ALNY Alnylam Pharmaceuticals Inc.

149.87
+1.1  (+1%)
Previous Close 148.77
Open 148.87
52 Week Low 69.11
52 Week High 158.37
Market Cap $17,207,946,160
Shares 114,819,151
Float 82,911,858
Enterprise Value $16,044,267,094
Volume 419,334
Av. Daily Volume 861,046
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Upcoming Catalysts

Drug Stage Catalyst Date
Lumasiran (ALN-GO1) ILLUMINATE-B
Primary Hyperoxaluria Type 1
Phase 3
Phase 3
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Lumasiran (ALN-GO1)
Primary Hyperoxaluria Type 1 (PH1)
PDUFA priority review
PDUFA priority review
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ALN-TTRsc02 - HELIOS-A
ATTR amyloidosis
Phase 3
Phase 3
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Fitusiran (ATLAS)
Hemophilia
Phase 3
Phase 3
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Lumasiran (ALN-GO1) ILLUMINATE-C
Impaired renal function
Phase 3
Phase 3
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Drug Pipeline

Drug Stage Notes
VIR-2218 and pegylated interferon-alpha
Chronic hepatitis B virus (HBV)
Phase 2
Phase 2
Phase 2 trial to commence 2H 2020.
Patisiran APOLLO-B
Wild-type ATTR amyloidosis patients with cardiomyopathy
Phase 3
Phase 3
Phase 3 enrolment to be completed in 2021.
VIR-2703
COVID-19
Phase 1
Phase 1
Human trials to commence around the end of 2020.
ALN-AAT02
alpha-1 anti-trypsin deficiency-associated liver disease
Phase 1/2
Phase 1/2
Phase 1/2 initial data released.
ALN-CC5 (cemdisiran)
IgA nephropathy
Phase 2
Phase 2
Phase 2 trial ongoing.
Inclisiran - ORION-9
Hypercholesterolemia
Phase 3
Phase 3
Phase 3 data met all endpoints - September 25, 2019. Data November 18, 2019 noted LDL-C reductions of 50%.
Inclisiran - ORION-10
Cardiovascular disease (ASCVD)
Phase 3
Phase 3
Phase 3 data met all endpoints - September 25, 2019. Detailed data due at AHA noted 58% LDL-C lowering.
Inclisiran - ORION 11
Cardiovascular disease (ASCVD)
Phase 3
Phase 3
Phase 3 trial met all primary and secondary efficacy endpoints. Noted September 2, 2019 a 54% LDL-C lowering after 11 months and 50% over 18 months.
ALN-TTRsc02 (vutrisiran) - HELIOS-B
ATTR amyloidosis with cardiomyopathy
Phase 3
Phase 3
Phase 3 trial has been initiated - noted November 22, 2019.
ALN-AGT
Hypertension
Phase 1
Phase 1
Phase 1 trial ongoing.
Givosiran
Acute hepatic porphyrias
Approved
Approved
FDA approval announced November 20, 2019.
Patisiran
Familial Amyloidotic Polyneuropathy (FAP) in Patients with ATTR
Approved
Approved
FDA Approval announced August 10, 2018.

Latest News

  1. − Long-Term Givosiran Dosing Showed Sustained Reduction in Annualized Rate of Composite Porphyria Attacks (AAR) With a Median AAR of Zero and Over 60 Percent of Patients Attack-Free in the Open-Label Extension Period −

    − Safety Profile Consistent With That Observed in the 6-Month Double-Blind Period, With No New Safety Findings

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced the presentation of new data from the open-label extension (OLE) period of the ENVISION Phase 3 study, reinforcing the long-term therapeutic benefit of givosiran in patients with acute hepatic porphyria (AHP)—an orphan disease that can be life threatening. The results were presented by study investigator Eliane Sardh…

    − Long-Term Givosiran Dosing Showed Sustained Reduction in Annualized Rate of Composite Porphyria Attacks (AAR) With a Median AAR of Zero and Over 60 Percent of Patients Attack-Free in the Open-Label Extension Period −

    − Safety Profile Consistent With That Observed in the 6-Month Double-Blind Period, With No New Safety Findings

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced the presentation of new data from the open-label extension (OLE) period of the ENVISION Phase 3 study, reinforcing the long-term therapeutic benefit of givosiran in patients with acute hepatic porphyria (AHP)—an orphan disease that can be life threatening. The results were presented by study investigator Eliane Sardh, M.D., Ph.D., during a webinar hosted by Alnylam. In an interim analysis of the OLE period, givosiran, which is approved in the U.S. and EU and marketed as GIVLAARI®, demonstrated sustained efficacy and safety through 12 months of treatment, with evidence for potentially improved efficacy over time.

    "Less than eight months after GIVLAARI's first regulatory approval based on the ENVISION Phase 3 study results, we are pleased to share encouraging new data from our OLE program that we believe continue to support the sustained therapeutic benefit of this RNAi therapeutic. The improvements in daily worst pain and quality of life exploratory endpoints, and consistent safety profile, help us better understand the potential of GIVLAARI to provide ongoing and long-term benefit for patients living with AHP," said Akin Akinc, Ph.D., General Manager of Givosiran at Alnylam. "We remain committed to bringing GIVLAARI to patients with AHP around the world as we pursue marketing authorizations in additional countries and territories."

