GAAP research and development expenses

     

    $

    185,899

     

     

    $

    169,571

     

    Non-GAAP research and development expenses

     

    $

    161,524

     

     

    $

    153,522

     

     

     

     

     

     

    GAAP selling, general and administrative expenses

     

    $

    146,859

     

     

    $

    126,761

     

    Non-GAAP selling, general and administrative expenses

     

    $

    115,544

     

     

    $

    108,232

     

     

     

     

     

     

    Research & Development (R&D) Expenses

    • GAAP and Non-GAAP R&D expenses increased compared to the first quarter of 2020 primarily due to increased investment in clinical activities in our late stage programs, and GAAP R&D expenses also increased due to higher performance-based stock expense.

    Selling, General & Administrative (SG&A) Expenses

    • GAAP and Non-GAAP SG&A expenses increased compared to the first quarter of 2020 primarily due to increased investment to support the global growth of our three commercial products, including the initial launch of OXLUMO, and GAAP SG&A expenses also increased due to higher performance-based stock expense.

    Other Financial Highlights

    Total Other (Expense) Income

    • Interest expense was $32.5 million in the first quarter 2021 which included $28.2 million associated with the sale of future royalties and $4.3 million from our long-term debt following the initial $200 million drawdown of our Blackstone credit facility at year-end 2020.
    • Change in the fair value of our development derivative liability associated with our R&D funding arrangement with Blackstone on vutrisiran and ALN-AGT was $22.5 million in the first quarter 2021.

    Cash and Investments

    • Cash, cash equivalents and marketable securities were $1.71 billion as of March 31, 2021 compared to $1.87 billion as of December 31, 2020 with the decrease primarily due to our operating loss in the first quarter of 2021.

    A reconciliation of our GAAP to non-GAAP results for the current quarter is included in the tables of this press release.

    2021 Financial Guidance

    Full year 2021 financial guidance is reiterated and consists of the following:

     

    Combined net product revenues for ONPATTRO,

    GIVLAARI and OXLUMO

     

     

    $610 million - $660 million

     

    Net revenues from collaborations and royalties

     

    $150 million - $200 million

     

    GAAP R&D and SG&A expenses

     

    $1,335 million - $1,455 million

     

    Non-GAAP R&D and SG&A expenses*

     

    $1,175 million - $1,275 million

     

     

     

     

     

    *Excludes $160-$180 million of stock-based compensation expenses from estimated GAAP R&D and SG&A expenses.

    Use of Non-GAAP Financial Measures

    This press release contains non-GAAP financial measures, including expenses adjusted to exclude certain non-cash expenses and non-recurring gains outside the ordinary course of the Company's business. These measures are not in accordance with, or an alternative to, GAAP, and may be different from non-GAAP financial measures used by other companies.

    The items included in GAAP presentations but excluded for purposes of determining non-GAAP financial measures for the periods presented in this press release are stock-based compensation expenses and unrealized gains on marketable equity securities. The Company has excluded the impact of stock-based compensation expense, which may fluctuate from period to period based on factors including the variability associated with performance-based grants for stock options and restricted stock units and changes in the Company's stock price, which impacts the fair value of these awards. The Company has excluded the impact of the unrealized gains on marketable equity securities because the Company does not believe these adjustments accurately reflect the performance of the Company's ongoing operations for the period in which such gains or losses are reported, as their sole purpose is to adjust amounts on the balance sheet.

    The Company believes the presentation of non-GAAP financial measures provides useful information to management and investors regarding the Company's financial condition and results of operations. When GAAP financial measures are viewed in conjunction with non-GAAP financial measures, investors are provided with a more meaningful understanding of the Company's ongoing operating performance and are better able to compare the Company's performance between periods. In addition, these non-GAAP financial measures are among those indicators the Company uses as a basis for evaluating performance, allocating resources and planning and forecasting future periods. Non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between GAAP and non-GAAP measures is provided later in this press release.

    Conference Call Information

    Management will provide an update on the Company and discuss first quarter 2021 results as well as expectations for the future via conference call on Thursday, April 29, 2021 at 8:30 am ET. To access the call, please dial 877-312-7507 (domestic) or +1-631-813-4828 (international) five minutes prior to the start time and refer to conference ID 7986608. A replay of the call will be available beginning at 11:30 am ET on the day of the call. To access the replay, please dial 855-859-2056 (domestic) or +1-404-537-3406 (international) and refer to conference ID 7986608.

    A live audio webcast of the call will be available on the Investors section of the Company's website at www.alnylam.com/events. An archived webcast will be available on the Alnylam website approximately two hours after the event.

    About ONPATTRO® (patisiran)

    ONPATTRO is an RNAi therapeutic that was approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby blocking the production of TTR protein before it is made. ONPATTRO blocks the production of TTR in the liver, reducing its accumulation in the body's tissues in order to halt or slow down the progression of the polyneuropathy associated with the disease. For more information about ONPATTRO, visit ONPATTRO.com.

    ONPATTRO Important Safety Information

    Infusion-Related Reactions

    Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO® (patisiran). In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache.

    To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.

    Reduced Serum Vitamin A Levels and Recommended Supplementation

    ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body.

    Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness).

    Adverse Reactions

    The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory tract infections (29%) and infusion-related reactions (19%).

    For additional information about ONPATTRO, please see the full Prescribing Information.

