Alnylam Files Clinical Trial Application to Initiate a Phase 1 Study for ALN-AS1, a Subcutaneously Administered, Investigational RNAi Therapeutic Targeting Aminolevulinic Acid Synthase-1 (ALAS-1) for the Treatment of Hepatic Porphyrias

Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, announced today that it has filed a Clinical Trial Application (CTA) with the Swedish Medical Products Agency (MPA) to initiate a Phase 1 clinical trial with ALN-AS1, a subcutaneously administered investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS-1) for the treatment of hepatic porphyrias, including acute intermittent porphyria (AIP). Per the filed CTA, the Phase 1 trial of ALN-AS1 will be performed first in AIP patients who are asymptomatic “high excreters” (ASHE) – patients with a mutation in the porphobilinogen deaminase (PBGD) gene and elevated urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) levels, but no recent symptoms of a porphyria attack – and then in AIP patients who experience recurrent porphyria attacks. Following approval of the CTA, the company expects to initiate the Phase 1 study in mid-2015, with initial data expected to be reported in early 2016. ALN-AS1 now becomes the company’s fifth clinical stage program in its Genetic Medicine Strategic Therapeutic Area (STAr) and the sixth clinical pipeline program overall.

“We are very pleased to advance ALN-AS1, a key program in our Genetic Medicine STAr, to the clinical stage with this CTA filing. Our pre-clinical data show that subcutaneous administration of ALN-AS1 results in complete suppression of the toxic heme biosynthesis intermediates that cause the symptoms and pathology of AIP, the most common hepatic porphyria. Accordingly, we believe ALN-AS1 could become a transformative therapy for patients with hepatic porphyrias, a group of ultra-rare monogenic diseases with enormous unmet medical need,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “ALN-AS1 now becomes our fifth RNAi therapeutic that utilizes our proprietary, clinically validated GalNAc conjugate delivery platform to enter a clinical development stage, and the fourth that utilizes our optimized Enhanced Stabilization Chemistry GalNAc technology. We very much look forward to the continued advancement of ALN-AS1, including the start of our Phase 1 trial in mid-2015, with data expected in early 2016.”

“Patients with AIP present with acute, and at times recurrent attacks that are characterized by severe abdominal pain, peripheral and autonomic neuropathy, neuropsychiatric manifestations, and in very severe cases paralysis and respiratory failure. Recurrent attack patients can spend a significant number of days in the hospital every month and many have a very poor quality of life,” said Robert J. Desnick, M.D., Ph.D., Dean for Genetic and Genomic Medicine and Professor and Chair Emeritus of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City. “Our lab's pre-clinical studies with ALN-AS1 support the potential for an RNAi therapeutic as a new investigational medicine for patients with hepatic porphyrias, and I am pleased with Alnylam's efforts and commitment to advance this program to the clinic. Based on its mechanism of action and pharmacological properties, I believe that ALN-AS1 could represent an attractive therapeutic strategy and potential new treatment option for patients with hepatic porphyrias.”

ALN-AS1 is a subcutaneously administered, investigational RNAi therapeutic that utilizes Alnylam’s proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-siRNA conjugate delivery platform. ESC-GalNAc-siRNA conjugates are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor, and enable subcutaneous dosing with increased potency and durability and a wide therapeutic index. In pre-clinical studies, multi-dose administration of a GalNAc-siRNA targeting ALAS-1 led to rapid, dose-dependent, and long-lasting knockdown of the ALAS-1 mRNA in non-human primates, with an ED₅₀ of approximately 1.25 mg/kg. Further, in a rat model of AIP, ALN-AS1 administration at doses as low as 2.5 mg/kg resulted in a complete blunting of phenobarbital-induced over-production of ALA and PBG, the toxic heme intermediates in AIP.

As per the filed CTA, the Phase 1 trial of ALN-AS1 will be conducted in three parts. Parts A and B will be randomized (3:1, drug:placebo), single-blind, single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 40 ASHE patients. The primary objective of these first two parts of the study is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-AS1. Secondary objectives include evaluation of clinical activity for ALN-AS1 as measured by reduction in plasma and urine levels of ALA and PBG. Part C will be an open-label, multi-dose study in up to eight AIP patients who experience recurrent porphyria attacks, and will assess safety, tolerability, PK/PD, and clinical activity of multiple doses of ALN-AS1. In addition, this part of the study will include an exploratory evaluation of the effects of ALN-AS1 on the number and severity of attacks, hematin and pain medication use, and number and duration of hospitalizations.

