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Alnylam Announces Publication of ENVISION Phase 3 Study Results for Givosiran in the New England Journal of Medicine

− 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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