    About GIVLAARI® (givosiran)

    GIVLAARI is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) approved in the United States and Brazil for the treatment of adults with acute hepatic porphyria (AHP). GIVLAARI is also approved in the European Union for the treatment of AHP in adults and adolescents aged 12 years and older. In the pivotal study, givosiran was shown to significantly reduce the rate of porphyria attacks that required hospitalizations, urgent healthcare visits or intravenous hemin administration at home compared to placebo. GIVLAARI is Alnylam's first commercially available therapeutic based on its Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology to increase potency and durability. GIVLAARI is administered via subcutaneous injection once monthly at a dose based on actual body weight and should be administered by a healthcare professional. GIVLAARI works by specifically reducing elevated levels of aminolevulinic acid synthase 1 (ALAS1) messenger RNA (mRNA), leading to reduction of toxins associated with attacks and other disease manifestations of AHP. For more information about GIVLAARI, visit GIVLAARI.com.

    GIVLAARI Important Safety Information

    Contraindications

    GIVLAARI is contraindicated in patients with known severe hypersensitivity to givosiran. Reactions have included anaphylaxis.

    Anaphylactic Reaction

    Anaphylaxis has occurred with GIVLAARI treatment (<1% of patients in clinical trials). Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms of anaphylaxis. If anaphylaxis occurs, immediately discontinue administration of GIVLAARI and institute appropriate medical treatment.

    Hepatic Toxicity

    Transaminase elevations (ALT) of at least 3 times the upper limit of normal (ULN) were observed in 15% of patients receiving GIVLAARI in the placebo-controlled trial. Transaminase elevations primarily occurred between 3 to 5 months following initiation of treatment.

    Measure liver function tests prior to initiating treatment with GIVLAARI, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter. Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations. In patients who have dose interruption and subsequent improvement, reduce the dose to 1.25 mg/kg once monthly. The dose may be increased to the recommended dose of 2.5 mg/kg once monthly if there is no recurrence of severe or clinically significant transaminase elevations at the 1.25 mg/kg dose.

    Renal Toxicity

    Increases in serum creatinine levels and decreases in estimated glomerular filtration rate (eGFR) have been reported during treatment with GIVLAARI. In the placebo-controlled study, 15% of patients receiving GIVLAARI experienced a renally-related adverse reaction. The median increase in creatinine at Month 3 was 0.07 mg/dL. Monitor renal function during treatment with GIVLAARI as clinically indicated.

    Injection Site Reactions

    Injection site reactions were reported in 25% of patients receiving GIVLAARI in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. One (2%) patient experienced a single, transient, recall reaction of erythema at a prior injection site with a subsequent dose administration.

    Drug Interactions

    Concomitant use of GIVLAARI increases the concentration of CYP1A2 or CYP2D6 substrates, which may increase adverse reactions of these substrates. Avoid concomitant use of GIVLAARI with CYP1A2 or CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP1A2 or CYP2D6 substrate dosage in accordance with approved product labeling.

    Adverse Reactions

    The most common adverse reactions that occurred in patients receiving GIVLAARI were nausea (27%) and injection site reactions (25%).

    For additional information about GIVLAARI, please see full Prescribing Information.

    About OXLUMO® (lumasiran)

    OXLUMO is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients. HAO1 encodes glycolate oxidase (GO), an enzyme upstream of the disease-causing defect in PH1. OXLUMO works by degrading HAO1 messenger RNA and reducing the synthesis of GO, which inhibits hepatic production of oxalate – the toxic metabolite responsible for the clinical manifestations of PH1. In the pivotal ILLUMINATE-A study, OXLUMO was shown to significantly reduce levels of urinary oxalate relative to placebo, with the majority of patients reaching normal or near-normal levels. Injection site reactions (ISRs) were the most common drug-related adverse reaction. In the ILLUMINATE-B pediatric Phase 3 study, OXLUMO demonstrated an efficacy and safety profile consistent to that observed in ILLUMINATE-A. OXLUMO utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc conjugate technology designed to increase potency and durability. OXLUMO is administered via subcutaneous injection once monthly for three months, then once quarterly thereafter at a dose based on actual body weight. For patients who weigh less than 10 kg, ongoing dosing remains monthly. OXLUMO should be administered by a healthcare professional. For more information about OXLUMO, visit OXLUMO.com.

    OXLUMO Important Safety Information

    Adverse Reactions

    The most common adverse reaction that occurred in patients treated with OXLUMO was injection site reaction (38%). Symptoms included erythema, pain, pruritus, and swelling.

    Pregnancy and Lactation

    No data are available on the use of OXLUMO in pregnant women. No data are available on the presence of OXLUMO in human milk or its effects on breastfed infants or milk production. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for OXLUMO and any potential adverse effects on the breastfed child from OXLUMO or the underlying maternal condition.

    For additional information about OXLUMO, please see the full Prescribing Information.

    About LNP Technology

    Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), and OXLUMO® (lumasiran), as well as Leqvio® (inclisiran), which is being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's expectations, plans and prospects, including, without limitation, its plans for additional global regulatory filings and the continuing product launches of its approved products and expectations regarding reimbursement for those products in various territories, expectations regarding FDA review of inclisiran, conditions at the third party manufacturer where inclisiran is manufactured and the expected timing of resubmission of the inclisiran NDA by Novartis, the achievement of additional pipeline milestones, including relating to ongoing clinical studies of patisiran and vutrisiran and the expected timing for completion of study enrollment in the APOLLO-B and HELIOS-B Phase 3 studies, lumasiran and the timing of topline results from the ILLUMINATE-C Phase 3 study, the expected timing for filing a CTA for ALN-APP, expectations relating to continued revenue growth for its approved products and the expected range of net product revenues and net revenues from collaborations and royalties for 2021, the expected range of aggregate annual GAAP and non-GAAP R&D and SG&A expenses, and expectations regarding Alnylam's ability to achieve its "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the potential impact of a current government investigation and the risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

    This release discusses investigational RNAi therapeutics and uses of previously approved RNAi therapeutics in development and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics or uses. There is no guarantee that any investigational therapeutics or expanded uses of commercial products will successfully complete clinical development or gain health authority approval.