    The ENVISION Phase 3 study evaluated the efficacy and safety of givosiran in patients with AHP. As previously reported and recently published in the New England Journal of Medicine, givosiran met the primary endpoint in the 6-month double-blind (DB) period, with a 74 percent mean reduction in the annualized rate of composite porphyria attacks (AAR) that required hospitalization, urgent healthcare visit or intravenous hemin administration at home, and a median AAR of 1.0. Givosiran also demonstrated an acceptable safety and tolerability profile in this high unmet need indication. Upon completion of dosing in the DB period, all eligible patients (93 out of 94; 99 percent) enrolled in the OLE period of the trial to receive monthly givosiran at either 2.5 mg/kg or 1.25 mg/kg. A dose of 1.25 mg/kg was initially studied in some patients to generate additional data at a lower dose level; all patients enrolled in the OLE period are now in the process of transitioning to the 2.5 mg/kg dose level, due to evidence for increased efficacy at the higher dose.

    Results at 12 months showed that continued givosiran treatment led to sustained AAR reduction in the OLE period (6-12 months) with a median AAR of 0.0. The proportion of attack-free patients receiving givosiran increased from 50.0 percent in the DB period to 61.7 percent in the first 6 months of the OLE period. Sustained lowering of aminolevulinic acid and porphobilinogen in givosiran patients in the OLE period was accompanied by durable reductions in hemin use, lower levels of patient-reported daily worst pain and ongoing improvements in patient-reported quality of life and ability to function. Patients who crossed over from placebo in the DB period to givosiran in the OLE period experienced a mean reduction in AAR of 76 percent, similar to that experienced by givosiran patients in the DB period. Moreover, placebo crossover patients had reductions in hemin use and lower levels of patient-reported daily worst pain in the OLE period, consistent with the reductions observed in givosiran patients during the DB period.

    The safety profile of givosiran in the OLE period was consistent with that observed in the DB period, and there were no new safety findings. In the combined DB and OLE periods, as of July 23, 2019 (median exposure of 11.2 months), the most common related adverse events (AEs) (reported in at least 10 percent of patients) on givosiran were injection site reactions, nausea and fatigue. Serious AEs (reported in at least 2 percent of patients) included chronic kidney disease in two patients during the DB period (as previously reported) and urinary tract infection in two patients during the OLE period. In the combined DB and OLE periods, hepatic and renal AEs were reported in 16 patients (17 percent) and 10 patients (11 percent), respectively. The majority of AEs were mild or moderate in severity, and there were no new treatment discontinuations due to AEs in the OLE period and no deaths.

    "AHP is a tremendously burdensome disease, characterized by painful, often disabling attacks and chronic symptoms that can greatly impact a patient's ability to function on a daily basis," said Eliane Sardh, M.D., Ph.D., Porphyria Centre Sweden, Centre for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. "In the placebo-controlled period of the ENVISION Phase 3 study, givosiran showed a reduction in AAR and, based on secondary and exploratory measures, an improvement in patients' health status, daily functioning and quality of life. These results, paired with the new long-term efficacy and safety data, provide further evidence that treatment with givosiran has the potential to significantly reduce the high burden of disease for patients and families affected by AHP."

    GIVLAARI was approved by the U.S. Food and Drug Administration for the treatment of adults with AHP in November 2019 and by the European Commission for the treatment of AHP in adults and adolescents 12 years and older in March 2020. It is undergoing priority review by both Health Canada and the Brazilian Health Regulatory Agency (ANVISA).

    To view the presentation recording and materials, please visit www.alnylam.com/capella.

    About the ENVISION Phase 3 Study

    The ENVISION Phase 3 study was a randomized, double-blind (DB), placebo-controlled, global, multicenter trial designed to evaluate the efficacy and safety of givosiran in patients with a documented diagnosis of acute hepatic porphyria (AHP). The primary endpoint of the trial was the annualized rate of composite porphyria attacks (AAR) in patients with acute intermittent porphyria (AIP) over the 6-month DB period. Secondary endpoints included: urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) levels in patients with AIP, AAR in patients with AHP, hemin use and daily worst pain in patients with AIP. The trial enrolled 94 patients with AHP at 36 study sites in 18 countries around the world and is the largest interventional study ever conducted in AHP. Patients were randomized 1:1 to givosiran or placebo, with givosiran administered subcutaneously at 2.5 mg/kg monthly. Upon completion of dosing in the 6-month DB period, 93 out of 94 patients (99 percent) enrolled in the ENVISION open-label extension period to receive givosiran on an ongoing basis.

    About GIVLAARI® (givosiran)

    GIVLAARI is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) approved for the treatment of adults with acute hepatic porphyria (AHP) in the U.S. and for the treatment of AHP in adults and adolescents aged 12 years and older in the EU. In the pivotal ENVISION Phase 3 study, givosiran was shown to significantly reduce the annualized rate of composite porphyria attacks that required hospitalization, urgent healthcare visit 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 ALAS1 messenger RNA, leading to reduction of toxins associated with attacks and other disease manifestations of AHP.