About ALN-AS1

Alnylam is developing ALN-AS1, a subcutaneously administered, investigational RNAi therapeutic targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of 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 suffer from acute and/or recurrent life-threatening attacks characterized by severe abdominal pain, peripheral and autonomic neuropathy, and neuropsychiatric manifestations. ALN-AS1 is an ESC-GalNAc-siRNA conjugate targeting ALAS-1, a liver-expressed, rate-limiting enzyme upstream of PBGD in the heme biosynthesis pathway. Inhibition of ALAS-1 is known to reduce the accumulation of heme intermediates that cause the clinical manifestations of AIP. ALN-AS1 has the potential to be a therapy for the treatment of acute porphyria attacks, as well as a prophylactic approach for the prevention of recurrent attacks. ALN-AS1 is a key program in Alnylam’s Genetic Medicine Strategic Therapeutic Area (STAr).

About Hepatic Porphyrias

The porphyrias are a family of rare metabolic disorders with autosomal dominant inheritance predominately caused by a genetic mutation in one of the eight enzymes responsible for heme biosynthesis. Hepatic porphyrias constitute a subset where the enzyme deficiency occurs within the liver, and includes acute intermittent porphyria (AIP), hereditary coproporphyria, and variegate porphyria. Exposure of hepatic porphyria patients to certain drugs, dieting, or hormonal changes can trigger strong induction of aminolevulinic acid synthase-1 (ALAS-1), another enzyme in the heme biosynthesis pathway, which can lead to accumulation of heme intermediates that precipitate disease symptoms. Patients with hepatic porphyrias 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 death if untreated or if there are delays in treatment. The only available treatment for AIP is the use of hematin (Panhematin® or Normosang®), which are preparations of heme derived from human blood. Hematin requires administration through a central intravenous line and is associated with a number of complications including thrombophlebitis and iron overload.

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 several of Alnylam’s genetic medicine programs, including programs in clinical development.

About RNAi

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines. In late 2014, Alnylam launched its pipeline growth strategy for RNAi therapeutics in three strategic therapeutic areas (STArs): Genetic Medicines, Cardio-metabolic Disease, and Hepatic Infectious Disease. Alnylam’s Genetic Medicine STAr investigational pipeline includes: patisiran (ALN-TTR02) targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); revusiran (ALN-TTRsc) targeting TTR for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC); ALN-AT3 targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5 targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1 targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-AAT targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-TMP targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-GO1 targeting glycolate oxidase (GO) for the treatment of primary hyperoxaluria type 1 (PH1); and other programs yet to be disclosed. Alnylam’s Cardio-metabolic Disease STAr investigational pipeline includes: ALN-PCSsc targeting PCSK9 for the treatment of hypercholesterolemia; ALN-ANG targeting angiopoietin-like 3 (ANGPTL3) for the treatment of mixed hyperlipidemia and hypertriglyceridemia; ALN-AC3 targeting apolipoprotein C-3 (apoC3) for the treatment of hypertriglyceridemia; ALN-AGT targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia; and other programs yet to be disclosed. Alnylam’s Hepatic Infectious Disease STAr investigational pipeline includes: ALN-HBV targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection; ALN-HDV targeting the hepatitis delta virus (HDV) genome for the treatment of HDV infection; ALN-PDL targeting programmed death ligand 1 (PD-L1) for the treatment of chronic liver infections; and other programs yet to be disclosed. The company’s demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, and The Medicines Company. In early 2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product geographic alliance on Alnylam's genetic medicine programs in the rare disease field. Specifically, Alnylam will lead development and commercialization of programs in North America and Europe, while Genzyme will develop and commercialize products in the rest of world. In addition, Alnylam and Genzyme will co-develop and co-commercialize revusiran in North America and Europe. In March 2014, Alnylam acquired Sirna Therapeutics, a wholly owned subsidiary of Merck. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world’s top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, Cell, New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

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 potential for RNAi therapeutics, including ALN-AS1 for the treatment of hepatic porphyrias, the design and timing of clinical studies, the expected timing for reporting of data from clinical studies, its expectations regarding the potency and therapeutic index of GalNAc-siRNA conjugates, including Enhanced Stabilization Chemistry (ESC)-GalNAc conjugates, its expectations regarding its STAr pipeline growth strategy, and its plans regarding 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 may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Alnylam’s ability to discover and develop novel drug candidates and delivery approaches, successfully demonstrate the efficacy and safety of its drug candidates, the pre-clinical and clinical results for its product candidates, which may not support further development of product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials, obtaining, maintaining and protecting intellectual property, Alnylam’s ability to enforce its patents against infringers and defend its patent portfolio against challenges from third parties, obtaining regulatory approval for products, competition from others using technology similar to Alnylam’s and others developing products for similar uses, Alnylam’s ability to manage operating expenses, Alnylam’s ability to obtain additional funding to support its business activities and establish and maintain strategic business alliances and new business initiatives, Alnylam’s dependence on third parties for development, manufacture, marketing, sales and distribution of products, the outcome of litigation, 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 to update any forward-looking statements.