    ALNYLAM PHARMACEUTICALS, INC.

    CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS

    (In thousands, except per share amounts)

    (Unaudited)

       

     

     

    Three Months Ended

     

     

    March 31,

    2021

     

    March 31,

    2020

    Statements of Operations

     

     

     

     

    Revenues:

     

     

     

     

    Net product revenues

     

    $

    135,769

     

     

    $

    71,938

     

    Net revenues from collaborations

     

    41,797

     

     

    27,538

     

    Total revenues

     

    177,566

     

     

    99,476

     

     

     

     

     

     

    Operating costs and expenses:

     

     

     

     

    Cost of goods sold

     

    23,023

     

     

    13,302

     

    Cost of collaborations

     

    8,039

     

     

     

    Research and development

     

    185,899

     

     

    169,571

     

    Selling, general and administrative

     

    146,859

     

     

    126,761

     

    Total operating costs and expenses

     

    363,820

     

     

    309,634

     

    Loss from operations

     

    (186,254)

     

     

    (210,158)

     

    Other (expense) income:

     

     

     

     

    Interest expense

     

    (32,515)

     

     

     

    Interest income

     

    450

     

     

    5,480

     

    Other income, net

     

    19,044

     

     

    23,032

     

    Total other (expense) income

     

    (13,021)

     

     

    28,512

     

    Loss before income taxes

     

    (199,275)

     

     

    (181,646)

     

    Provision for income taxes

     

    (1,016)

     

     

    (575)

     

    Net loss

     

    $

    (200,291)

     

     

    $

    (182,221)

     

    Net loss per common share - basic and diluted

     

    $

    (1.71)

     

     

    $

    (1.62)

     

    Weighted-average common shares used to compute basic and

    diluted net loss per common share

     

    117,080

     

     

    112,748

     

     

     

     

     

     

    ALNYLAM PHARMACEUTICALS, INC.

    RECONCILIATION OF SELECTED GAAP MEASURES TO NON-GAAP MEASURES

    (In thousands, except per share amounts)

       

     

     

    Three Months Ended

     

     

    March 31,

    2021

     

    March 31,

    2020

    Reconciliation of GAAP to Non-GAAP research and development:

     

     

     

     

    GAAP Research and development

     

    $

    185,899

     

     

    $

    169,571

     

    Less: Stock-based compensation expenses

     

    (24,375)

     

     

    (16,049)

     

    Non-GAAP Research and development

     

    $

    161,524

     

     

    $

    153,522

     

     

     

     

     

     

    Reconciliation of GAAP to Non-GAAP selling, general and administrative:

     

     

     

     

    GAAP Selling, general and administrative

     

    $

    146,859

     

     

    $

    126,761

     

    Less: Stock-based compensation expenses

     

    (31,315)

     

     

    (18,529)

     

    Non-GAAP Selling, general and administrative

     

    $

    115,544

     

     

    $

    108,232

     

     

     

     

     

     

    Reconciliation of GAAP to Non-GAAP operating loss:

     

     

     

     

    GAAP operating loss

     

    $

    (186,254)

     

     

    $

    (210,158)

     

    Add: Stock-based compensation expenses

     

    55,690

     

     

    34,578

     

    Non-GAAP operating loss

     

    $

    (130,564)

     

     

    $

    (175,580)

     

     

     

     

     

     

    Reconciliation of GAAP to Non-GAAP net loss:

     

     

     

     

    GAAP net loss

     

    $

    (200,291)

     

     

    $

    (182,221)

     

    Add: Stock-based compensation expenses

     

    55,690

     

     

    34,578

     

    Less: Unrealized gain on marketable equity securities

     

    (47,016)

     

     

    (24,111)

     

    Non-GAAP net loss

     

    $

    (191,617)

     

     

    $

    (171,754)

     

     

     

     

     

     

    Reconciliation of GAAP to Non-GAAP net loss per common share-basic and diluted:

     

     

     

     

    GAAP net loss per common share - basic and diluted

     

    $

    (1.71)

     

     

    $

    (1.62)

     

    Add: Stock-based compensation expenses

     

    0.48

     

     

    0.31

     

    Less: Unrealized gain on marketable equity securities

     

    (0.40)

     

     

    (0.21)

     

    Non-GAAP net loss per common share - basic and diluted

     

    $

    (1.64)

     

     

    $

    (1.52)

     

     

     

     

     

     

    Please note that the figures presented above may not sum exactly due to rounding

    ALNYLAM PHARMACEUTICALS, INC.

    CONDENSED CONSOLIDATED BALANCE SHEETS

    (In thousands, except share amounts)

    (Unaudited)

     

     

     

     

    March 31, 2021

    December 31, 2020

    Cash, cash equivalents, and marketable debt and equity securities

    $

    1,709,537

     

    $

    1,874,395

     

    Restricted investments

    40,725

     

    40,725

     

    Accounts receivable, net

    110,626

     

    102,413

     

    Inventory

    91,040

     

    92,302

     

    Prepaid expenses and other assets

    101,556

     

    90,712

     

    Property, plant and equipment, net

    464,572

     

    465,029

     

    Operating lease right-of-use lease assets

    237,213

     

    241,485

     

    Receivable related to the sale of future royalties

    500,000

     

    500,000

     

    Total assets

    $

    3,255,269

     

    $

    3,407,061

     

    Accounts payable, accrued expenses and other liabilities

    $

    386,369

     

    $

    445,783

     

    Total deferred revenue

    324,463

     

    352,301

     

    Operating lease liability

    326,932

     

    329,911

     

    Liability related to the sale of future royalties

    1,099,725

     

    1,071,541

     

    Long-term debt

    191,590

     

    191,278

     

    Total stockholders' equity (117.3 million shares issued and

    outstanding at March 31, 2021; 116.4 million shares issued and

    outstanding at December 31, 2020)

    926,190

     

    1,016,247

     

    Total liabilities and stockholders' equity

    $

    3,255,269

     

    $

    3,407,061

     

    This selected financial information should be read in conjunction with the consolidated financial statements and notes thereto included in Alnylam's Annual Report on Form 10-K which includes the audited financial statements for the year ended December 31, 2020.