    GIVLAARI® (givosiran) 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 percent 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 percent 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 percent 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 percent of patients receiving GIVLAARI in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. One (2 percent) 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 percent) and injection site reactions (25 percent).

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

    About Acute Hepatic Porphyria

    Acute hepatic porphyria (AHP) refers to a family of ultra-rare, genetic diseases characterized by debilitating, potentially life-threatening attacks and, for some patients, chronic manifestations that negatively impact daily functioning and quality of life. AHP is comprised of four subtypes: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA dehydratase-deficiency porphyria (ADP). Each type of AHP results from a genetic defect leading to a lack of certain enzymes needed to produce heme in the liver, which leads to an accumulation of porphyrins in the body to toxic amounts. AHP disproportionately impacts women of working and childbearing age, and symptoms of the disease vary widely. Severe, unexplained abdominal pain is the most common symptom, which can be accompanied by limb, back, or chest pain, nausea, vomiting, confusion, anxiety, seizures, weak limbs, constipation, diarrhea, or dark or reddish urine. AHP is life-threatening due to the possibility of paralysis and respiratory arrest during attacks. The nonspecific nature of AHP signs and symptoms can often lead to misdiagnoses of other more common conditions such as gynecological disorders, viral gastroenteritis, irritable bowel syndrome (IBS), and appendicitis. Consequently, on a global perspective, patients with AHP can wait up to 15 years for a confirmed diagnosis, with the risk of addiction problems. In addition, long-term complications and comorbidities of AHP can include hypertension, chronic kidney disease or liver disease, including hepatocellular carcinoma.

    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), approved in the U.S., EU, Canada, Japan, Brazil, and Switzerland, and GIVLAARI® (givosiran), approved in the U.S and the EU. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam 2020" strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options. Alnylam is headquartered in Cambridge, MA.

    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 GIVLAARI® (givosiran) injection for subcutaneous use, as further demonstrated in the open-label extension (OLE) portion of the ENVISION study, its views that new data from its OLE program confirm the sustained therapeutic benefit of givosiran for patients living with AHP, its views regarding the clinical benefit of givosiran and the potential therapeutic impact of givosiran for patients afflicted with AHP, including the potential to significantly reduce the high burden of disease for patients and families, expectations regarding the regulatory review of GIVLAARI in Canada and Brazil, and expectations regarding the continued execution on its "Alnylam 2020" guidance for the advancement and commercialization of RNAi therapeutics 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 a future pandemic, such as the scope and duration of the outbreak, government actions and restrictive measures implemented in response, material delays in diagnoses of rare diseases, initiation or continuation of treatment for diseases addressed by Alnylam products, or in patient enrollment in clinical trials, potential supply chain disruptions, and other potential impacts to Alnylam's business, the effectiveness or timeliness of steps taken by Alnylam to mitigate the impact of the pandemic, and Alnylam's ability to execute business continuity plans to address disruptions caused by the COVID-19 or a future 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, which may not be replicated or continue to occur in other subjects or in additional studies or otherwise support further development of product candidates for a specified indication or at all; actions or advice of regulatory agencies, which may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional pre-clinical and/or clinical testing; delays, interruptions or failures in the manufacture and supply of its product candidates, including lumasiran, or its marketed products; obtaining, maintaining and protecting intellectual property; intellectual property matters including potential patent litigation relating to its platform, products or product candidates; obtaining regulatory approval for its product candidates, including lumasiran, and maintaining regulatory approval and obtaining pricing and reimbursement for its products, including ONPATTRO and GIVLAARI; progress in continuing to establish a commercial and ex-United States infrastructure; successfully launching, marketing and selling its approved products globally, including ONPATTRO and GIVLAARI, and achieving net product revenues for ONPATTRO within its revised expected range during 2020; Alnylam's ability to successfully expand the indication for ONPATTRO in the future; competition from others using technology similar to Alnylam's and others developing products for similar uses; Alnylam's ability to manage its growth and operating expenses within the ranges of guidance provided by Alnylam through the implementation of further discipline in operations to moderate spend and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to establish and maintain strategic business alliances and new business initiatives, including completing an agreement for funding by Blackstone of certain R&D activities for vutrisiran and ALN-AGT; Alnylam's dependence on third parties, including Regeneron, for development, manufacture and distribution of certain products, including eye and CNS products, Ironwood, for assistance with the education about and promotion of GIVLAARI, and Vir for the development of ALN-COV and other potential RNAi therapeutics targeting SARS-CoV-2 and host factors for SARS-CoV-2; 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 other filings that Alnylam makes with the SEC. 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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  2. Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that it plans to host its 7th annual series of "RNAi Roundtable" webinars over the coming weeks. The series will offer a range of presentations from Alnylam scientists and program leaders, as well as clinical collaborators, who will review recent progress in many of the Company's pipeline programs and platform. 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 initial 2020 RNAi Roundtable schedule will be as follows:

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

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that it plans to host its 7th annual series of "RNAi Roundtable" webinars over the coming weeks. The series will offer a range of presentations from Alnylam scientists and program leaders, as well as clinical collaborators, who will review recent progress in many of the Company's pipeline programs and platform. 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 initial 2020 RNAi Roundtable schedule will be as follows:

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

      Tuesday, June 23, 2:30 pm ET
    • Early Stage RNAi Therapeutics Pipeline

      Friday, July 17, 9:30 am ET

    Additional RNAi Roundtables will be scheduled over the coming weeks, and will include:

    • Lumasiran, in Development for the Treatment of Primary Hyperoxaluria Type 1
    • Patisiran and Vutrisiran, in Development for the Treatment of ATTR Amyloidosis
    • Givosiran, for the Treatment of Acute Hepatic Porphyria

    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), approved in the U.S., EU, Canada, Japan, Brazil, and Switzerland, and GIVLAARI® (givosiran), approved in the U.S and the EU. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam 2020" strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options. 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 or on LinkedIn.

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  3. Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that management will present a company overview at the Bank of America Securities 2020 Napa Biopharma Conference on Wednesday, June 24, 2020 at 10:30 am PT (1:30 pm ET) via webcast.

    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 each 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…

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that management will present a company overview at the Bank of America Securities 2020 Napa Biopharma Conference on Wednesday, June 24, 2020 at 10:30 am PT (1:30 pm ET) via webcast.

    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 each 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), approved in the U.S., EU, Canada, Japan, Brazil, and Switzerland, and GIVLAARI® (givosiran), approved in the U.S and the EU. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam 2020" strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options. 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 or on LinkedIn.

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  4. − The ENVISION Phase 3 Study Evaluated the Efficacy and Safety of Givosiran in Patients with Acute Hepatic Porphyria (AHP) −

    − Givosiran Demonstrated Significant Reduction in the Rate of Porphyria Attacks Compared with Placebo in Patients with AHP –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that pivotal results from the ENVISION Phase 3 study of givosiran, an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyria (AHP), were published online in the New England Journal of Medicine (NEJM). GIVLAARI® (givosiran) was approved by the U.S. Food and Drug Administration for the treatment of adults with AHP in November 2019, marking the…

    − The ENVISION Phase 3 Study Evaluated the Efficacy and Safety of Givosiran in Patients with Acute Hepatic Porphyria (AHP) −

    − Givosiran Demonstrated Significant Reduction in the Rate of Porphyria Attacks Compared with Placebo in Patients with AHP –

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today that pivotal results from the ENVISION Phase 3 study of givosiran, an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyria (AHP), were published online in the New England Journal of Medicine (NEJM). GIVLAARI® (givosiran) was approved by the U.S. Food and Drug Administration for the treatment of adults with AHP in November 2019, marking the first ever approval of a GalNAc-conjugate RNAi therapeutic—a landmark in the advancement of precision genetic medicines. It also received marketing authorization from the European Commission in March 2020 for the treatment of AHP in adults and adolescents aged 12 years and older. The full manuscript, titled "Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria," will appear in the June 11, 2020 issue of NEJM.

    The data reported in the ENVISION Phase 3 study publication demonstrated that RNAi-mediated targeting of liver ALAS1 by givosiran led to sustained reductions in aminolevulinic acid (ALA) and porphobilinogen (PBG)—the toxic heme synthesis intermediates believed to be causal for the disease manifestations of AHP. Relative to placebo, treatment with givosiran resulted in a significant and clinically meaningful reduction of 74 percent in the primary endpoint of the annualized rate of composite porphyria attacks (AAR), defined as those attacks requiring hospitalization, urgent healthcare visit, or intravenous hemin administration at home, in patients with acute intermittent porphyria (AIP), the most common form of AHP, over six months.

    Improvements were also observed in a number of secondary endpoints (assessed in patients with AIP), including reductions in urinary ALA and PBG levels, days of intravenous hemin use and daily worst pain. Additionally, in all patients with AHP, mean AAR was significantly reduced by 73 percent relative to placebo. Patients treated with givosiran also reported favorable effects on exploratory endpoints related to use of analgesics, overall health status and daily functioning.

    "Patients with AHP suffer through debilitating and potentially life-threatening attacks, and for some, chronic pain between attacks, resulting in a diminished quality of life and ability to function day-to-day," said Manisha Balwanii, M.D., M.S., Associate Professor of the Department of Genetics and Genomic Sciences and Department of Medicine at the Icahn School of Medicine at Mount Sinai, principal investigator of the ENVISION Phase 3 study and lead author of the manuscript. "We believe the publication of the ENVISION Phase 3 study results in NEJM further underscores the clinical benefit of givosiran. The significant reduction in annualized attack rate, paired with improvement in multiple other disease manifestations in patients experiencing ongoing attacks, demonstrate the potential therapeutic impact of givosiran for patients afflicted with AHP."

    "GIVLAARI represents an important advance for the treatment of AHP, offering a therapeutic option which can help prevent or reduce the painful, often-incapacitating attacks and reduce daily worst pain associated with the disease," said Akin Akinc, Ph.D., General Manager of the Givosiran Program at Alnylam. "Publication of the pivotal ENVISION Phase 3 data in NEJM is a recognition of the clinical impact possible with GIVLAARI and, more generally, with RNAi therapeutics, a whole new class of medicines."

