− 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 –

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- 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 (