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  19. – At 9 Months, Vutrisiran Met Primary and All Secondary Endpoints, with Statistically Significant Improvements in Neuropathy, Quality of Life (QoL), and Gait Speed, Relative to Placebo –

    – In Majority of Patients, Vutrisiran Showed Reversal of Polyneuropathy Manifestations with Improvements in Neuropathy and QoL, Relative to Baseline –

    – Vutrisiran Also Met Key Exploratory Endpoints Including Measures of Nutritional Status, Overall Disability, and Cardiac Biomarker (NT-proBNP), Relative to Placebo –

    – Vutrisiran Demonstrated Encouraging Safety and Tolerability Profile –

    – In Addition, Alnylam Submits New Drug Application (NDA) with U.S. Food and Drug Administration (FDA) for Vutrisiran for the Treatment of the Polyneuropathy of Hereditary

    – At 9 Months, Vutrisiran Met Primary and All Secondary Endpoints, with Statistically Significant Improvements in Neuropathy, Quality of Life (QoL), and Gait Speed, Relative to Placebo –

    – In Majority of Patients, Vutrisiran Showed Reversal of Polyneuropathy Manifestations with Improvements in Neuropathy and QoL, Relative to Baseline –

    – Vutrisiran Also Met Key Exploratory Endpoints Including Measures of Nutritional Status, Overall Disability, and Cardiac Biomarker (NT-proBNP), Relative to Placebo –

    – Vutrisiran Demonstrated Encouraging Safety and Tolerability Profile –

    – In Addition, Alnylam Submits New Drug Application (NDA) with U.S. Food and Drug Administration (FDA) for Vutrisiran for the Treatment of the Polyneuropathy of Hereditary ATTR (hATTR) Amyloidosis in Adults –

    – Company to Host Conference Call Today at 4:00 pm ET –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced full positive results from the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis, which met its primary and both secondary endpoints at nine months in patients with hereditary ATTR (hATTR) amyloidosis with polyneuropathy. The results were presented today in an oral session at the 2021 American Academy of Neurology (AAN) Virtual Annual Meeting.

    The 9-month results achieved the study's primary endpoint, with vutrisiran showing improvement in the mean change from baseline in the modified Neuropathy Impairment Score (mNIS+7) as compared to external placebo data from the APOLLO Phase 3 study of patisiran. At 9 months vutrisiran also met all secondary endpoints, demonstrating improvement in quality of life as assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) instrument and improvement in gait speed as assessed by the timed 10-meter walk test (10-MWT), both compared to the external placebo group. The majority of patients experienced improvement in neuropathy and in quality of life, both relative to baseline, showing the potential for vutrisiran to reverse polyneuropathy manifestations of hATTR amyloidosis. Vutrisiran also demonstrated an encouraging safety profile with no drug-related discontinuations or deaths. Based on these positive data, Alnylam has submitted a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for the approval of vutrisiran for the treatment of the polyneuropathy of hATTR amyloidosis in adults.

    "The HELIOS-A study results demonstrate that vutrisiran improves neuropathy, quality of life and gait speed as soon as 9 months – compared to the external placebo arm of APOLLO – in patients with hATTR amyloidosis with polyneuropathy, with an encouraging safety and tolerability profile. The reversal of polyneuropathy manifestations of disease demonstrated in patients treated with vutrisiran in the study, the encouraging safety profile, and the totality of data from the trial, reinforce our belief in the promise of our RNAi therapeutics' mechanism of action, as first established with ONPATTRO® (patisiran). Further, we are encouraged by the exploratory endpoint results showing the impact of vutrisiran on NT-proBNP, a marker of cardiac stress, and look forward to additional data on exploratory cardiac endpoints at the 18-month readout, expected in late 2021," said Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. "With our NDA filing now completed, we look forward to potentially bringing vutrisiran to patients as a new treatment option for the polyneuropathy of hATTR amyloidosis with subcutaneous administration and quarterly dosing. The positive HELIOS-A study and our NDA filing are key milestones as we continue our progress towards building an industry-leading franchise of medicines for the treatment of ATTR amyloidosis and towards our goal of expanding in the future the population of patients who may benefit from treatment with an RNAi therapeutic."

    HELIOS-A Study Results

    At 9 months, vutrisiran met the primary and all secondary endpoints in HELIOS-A, specifically:

    • Vutrisiran achieved a rapid and sustained reduction in serum TTR levels with an 83 percent mean steady-state serum TTR reduction from baseline.
      • Consistent results in serum TTR level reduction were observed between the vutrisiran and patisiran arms of HELIOS-A, aligned with the therapeutic hypothesis.
    • Vutrisiran treatment (N=122) resulted in a 2.24 point mean decrease (improvement) in mNIS+7 score from baseline at 9 months as compared to a 14.76 point mean increase (worsening) reported for the external placebo group (N=77), resulting in a 17.0 point mean difference relative to placebo (p equal to 3.54x10-12).
      • Improvement in mNIS+7 from vutrisiran treatment was also consistently observed across all pre-specified patient subgroups, including age, sex, race, geographic region, baseline neuropathy impairment, genotype, prior TTR stabilizer use, baseline Familial Amyloid Polyneuropathy (FAP) stage, and inclusion in the pre-specified cardiac subpopulation.
      • Patients randomized to the patisiran reference arm in HELIOS-A showed results consistent with the vutrisiran arm.
    • Vutrisiran treatment resulted in a 3.3 point mean decrease (improvement) in Norfolk QoL-DN score from baseline at 9 months as compared to a 12.9 point mean increase (worsening) reported for the external placebo group, resulting in a mean 16.2 point difference relative to placebo (p equal to 5.43x10-9).
    • Patients treated with vutrisiran remained stable in gait speed (mean decrease of 0.001 meters/second in 10-MWT), while patients in the external placebo group demonstrated worsening (mean decrease of 0.133 meters/second in 10-MWT) (p equal to 3.10x10-5).
    • Improvement in the exploratory cardiac endpoint, NT-proBNP, a measure of cardiac stress, was observed in the vutrisiran arm in both the pre-specified cardiac sub-population and the modified intent-to-treat (mITT) population, relative to the external placebo group.
      • The cardiac subpopulation was defined as patients who had pre-existing evidence of cardiac amyloid involvement (baseline left ventricular wall thickness ≥1.3 cm and no aortic valve disease or hypertension in medical history). NT-proBNP adjusted geometric fold change from baseline was 0.95 for the vutrisiran cardiac subpopulation group (N=35) and 1.60 for the external placebo cardiac subpopulation (N=34) group, with an adjusted geometric fold change ratio of 0.60 (p equal to 0.0016) in favor of vutrisiran.
      • Similar results from baseline were seen in the mITT population in favor of vutrisiran relative to the external placebo group (p equal to 9.20x10-7).
    • In addition, vutrisiran demonstrated improvements in other exploratory endpoints measured at 9 months, including change from baseline in modified body mass index (mBMI) and the Rasch-built overall disability scale (R-ODS), relative to external placebo.

    In the study and as previously reported with topline results from the HELIOS-A study, vutrisiran demonstrated an encouraging safety and tolerability profile relative to placebo with 9 months of dosing and there were no drug-related discontinuations or deaths. There were two study discontinuations (1.6 percent) due to adverse events in the vutrisiran arm by Month 9, both due to death, neither of which was considered related to study drug. There were two serious adverse events (SAEs) considered related to vutrisiran by the study investigator, consisting of dyslipidemia and urinary tract infection. Treatment emergent adverse events (AEs) occurring in 10 percent or more patients included diarrhea, pain in extremity, fall, and urinary tract infections, with each of these events occurring at a similar or lower rate as compared with external placebo arm. Injection site reactions (ISRs) were reported in five patients (4.1 percent) and were all mild and transient. There were no safety signals regarding hematology, renal function or liver function tests (LFTs).

    "The results of the HELIOS-A Phase 3 study underscore the potential of vutrisiran as an attractive new treatment option that can be administered subcutaneously once every three months, considerably simplifying the treatment for patients with hATTR amyloidosis with polyneuropathy, a progressive, life-threatening, multi-system disease," said David Adams, M.D., Ph.D., Department of Neurology, Bicetre hospital, Greater Paris University Hospitals, AP-HP, University Paris Saclay and Principal Investigator for the HELIOS-A trial. "The data released today are encouraging for the amyloidosis community who suffer from this devastating disease as we continue to see exciting progress from ongoing research focused on meeting the needs of this diverse group of patients."

    Regulatory Submissions

    Alnylam also announced that it has submitted an NDA to the U.S. FDA for the approval of vutrisiran for the treatment of the polyneuropathy of hATTR amyloidosis in adults. Vutrisiran has been granted Orphan Drug Designation in the U.S. and the European Union (EU) for the treatment of ATTR amyloidosis. Vutrisiran has also been granted a Fast-Track designation in the U.S. for the treatment of the polyneuropathy of hATTR amyloidosis in adults. The Company plans to follow the FDA submission with regulatory filings in Brazil and Japan. The Company also plans to submit a Marketing Authorisation Application (MAA) in the EU upon obtaining the results of the 18-month analysis from the HELIOS-A Phase 3 Study, as previously aligned with the European Medicines Agency (EMA).

    Conference Call

    Alnylam management will discuss the full 9-month results from the HELIOS-A Phase 3 clinical trial via conference call on Monday, April 19th at 4:00 pm ET. A webcast presentation will also be available on the Investors page of the Company's website, www.alnylam.com. To access the call, please dial 877-312-7507 (domestic) or +1-631-813-4828 (international) five minutes prior to the start time and refer to conference ID 9580096. A replay of the call will be available beginning at 7:00 pm ET on the day of the call. To access the replay, please dial 855-859-2056 (domestic) or +1-404-537-3406 (international) and refer to conference ID 9580096.

    About Vutrisiran

    Vutrisiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hereditary (hATTR) and wild-type (wtATTR) amyloidosis. It is designed to target and silence specific messenger RNA, blocking the production of wild-type and variant transthyretin (TTR) protein before it is made. Quarterly administration of vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues. Vutrisiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability that allows for infrequent subcutaneous injections. The safety and efficacy of vutrisiran have not been evaluated by the U.S. Food and Drug Administration, European Medicines Agency or any other health authority.

    About HELIOS-A Phase 3 Study

    HELIOS-A (NCT03759379) is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran. The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries. Patients were randomized 3:1 to receive either 25mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (as a reference comparator) for 18 months. The primary endpoint is the change from baseline in mNIS+7 score at 9 months, relative to an external placebo group (APOLLO). Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT, relative to an external placebo group. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at 9 months. The efficacy results of vutrisiran in HELIOS-A are compared to the placebo group from the landmark APOLLO Phase 3 study, which evaluated the efficacy and safety of patisiran in a patient population similar to that studied in HELIOS-A. Additional secondary endpoints at 18 months will be evaluated in the HELIOS-A study, including change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum transthyretin (TTR) levels. Additional exploratory cardiac endpoint data at the 18-month time point will be evaluated, including NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging. Following the 18-month study period, all patients are eligible to receive vutrisiran for an additional 18 months as part of an open-label extension study.