    The most common adverse events observed in the givosiran group during the 6-month double-blind (DB) period (reported in at least 15 percent of patients) were nausea (27 percent) and injection site reactions (25 percent). Other adverse events seen more frequently (by greater than 5 percent) in patients treated with givosiran compared to placebo included chronic kidney disease (10 percent), fatigue (10 percent), alanine aminotransferase increase (8 percent), glomerular filtration rate decrease (6 percent) and rash (6 percent).

    Upon completion of dosing in the 6-month DB period, 93 out of 94 patients (99 percent) enrolled in the ENVISION open-label extension (OLE) period to receive givosiran on an ongoing basis. Detailed results from the 12-month OLE period, demonstrating sustained AAR reduction with no new adverse events or safety concerns leading to discontinuation in the study, will be presented by study investigator Eliane Sardh, M.D., Ph.D., Porphyria Centre Sweden, Centre for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, during an upcoming webinar for healthcare professionals hosted by Alnylam; the presentation recording and materials will be made available on www.alnylam.com/capella.

    About the ENVISION Phase 3 Study

    The ENVISION Phase 3 study was a randomized, double-blind, placebo-controlled, global, multicenter trial designed to evaluate the efficacy and safety of givosiran in patients with a documented diagnosis of acute hepatic porphyria (AHP). The primary endpoint of the trial was the annualized rate of composite porphyria attacks (AAR) in patients with acute intermittent porphyria (AIP) over the 6-month double-blind period. Secondary endpoints included: urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) levels in patients with AIP, AAR in patients with AHP, hemin use and daily worst pain in patients with AIP. The trial enrolled 94 patients with AHP, at 36 study sites in 18 countries around the world and is the largest ever interventional study ever conducted in AHP. Patients were randomized 1:1 to givosiran or placebo, with givosiran administered subcutaneously at 2.5 mg/kg monthly.

    About GIVLAARI® (givosiran)

    GIVLAARI is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of adults with acute hepatic porphyria (AHP) in the U.S. and for the treatment of AHP in adults and adolescents aged 12 years and older in the European Union. 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 ALAS1 messenger RNA (mRNA), leading to reduction of toxins associated with attacks and other disease manifestations of AHP.

    GIVLAARI® (givosiran) 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 percent 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 percent 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 percent 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 percent of patients receiving GIVLAARI in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. One (2 percent) 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 percent) and injection site reactions (25 percent).

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

    About Acute Hepatic Porphyria

    Acute hepatic porphyria (AHP) refers to a family of ultra-rare, genetic diseases characterized by debilitating, potentially life-threatening attacks and, for some patients, chronic manifestations that negatively impact daily functioning and quality of life. AHP is comprised of four subtypes: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA dehydratase-deficiency porphyria (ADP). Each type of AHP results from a genetic defect leading to a lack of certain enzymes needed to produce heme in the liver, which leads to an accumulation of porphyrins in the body to toxic amounts. AHP disproportionately impacts women of working and childbearing age, and symptoms of the disease vary widely. Severe, unexplained abdominal pain is the most common symptom, which can be accompanied by limb, back, or chest pain, nausea, vomiting, confusion, anxiety, seizures, weak limbs, constipation, diarrhea, or dark or reddish urine. AHP is life-threatening due to the possibility of paralysis and respiratory arrest during attacks. The nonspecific nature of AHP signs and symptoms can often lead to misdiagnoses of other more common conditions such as gynecological disorders, viral gastroenteritis, irritable bowel syndrome (IBS), and appendicitis. Consequently, on a global perspective, patients with AHP can wait up to 15 years for a confirmed diagnosis, with the risk of addiction problems. In addition, long-term complications and comorbidities of AHP can include hypertension, chronic kidney disease or liver disease, including hepatocellular carcinoma.

    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), approved in the U.S., EU, Canada, Japan, Brazil, and Switzerland, and GIVLAARI® (givosiran), approved in the U.S and the EU. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam 2020" strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options. Alnylam is headquartered in Cambridge, MA.

