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PRESS RELEASE
Alnylam Receives European Medicines Agency PRIME Designation for Accelerated Assessment of Givosiran, an Investigational RNAi Therapeutic for the Treatment of Acute Hepatic Porphyrias
March 1, 2017 5:20 a.m. ET
CAMBRIDGE, Mass.--(BUSINESS WIRE)--March 01, 2017--
Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), the leading RNAi therapeutics company, announced today that the European Medicines Agency (EMA) has granted access to its Priority Medicines (PRIME) scheme for givosiran (ALN-AS1), an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias. The purpose of the PRIME initiative is to bring treatments to patients faster by enhancing the EMA's support for the development of medicines for diseases where there is an unmet medical need and where early clinical data show potential to benefit patients.

Promising results from the Phase 1 study of givosiran formed the basis of the application for PRIME. The ongoing Phase 1 trial is being conducted as a randomized, double-blind, placebo-controlled study. Specifically, data were recently reported in patients with acute intermittent porphyria (AIP) experiencing recurrent attacks. As presented at the 2016 American Society of Hematology (ASH) meeting, givosiran demonstrated initial evidence for clinical activity in AIP patients with meaningful reductions in the number and frequency of porphyria attacks. In the first two dose cohorts, givosiran was found to be generally well tolerated with no drug-related serious adverse events. In the third dose cohort, which remains blinded, one death due to acute pancreatitis, considered unlikely related to givosiran or placebo, was reported after the data transfer date.

"We are pleased to have givosiran accepted into the PRIME program. We believe givosiran could be a potentially transformative treatment option for patients with acute hepatic porphyrias, a family of debilitating and life threatening diseases with enormous unmet medical need," said Jeff Miller, Vice President, General Manager, Givosiran Program at Alnylam. "We look forward to collaborating with the EMA on the accelerated assessment of givosiran, with the goal of advancing this investigational medicine into a Phase 3 trial in late 2017."

Givosiran has previously been granted Orphan Drug Designations in both the EU and the U.S. for the treatment of acute hepatic porphyrias. Through the PRIME program Alnylam will have enhanced scientific and regulatory support from the EMA, including its advice on optimization of the development pathway and the potential for accelerated assessment of the Marketing Authorisation Application (MAA).

About Givosiran

Alnylam is developing givosiran (formerly known as ALN-AS1), a subcutaneously administered, investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias, including acute intermittent porphyria (AIP). AIP is an ultra-rare autosomal dominant disease caused by loss of function mutations in porphobilinogen deaminase (PBGD), an enzyme in the heme biosynthesis pathway that can result in accumulation of toxic heme intermediates, including aminolevulinic acid (ALA) and porphobilinogen (PBG). Patients with AIP can suffer from acute and/or recurrent life-threatening attacks characterized by severe abdominal pain, neuropathy (affecting the central, peripheral or autonomic nervous system), and neuropsychiatric manifestations. Givosiran is an ESC-GalNAc-siRNA conjugate targeting ALAS1, a liver-expressed, rate-limiting enzyme upstream of PBGD in the heme biosynthesis pathway. Inhibition of ALAS1 is known to reduce the accumulation of heme intermediates that cause the clinical manifestations of AIP. Givosiran has the potential to be a novel treatment approach for the prevention of recurrent attacks. Givosiran is an investigational compound, currently in early stage clinical development. The safety and efficacy of givosiran have not been evaluated by the U.S. Food and Drug Administration or any other health authority.

About Acute Hepatic Porphyrias

The porphyrias are a family of rare metabolic disorders with mostly autosomal dominant inheritance predominantly caused by a genetic mutation in one of the eight enzymes responsible for heme biosynthesis. Acute hepatic porphyrias (AHP) constitute a subset where the enzyme deficiency occurs within the liver, and includes acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). Exposure of AHP patients to certain drugs, dieting, or hormonal changes can trigger strong induction of aminolevulinic acid synthase 1 (ALAS1), another enzyme in the heme biosynthesis pathway, which can lead to accumulation of neurotoxic heme intermediates that precipitate disease symptoms. Patients with AHP can suffer from a range of symptoms that, depending on the specific type, can include acute and/or recurrent life-threatening attacks with severe abdominal pain, peripheral and autonomic neuropathy, neuropsychiatric manifestations, cutaneous lesions and possibly paralysis and death if untreated or if there are delays in treatment. There are no approved treatments for the prevention of attacks; the only approved treatment for acute attacks is hemin for injection (Panhematin(R) or Normosang(R)), a preparation of heme derived from human blood. Hemin requires administration through a large vein or a central intravenous line and is associated with a number of complications including thrombophlebitis or coagulation abnormalities. Chronic administration of hemin may result in renal insufficiency, iron overload, systemic infections (due to the requirement for central venous access) and, in some instances, tachyphylaxis.


About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-GalNAc Conjugates

GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. This delivery platform is being employed in nearly all of Alnylam's pipeline programs, including programs in clinical development.
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