    About hATTR Amyloidosis

    Hereditary transthyretin (TTR)-mediated amyloidosis (hATTR) is an inherited, progressively debilitating, and fatal disease caused by variants (i.e., mutations) in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis, represents a major unmet medical need with significant morbidity and mortality affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's expectations, plans, aspirations, and goals, including those related to vutrisiran and its potential as a low-dose, once quarterly, subcutaneously administered treatment option with an encouraging safety profile for patients with hATTR amyloidosis with polyneuropathy, encouraging exploratory cardiac endpoint results, the expected timing of regulatory filings for vutrisiran outside the U.S., building an industry-leading franchise in medicines for the treatment of ATTR amyloidosis and further growing the population of hATTR amyloidosis patients with polyneuropathy who may potentially benefit from treatment with an RNAi therapeutic, becoming a leading biotech company, and the achievement of its "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

    This release is not intended to convey conclusions about efficacy or safety as to any investigational RNAi therapeutics or investigational uses of previously approved therapeutics. There is no guarantee that any investigational therapeutics or expanded uses of commercial products will successfully complete clinical development or gain health authority approval.

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  20. Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that it will report financial results for the first quarter ending March 31, 2021 on Thursday, April 29, 2021, before the U.S. financial markets open.

    Management will provide an update on the Company and discuss first quarter 2021 results as well as expectations for the future via conference call on Thursday, April 29, 2021 at 8:30 am ET. To access the call, please dial 877-312-7507 (domestic) or +1-631-813-4828 (international) five minutes prior to the start time and refer to conference ID 7986608. A replay of the call will be available beginning at 11:30 am ET on the day of the call. To access the replay, please dial 855-859-2056 (domestic…

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that it will report financial results for the first quarter ending March 31, 2021 on Thursday, April 29, 2021, before the U.S. financial markets open.

    Management will provide an update on the Company and discuss first quarter 2021 results as well as expectations for the future via conference call on Thursday, April 29, 2021 at 8:30 am ET. To access the call, please dial 877-312-7507 (domestic) or +1-631-813-4828 (international) five minutes prior to the start time and refer to conference ID 7986608. A replay of the call will be available beginning at 11:30 am ET on the day of the call. To access the replay, please dial 855-859-2056 (domestic) or +1-404-537-3406 (international) and refer to conference ID 7986608.

    A live audio webcast of the call will be available on the Investors section of the Company's website at www.alnylam.com/events. An archived webcast will be available on the Alnylam website approximately two hours after the event.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO™ (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

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  21. – Single Doses of Investigational ALN-AGT Achieved Sustained Reductions in Serum Angiotensinogen (AGT) at 12 Weeks Resulting in Reduced Blood Pressure –

    – Durability of AGT Knockdown Supports the Potential of Once Quarterly or Biannual Dosing –

    – ALN-AGT was Generally Well Tolerated, with No Serious Treatment-Related Adverse Events or Study Withdrawals –

    – Data Confirm Potential for AGT Silencing as a Novel Approach for Treatment of Hypertension and Support Initiation of Phase 2 KARDIA Studies Mid-Year –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today positive interim results from the ongoing Phase 1 study of ALN-AGT, a subcutaneous investigational RNAi therapeutic targeting liver-expressed…

    – Single Doses of Investigational ALN-AGT Achieved Sustained Reductions in Serum Angiotensinogen (AGT) at 12 Weeks Resulting in Reduced Blood Pressure –

    – Durability of AGT Knockdown Supports the Potential of Once Quarterly or Biannual Dosing –

    – ALN-AGT was Generally Well Tolerated, with No Serious Treatment-Related Adverse Events or Study Withdrawals –

    – Data Confirm Potential for AGT Silencing as a Novel Approach for Treatment of Hypertension and Support Initiation of Phase 2 KARDIA Studies Mid-Year –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today positive interim results from the ongoing Phase 1 study of ALN-AGT, a subcutaneous investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) for the treatment of hypertension. Results were presented during a late-breaking oral presentation at the 2021 Joint Meeting of the European Society of Hypertension (ESH) and the International Society of Hypertension (ISH). ALN-AGT treatment was associated with dose-dependent knockdown of AGT and reductions in blood pressure (BP) with a durability that supports the potential for a once quarterly or biannual dosing regimen, and was found to be generally safe and well tolerated.

    "We face an intractable challenge in controlling hypertension, which affects an estimated 1.13 billion people worldwide and is a major risk factor for cardiovascular disease morbidity and premature mortality.i Despite well-established treatments including lifestyle modifications and several classes of available anti-hypertensive medications, fewer than 20 percent of people with hypertension globally have it under control,"i said Reinhold Kreutz, M.D., Ph.D., Professor, Charité and Berlin Institute of Health, Institute of Clinical Pharmacology and Toxicology and President, ESH. "While several factors contribute to the high rate of uncontrolled hypertension, inconsistent blood pressure control and medication adherence in those patients receiving treatment may play critical roles, and the encouraging early-stage results for ALN-AGT suggest its potential as a novel therapeutic approach to address long-standing treatment gaps."

    Eighty-four patients with hypertension were randomized in this double-blind, placebo-controlled, single ascending dose (SAD) study evaluating the safety, tolerability and preliminary pharmacokinetic and pharmacodynamic activity of ALN-AGT. Patients, who were either treatment naïve or had discontinued other anti-hypertensive medications prior to study entry, enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg or 800 mg ALN-AGT.