    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 GIVLAARI® (givosiran) injection for subcutaneous use, its views regarding the clinical benefit of givosiran and the potential therapeutic impact of givosiran for patients afflicted with AHP, its views that GIVLAARI represents an important advance for the treatment of AHP and that publication of the pivotal ENVISION Phase 3 data in the New England Journal of Medicine is a recognition of the clinical impact possible with GIVLAARI and, more generally, with RNAi therapeutics, as a whole new class of medicines, and expectations regarding the continued execution on its "Alnylam 2020" guidance for the advancement and commercialization of RNAi therapeutics 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 a future pandemic, such as the scope and duration of the outbreak, government actions and restrictive measures implemented in response, material delays in diagnoses of rare diseases, initiation or continuation of treatment for diseases addressed by Alnylam products, or in patient enrollment in clinical trials, potential supply chain disruptions, and other potential impacts to Alnylam's business, the effectiveness or timeliness of steps taken by Alnylam to mitigate the impact of the pandemic, and Alnylam's ability to execute business continuity plans to address disruptions caused by the COVID-19 or a future 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, which may not be replicated or continue to occur in other subjects or in additional studies or otherwise support further development of product candidates for a specified indication or at all; actions or advice of regulatory agencies, which may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional pre-clinical and/or clinical testing; delays, interruptions or failures in the manufacture and supply of its product candidates, including lumasiran, or its marketed products; obtaining, maintaining and protecting intellectual property; intellectual property matters including potential patent litigation relating to its platform, products or product candidates; obtaining regulatory approval for its product candidates, including lumasiran, and maintaining regulatory approval and obtaining pricing and reimbursement for its products, including ONPATTRO and GIVLAARI; progress in continuing to establish a commercial and ex-United States infrastructure; successfully launching, marketing and selling its approved products globally, including ONPATTRO and GIVLAARI, and achieving net product revenues for ONPATTRO within its revised expected range during 2020; Alnylam's ability to successfully expand the indication for ONPATTRO in the future; competition from others using technology similar to Alnylam's and others developing products for similar uses; Alnylam's ability to manage its growth and operating expenses within the ranges of guidance provided by Alnylam through the implementation of further discipline in operations to moderate spend and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to establish and maintain strategic business alliances and new business initiatives, including completing an agreement for funding by Blackstone of certain R&D activities for vutrisiran and ALN-AGT; Alnylam's dependence on third parties, including Regeneron, for development, manufacture and distribution of certain products, including eye and CNS products, Ironwood, for assistance with the education about and promotion of GIVLAARI, and Vir for the development of ALN-COV and other potential RNAi therapeutics targeting SARS-CoV-2 and host factors for SARS-CoV-2; 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 other filings that Alnylam makes with the SEC. 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 Dr. Manisha Balwani (the Principal Investigator in this study) receives financial compensation as a consultant for Alnylam Pharmaceuticals (the study sponsor). In addition, Mount Sinai faculty are named Co-Inventors with Alnylam on a patent related to the development of givosiran, the study drug. The Icahn School of Medicine at Mount Sinai receives payments related to this patent from Alnylam, and a portion of these payments are also distributed to faculty and other co-inventors.

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  5. - Lumasiran Achieved Primary Endpoint with 53.5 Percent Mean Reduction in Urinary Oxalate Relative to Placebo and Showed a 65.4 Percent Reduction Relative to Baseline -

    - 84 Percent of Patients on Lumasiran Achieved Normal or Near-Normal Levels of Urinary Oxalate and More than Half of Patients Reached Normalization, Compared with Zero Percent in the Placebo Group -

    - Lumasiran Demonstrated an Encouraging Safety and Tolerability Profile -

    - Alnylam to Host Conference Call Today at 8:30 am ET -

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

    - Lumasiran Achieved Primary Endpoint with 53.5 Percent Mean Reduction in Urinary Oxalate Relative to Placebo and Showed a 65.4 Percent Reduction Relative to Baseline -

    - 84 Percent of Patients on Lumasiran Achieved Normal or Near-Normal Levels of Urinary Oxalate and More than Half of Patients Reached Normalization, Compared with Zero Percent in the Placebo Group -

    - Lumasiran Demonstrated an Encouraging Safety and Tolerability Profile -

    - Alnylam to Host Conference Call Today at 8:30 am ET -

    Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, announced today positive Phase 3 results from the ILLUMINATE-A study of lumasiran, an investigational RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) – the gene encoding glycolate oxidase (GO) – in development for the treatment of primary hyperoxaluria type 1 (PH1). The clinical data were presented at a late-breaking session at the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) International Congress being held as a virtual event on June 6-9.

    Lumasiran achieved the ILLUMINATE-A primary endpoint with a 53.5 percent mean reduction in urinary oxalate relative to placebo (p=1.7x10-14) and showed a 65.4 percent mean reduction in urinary oxalate relative to baseline. All tested study secondary endpoints were met, including the proportion of patients achieving near-normalization (84 percent) or normalization (52 percent) of urinary oxalate, compared with zero percent in the placebo group. Lumasiran administration was associated with an encouraging safety and tolerability profile, with no serious or severe adverse events (AEs) and with mild injection site reactions (ISRs) as the most common drug-related AE.

    PH1 is an ultra-rare orphan disease caused by excessive oxalate production, and elevated urinary oxalate levels are associated with progression to end-stage kidney disease and other systemic complications.1,2

    Based on the ILLUMINATE-A results, Alnylam filed a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA). The FDA has granted a Priority Review for the NDA and has set an action date of December 3, 2020 under the Prescription Drug User Fee Act (PDUFA). In addition, the Marketing Authorisation Application (MAA) for lumasiran has been submitted to and validated by the European Medicines Agency (EMA), and has received Accelerated Assessment designation.