    Patients treated with single doses of ALN-AGT at 100 mg or higher experienced durable reductions in serum AGT of more than 90 percent through 12 weeks. In the 800 mg dose cohort, all patients experienced reductions in serum AGT of 96 – 98 percent at Week 12. Concomitant reductions in BP were observed with AGT knockdown, with clinically meaningful mean reductions in 24-hour systolic blood pressure (SBP) of >10 mm Hg observed at Week 8 after single doses of 100 mg or higher. At 800 mg, mean reductions in 24-hour SBP of 17 mm Hg were observed at Week 8 (compared to a mean increase of 1 mm Hg in the placebo group) and sustained through Week 12. All data are as of a February 25, 2021 cut-off date.

    Suboptimal BP control remains the most common attributable risk factor for cardiovascular disease and cerebrovascular disease, and a leading cause of chronic kidney disease progression. These durable pharmacologic effects of ALN-AGT may support tonic control of BP with once quarterly and potentially biannual dosing. Less frequent dosing than available with current treatment options may help achieve improved medication adherence, an important part of maintaining BP control.ii

    ALN-AGT was shown to be generally well tolerated with an acceptable safety profile that supports advancement into Phase 2 studies. Most adverse events (AEs) were mild or moderate in severity and resolved without intervention, with the most common AE consisting of mild and transient injection site reactions in 5 out of 56 patients (8.9 percent) receiving ALN-AGT. There were no clinically significant elevations in serum alanine aminotransferase (ALT), serum creatinine or serum potassium, and no patient required intervention for hypotension. There were no treatment-related serious AEs, deaths or AEs leading to study withdrawal.

    "We believe the results for ALN-AGT are highly encouraging and demonstrate the potential of an RNAi therapeutic to help people reach and maintain their blood pressure goals," said Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. "We believe ALN-AGT has the potential to transform the way hypertension is managed, a disease that has been devoid of new therapeutic interventions for decades and remains a major contributing risk factor for stroke, heart attack and sudden death. Based on these findings, we look forward to advancing the clinical program for ALN-AGT with the initiation of Phase 2 KARDIA studies planned in mid-2021."

    To view the data presented at the ESH-ISH 2021 Joint Meeting, please visit www.alnylam.com/capella.

    About ALN-AGT Phase 1 Study

    The Phase 1 study is a multi-center, randomized, double-blind, placebo-controlled, single dose (SD) and active comparator-controlled multiple dose (MD) trial designed to evaluate the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of ALN-AGT in patients with essential hypertension. The study is being conducted in four parts: single ascending dose (SAD) phase in hypertensive patients; SD phase in hypertensive patients with controlled salt intake; MD phase in hypertensive patients who are obese, with once daily oral doses of irbesartan (angiotensin II receptor blocker) used as the active comparator; and open-label SD phase with co-administration of irbesartan in hypertensive patients. Patients will be randomized 2:1 ALN-AGT to placebo or ALN-AGT to irbesartan. The planned enrollment for this study, including optional cohorts, is up to 160 patients.

    About ALN-AGT

    ALN-AGT is an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen (AGT) in development for the treatment of hypertension in high unmet need populations. AGT is the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS), a cascade which has a demonstrated role in blood pressure regulation and whose inhibition has well-established anti-hypertensive effects. ALN-AGT inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin (Ang) II. ALN-AGT utilizes Alnylam's Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, which enables subcutaneous dosing with increased selectivity and a wide therapeutic index. The safety and efficacy of ALN-AGT have not been evaluated by the FDA, EMA or any other health authority.

    About Hypertension

    Hypertension is a complex multifactorial disease clinically defined by most major guidelines as a systolic blood pressure (SBP) of above 140 mm Hg or a diastolic blood pressure (DBP) greater than 90 mm Hg, though AHA/ACC guidelines have a lower threshold of a SBP above 130 mm Hg or a DBP greater than 80 mm Hg. More than one billion people worldwide live with hypertension. In the U.S. alone, approximately 47 percent of adults live with hypertension, with more than half of patients on medication remaining above the blood pressure target level. Despite the availability of anti-hypertensive medications, there remains a significant unmet medical need, especially given the poor rates of adherence to existing therapies and peak and trough effects. In particular, there are a number of high unmet need settings where novel approaches to hypertension are warranted, including resistant and refractory hypertension, chronic kidney disease, and heart failure.

    About RNAi

    RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

    About Alnylam Pharmaceuticals

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO™ (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

    Alnylam Forward Looking Statements

    Various statements in this release concerning Alnylam's future expectations, plans and prospects, including, without limitation, Alnylam's views with respect to the effects of treatment with ALN-AGT in knocking down AGT and reducing BP and the associated safety profile, the durability of ALN-AGT potentially supporting a once quarterly or biannual dosing regimen, the potential of ALN-AGT to transform the way hypertension is managed, expectations regarding the initiation of Phase 2 studies of ALN-AGT, and Alnylam's ability to achieve its "Alnylam P5x25" strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam's business, results of operations and financial condition and the effectiveness or timeliness of Alnylam's efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to successfully expand the indication for ONPATTRO in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

    ____________________________

    i Hypertension. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/hypertension. Published September 2019. Accessed April 2021.

    ii Improving Medication Adherence Among Patients with Hypertension. Million Hearts. https://millionhearts.hhs.gov/data-reports/factsheets/adherence.html. Published April 2020. Accessed April 2021.

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  22. Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that management will present a company overview at the 20th Annual Needham Virtual Healthcare Conference on Tuesday, April 13, 2021 at 1:30 pm ET.

    A live audio webcast of the presentation will be available on the Investors section of the Company's website at www.alnylam.com/events. A replay will be available on the Alnylam website within 48 hours after the event.

    About Alnylam

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system…

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that management will present a company overview at the 20th Annual Needham Virtual Healthcare Conference on Tuesday, April 13, 2021 at 1:30 pm ET.

    A live audio webcast of the presentation will be available on the Investors section of the Company's website at www.alnylam.com/events. A replay will be available on the Alnylam website within 48 hours after the event.

    About Alnylam

    Alnylam (NASDAQ:ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam's commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO™ (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam's partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

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  23. - ILLUMINATE-A Phase 3 Study Evaluated the Efficacy and Safety of Lumasiran in Adult and Pediatric Patients with Primary Hyperoxaluria Type 1 (PH1) -

    - Lumasiran Demonstrated a Clinically Significant Reduction in Urinary Oxalate, a Primary Determinant of Progression to Renal Failure in PH1, Compared to Placebo -

    - Manuscript Marks the Tenth Publication of Clinical Trial Results for Alnylam Programs in The New England Journal of Medicine, Highlighting the Impact of RNAi Therapeutics as a New Class of Medicines -

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that pivotal trial results from the ILLUMINATE-A Phase 3 study of lumasiran, an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1)

    - ILLUMINATE-A Phase 3 Study Evaluated the Efficacy and Safety of Lumasiran in Adult and Pediatric Patients with Primary Hyperoxaluria Type 1 (PH1) -

    - Lumasiran Demonstrated a Clinically Significant Reduction in Urinary Oxalate, a Primary Determinant of Progression to Renal Failure in PH1, Compared to Placebo -

    - Manuscript Marks the Tenth Publication of Clinical Trial Results for Alnylam Programs in The New England Journal of Medicine, Highlighting the Impact of RNAi Therapeutics as a New Class of Medicines -

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that pivotal trial results from the ILLUMINATE-A Phase 3 study of lumasiran, an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) – the gene encoding glycolate oxidase (GO) – for the treatment of primary hyperoxaluria type 1 (PH1), were published online in The New England Journal of Medicine (NEJM). In November 2020, OXLUMO™ (lumasiran) was approved by the U.S. Food and Drug Administration for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients, and received marketing authorization from the European Commission for the treatment of PH1 in all age groups. OXLUMO is the first-ever treatment approved for PH1 and the first RNAi therapeutic evaluated in both children and adults. The full manuscript titled "Phase 3 Trial of Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1," will appear in the April 1, 2021 issue of NEJM.

    The data reported in the ILLUMINATE-A Phase 3 study publication demonstrated that RNAi-mediated targeting of liver GO by lumasiran led to substantial and sustained reductions in urinary oxalate—the toxic metabolite responsible for the debilitating and life-threatening clinical manifestations of PH1. Relative to placebo, treatment with lumasiran resulted in a clinically significant (53.5 percent) reduction in 24-hour urinary oxalate excretion from baseline to month 6 – the primary endpoint of the study.

    Improvements were also observed in a number of secondary endpoints, including the proportion of patients achieving normala or near-normalb levels of urinary oxalate, with 84 percent of lumasiran-treated patients meeting this endpoint compared with no patients (0 percent) on placebo. Patients treated with lumasiran also experienced favorable effects on exploratory endpoints related to nephrocalcinosis and the rate of renal stone eventsc compared with placebo.

    Lumasiran administration was associated with an encouraging safety and tolerability profile, with no serious or severe adverse events (AEs). The most common AEs that occurred more frequently with lumasiran than placebo were injection site reactions (38 versus 0 percent). All injection site reactions were mild and transient and did not result in discontinuation of treatment.

    "PH1 often presents in early life, with kidney stones, nephrocalcinosis, renal failure and, in advanced stages, systemic spread of oxalate throughout the body with life-threatening consequences. Oxalate drives disease manifestations and progression, and is the toxic mediator of end-organ damage in PH1," said Prof. Yaacov Frishberg, M.D., Head of Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel, and lead co-author on the manuscript. "We believe the publication of the ILLUMINATE-A Phase 3 study results in the NEJM is a testament to lumasiran as an oxalate-lowering therapy which is expected to confer significant clinical benefit to children and adults living with this disease."

    "Publication of the ILLUMINATE-A results in NEJM is an exciting achievement, highlighting the tremendous unmet need for novel therapies for this devastating disease and the role lumasiran is playing to fill this need. We are thrilled by the fact that this is now the tenth publication in NEJM on results from clinical studies of Alnylam's RNAi therapeutics, a noteworthy milestone underscoring the impact of RNAi on clinical research and the practice of medicine," said Pritesh J. Gandhi, PharmD., Vice President and General Manager, Lumasiran Program at Alnylam. "We look forward to reporting and publishing additional data from the ILLUMINATE program including in patients under the age of six and those with impaired kidney function later this year."

    A total of 38d of 39 patients completed the ILLUMINATE-A 6-month primary analysis period and all eligible patients transitioned to the study extension period. Results from the 12-Month extension period were presented at the American Society of Nephrology (ASN) virtual congress in October 2020 and demonstrated sustained efficacy with no safety findings leading to discontinuation in the study.

    IMPORTANT SAFETY INFORMATION

    Adverse Reactions

    The most common adverse reaction that occurred in patients treated with OXLUMO was injection site reaction (38%). Symptoms included erythema, pain, pruritus, and swelling.

    Pregnancy and Lactation

    No data are available on the use of OXLUMO in pregnant women. No data are available on the presence of OXLUMO in human milk or its effects on breastfed infants or milk production. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for OXLUMO and any potential adverse effects on the breastfed child from OXLUMO or the underlying maternal condition.

    For additional information about OXLUMO, please see the full Prescribing Information.

    About OXLUMO™ (lumasiran)

    OXLUMO is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients. HAO1 encodes glycolate oxidase (GO), an enzyme upstream of the dis