    "We are very pleased to report positive Phase 3 results from the ILLUMINATE-A study of lumasiran. The substantial and sustained reductions in urinary and plasma oxalate reported demonstrate that lumasiran addresses the underlying pathophysiology of PH1 by reducing the production of the toxic metabolite responsible for the clinical manifestations of this serious and progressive disease. Thus, we believe lumasiran has the potential to have a favorable impact on disease manifestations, including nephrocalcinosis and renal stones, and overall disease progression, which we are continuing to evaluate in the ongoing ILLUMINATE program," said Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. "The ILLUMINATE-A study represents the sixth positive Phase 3 study for an investigational RNAi therapeutic, and we believe it further highlights the transformational potential of this modality as a whole new class of medicines. Assuming favorable regulatory reviews, we look forward to bringing lumasiran to patients with PH1 around the world."

    "For those living with PH1, the continuous overproduction of oxalate can have a devastating impact on the kidneys and other organs. Current disease management strategies aim to lessen the damage to the kidneys, with liver transplantation as the only means to correct the metabolic deficiency and normalize the high oxalate production. As patients approach end-stage kidney disease, they may require intensive dialysis as a bridge to a dual liver/kidney transplant," said Professor Jaap Groothoff, M.D., Ph.D., Head of the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, The Netherlands. "Based on results from the ILLUMINATE-A study, lumasiran shows potential to substantially curb oxalate overproduction – the cause of progressive kidney failure in PH1. Reduction in hepatic oxalate production is expected to confer clinical benefit in PH1 patients and has the potential to change the course of disease."

    Efficacy Results

    In the ILLUMINATE-A study (N=39), lumasiran met the primary efficacy endpoint of 24-hour urinary oxalate reduction from Month 3 to Month 6 (averaged across timepoints) relative to placebo and all tested secondary endpoints. Specifically, lumasiran treatment (N=26) in PH1 patients, aged six years and older with an estimated glomerular filtration rate (eGFR) greater than or equal to 30 mL/min/1.73m2, resulted in 65.4 percent mean reduction in urinary oxalate relative to baseline, with a mean treatment difference of 53.5 percent relative to placebo (N=13) (p=1.7 x 10-14). The mean maximal reduction with lumasiran was 76 percent, similar to results (75-76 percent) reported in Phase 1/2 and Phase 2 open-label extension (OLE) studies using a different assay method. Lumasiran also demonstrated a 62.5 percent mean reduction in 24-hour urinary oxalate:creatinine ratio – an alternative measure of urinary oxalate excretion – relative to baseline, with a mean treatment difference of 51.8 percent relative to placebo (p=5.0 x 10-10). At Month 6, the majority (21/25 or 84 percent) of patients randomized to lumasiran achieved urinary oxalate levels at or below 1.5 times the upper limit of normal (1.5 x ULN = 0.77 mmol/24hr/1.73m2) (p=8.3x10-7). Approximately half (13/25 or 52 percent) of the lumasiran-treated patients achieved urinary oxalate levels within the normal range (less than or equal to 0.514 mmol/24hr/1.73m2) (p=0.001). In contrast, none of the patients on the placebo arm achieved normal or near-normal levels of oxalate. Lumasiran led to a rapid and sustained reduction in plasma oxalate levels in patients whose baseline plasma oxalate was at or above 1.5 times the lower limit of quantification, with patients on lumasiran (N=23) experiencing plasma oxalate reduction of 39.8 percent versus 0.3 percent for patients on placebo (N=10) (p=2.9 x 10-8).

    In a pre-specified subgroup analysis of the primary endpoint, lumasiran demonstrated a consistent treatment effect relative to placebo across all subgroups, including baseline kidney function. As expected, given the 6-month duration of the study, eGFR levels and renal stone eventsa were comparable between the two treatment arms. Three of 22 evaluable lumasiran patients demonstrated early signs of unilateral and bilateral improvements in nephrocalcinosis at six months, in a pre-specified analysis of this exploratory endpoint, including one patient in the lumasiran arm demonstrating a 2-grade improvement in one kidney and 1-grade improvement in the other kidney. In contrast, no improvement in nephrocalcinosis was reported for evaluable placebo patients (N=12) and one placebo patient experienced a unilateral, 1-grade worsening. As anticipated and consistent with the lumasiran mechanism of action, levels of plasma glycolate – a pharmacodynamic marker – initially increased and then reached a plateau in the lumasiran group. A total of 38b of 39 patients completed the 6-month primary analysis period and all eligible patients transitioned to the ILLUMINATE-A OLE study.

    Safety and Tolerability

    There were no deaths and no severe or serious AEs reported. AEs were reported in 22/26 (84.6 percent) of lumasiran patients and 9/13 (69.2 percent) of placebo patients. All AEs were mild to moderate in severity. AEs reported in greater than or equal to 10 percent of patients in both groups were ISRs, headache, rhinitis, and upper respiratory tract infection. The most common AEs related to lumasiran were ISRs reported in 9/26 (34.6 percent) of patients. All ISRs were mild in severity, transient, and did not result in treatment interruption or discontinuation. Most common ISR-related symptoms were erythema, pain, pruritus, or discomfort at the injection site. AEs leading to discontinuationc of study treatment were reported in 1/26 (3.8 percent) of lumasiran patients. No clinically relevant changes in laboratory parameters (including liver function tests), vital signs, and electrocardiograms related to lumasiran were observed.

    To view the results presented at ERA-EDTA, please visit www.alnylam.com/capella.

    Conference Call

    Alnylam Management will discuss the ILLUMINATE-A results via conference call on Sunday, June 7, 2020 at 8:30 am ET. A webcast presentation will also be available on the Investors section of the Company's website at www.alnylam.com/events. To access the call, please dial 800-239-9838 (domestic) or +1 323-794-2551 (international) five minutes prior to the start time and refer to conference ID 6976021. 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 888-203-1112 (domestic) or +1 719-457-0820 (international) and refer to conference ID 6976021.

    aRenal stone event was a pre-specified exploratory endpoint during the 6-month placebo-controlled treatment period and defined as an event which includes at least one of the following: visit to healthcare provider because of a renal stone, medication for renal colic, stone passage, or macroscopic hematuria due to a renal stone.

    b One patient discontinued study drug after receiving a single dose and withdrew from the study after Month 3. Parent/guardian stopped participation due to patient's inability to comply with protocol-specific testing.

    c Discontinuation of study treatment was attributed to AEs of fatigue and disturbance in attention.

    References

    1. Cochat & Rumsby. N Engl J Med 2013;369:649–58.
    2. Milliner et al. GeneReviews® [updated November 30, 2017]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1283.

    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 with a documented diagnosis of PH1. Patients were randomized 2:1 to receive three monthly doses of lumasiran or placebo followed by quarterly maintenance 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 Lumasiran

    Lumasiran is an investigational, 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 both U.S. and EU Orphan Drug Designations, Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA), and Priority Medicines (PRIME) designation from the European Medicines Agency (EMA). The safety and efficacy of lumasiran are under evaluation by the FDA and EMA.

    About Primary Hyperoxaluria Type 1 (PH1)

    PH1 is an ultra-rare disease in which excessive oxalate production 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. Compromised kidney function exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and crystallization in bones, eyes, skin, and heart, leading to severe illness and death. Current treatment options are very limited and include frequent renal dialysis or combined organ transplantation of liver and kidney, a procedure with high morbidity that is limited due to organ availability. Although a small minority of patients respond to vitamin B6 therapy, there are 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), approved in the U.S., EU, Canada, Japan, Brazil, and Switzerland, and GIVLAARI® (givosiran), approved in the U.S and the EU. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam 2020" strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options. Alnylam is headquartered in Cambridge, MA.

    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-A Phase 3 study and the potential for lumasiran to have a favorable impact on PH1 disease manifestations and overall disease progression, Alnylam's expectations with respect to the review timelines for the lumasiran NDA and MAA by the FDA and EMA, respectively, Alnylam's plans, assuming favorabale regulatory reviews, to bring lumasiran to patients with PH1 around the world, and expectations regarding the continued execution on its "Alnylam 2020" guidance for the advancement and commercialization of RNAi therapeutics, 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 a future pandemic, such as the scope and duration of the outbreak, government actions and restrictive measures implemented in response, material delays in diagnoses of rare diseases, initiation or continuation of treatment for diseases addressed by Alnylam products, or in patient enrollment in clinical trials, potential supply chain disruptions, and other potential impacts to Alnylam's business, the effectiveness or timeliness of steps taken by Alnylam to mitigate the impact of the pandemic, and Alnylam's ability to execute business continuity plans to address disruptions caused by the COVID-19 or a future 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, which may not be replicated or continue to occur in other subjects or in additional studies or otherwise support further development of product candidates for a specified indication or at all; actions or advice of regulatory agencies, which may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional pre-clinical and/or clinical testing; delays, interruptions or failures in the manufacture and supply of its product candidates, including lumasiran, or its marketed products; obtaining, maintaining and protecting intellectual property; intellectual property matters including potential patent litigation relating to its platform, products or product candidates; obtaining regulatory approval for its product candidates, including lumasiran, and maintaining regulatory approval and obtaining pricing and reimbursement for its products, including ONPATTRO and GIVLAARI; progress in continuing to establish a commercial and ex-United States infrastructure; successfully launching, marketing and selling its approved products globally, including ONPATTRO and GIVLAARI, and achieving net product revenues for ONPATTRO within its revised expected range during 2020; Alnylam's ability to successfully expand the indication for ONPATTRO in the future; competition from others using technology similar to Alnylam's and others developing products for similar uses; Alnylam's ability to manage its growth and operating expenses within the ranges of guidance provided by Alnylam through the implementation of further discipline in operations to moderate spend and and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to establish and maintain strategic business alliances and new business initiatives, including completing an agreement for funding by Blackstone of certain R&D activities for vutrisiran and ALN-AGT; Alnylam's dependence on third parties, including Regeneron, for development, manufacture and distribution of certain products, including eye and CNS products, Ironwood, for assistance with the education about and promotion of GIVLAARI, and Vir for the development of ALN-COV and other potential RNAi therapeutics targeting SARS-CoV-2 and host factors for SARS-CoV-2; 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 other filings that Alnylam makes with the SEC. 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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