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Alnylam Initiates EXPLORE, a Prospective Observational Study of Patients with Hepatic Porphyrias

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Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, and collaborators from the American Porphyria Consortium and The European Porphyria Network have initiated the EXPLORE trial, a prospective observational study of patients with hepatic porphyrias, including Acute Intermittent Porphyria (AIP), Variegate Porphyria, and Hereditary Coproporphyria, suffering from recurrent attacks. With this study, Alnylam and clinical investigators aim to learn more about the clinical course, management, and disease burden of patients with hepatic porphyrias that suffer from recurrent attacks. Alnylam is currently advancing ALN-AS1, a subcutaneously administered investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS-1) for the treatment of hepatic porphyrias, and expects to file an IND or IND equivalent in late 2014 or early 2015.

“We believe ALN-AS1 has the potential to be a transformative therapy for patients with hepatic porphyrias, a group of ultra-rare genetic diseases, including AIP, where there is enormous unmet medical need. With the initiation of EXPLORE, we aim to learn more about the clinical course, management, and overall disease burden through patient and physician assessments, in addition to a number of laboratory analyses, for patients with hepatic porphyrias. We believe that these results could give us critical insights in the disease course and management of porphyria, improving our ability to better design trials for our ALN-AS1 investigational therapy,” said Amy Simon, M.D., Senior Director of Clinical Development at Alnylam. “To date, we have generated encouraging pre-clinical data showing that ALN-AS1 can achieve potent, rapid, and durable suppression of the toxic heme biosynthesis intermediates that cause the symptoms and disease pathology of AIP. We’re pleased to report that we remain on track to file an IND or IND equivalent for ALN-AS1 later this year or early next year.”

“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. Patients with these frequent attacks can spend a significant number of days in the hospital 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. EXPLORE is an important component of this overall effort, since this study should help us more fully understand the clinical manifestations and treatment of AIP patients suffering from recurrent attacks.”

EXPLORE is a prospective, multi-center observational study designed to enroll up to 100 patients with hepatic porphyrias and a history of recurrent attacks. The study’s primary objective is to characterize the natural history, clinical management, and disease burden of patients with hepatic porphyrias. The study’s secondary objectives are to further characterize a number of disease features of hepatic porphyrias, including: (i) signs and symptoms of porphyria during acute attacks; (ii) levels of plasma and urinary aminolevulinic acid (ALA) and porphobilinogen (PBG), the toxic intermediates of the heme biosynthesis pathway that cause the symptoms and disease pathology of the acute hepatic porphyrias; (iii) expression levels of aminolevulinic acid synthase-1 (ALAS-1) during acute attacks; and (iv) medical and family history of hepatic porphyria patients. Data obtained from EXPLORE are expected to further the understanding of hepatic porphyrias and to assist the design of clinical trials with ALN-AS1.

Hepatic porphyrias are a set of ultra-rare orphan diseases caused by loss-of-function mutations in enzymes involved in heme biosynthesis, leading to accumulation of toxic heme intermediate precursors. In the case of AIP, there are approximately 5,000 patients in the U.S. and Europe that suffer acute, life-threatening porphyria attacks every year; there are approximately 500 patients afflicted with recurrent debilitating attacks, that can occur as frequently as once per month or more. Treatment options for AIP patients suffering from an attack are limited, and include the administration of intravenous heme, which can have a slow therapeutic onset, limited efficacy with repeat administration and side effects including phlebitis, iron overload, and infections related to the need for central venous access in some patients. Currently, there are no approved drugs available to prevent attacks from occurring. Alnylam’s approach is to knock down ALAS-1, the first enzyme in the heme biosynthesis pathway that is upstream of other enzymes defective in the hepatic porphyrias. RNAi-mediated silencing of ALAS-1 in hepatocytes could reduce the abnormal production of the toxic heme intermediates, specifically aminolevulinic acid (ALA) and porphobilinogen (PBG), which mediate the symptoms and disease pathology in multiple acute hepatic porphyrias. Alnylam believes that a subcutaneously administered RNAi therapeutic targeting ALAS-1 has the potential to be used as a prophylactic approach to prevent attacks, and also as a therapy for acute attacks.

“The hepatic porphyrias represent an enormous unmet medical need, and patients afflicted with these diseases are in need of new treatment options. These diseases are often misdiagnosed, since symptoms can be similar in appearance to more common conditions,” said Desiree Lyon Howe, Executive Director of the American Porphyria Foundation. “I applaud the efforts of Alnylam, the American Porphyria Consortium, and The European Porphyria Network to better understand the disease burden and clinical management of porphyria patients with recurrent attacks. I believe that the data obtained from EXPLORE will be important in the development of novel therapies for patients with hepatic porphyrias.”

Alnylam is advancing ALN-AS1 for the treatment of hepatic porphyrias. In pre-clinical studies and as published in the Proceedings of the National Academy of Sciences, silencing of ALAS-1 with either prophylaxis or acute treatment dosing regimens resulted in complete inhibition of ALA and PBG production in rodent models of AIP. ALN-AS1 utilizes the company’s proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform enabling subcutaneous dosing with increased potency and durability, and a wide therapeutic index.

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 in each case 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 left untreated.

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, durability, and a wide therapeutic index, and 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 with a core focus on RNAi therapeutics as genetic medicines, including programs as part of the company’s “Alnylam 5x15TM” product strategy. Alnylam’s genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-HBV, an RNAi therapeutic targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; ALN-AGT, an RNAi therapeutic targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia; and other programs yet to be disclosed. As part of its “Alnylam 5×15″ strategy, as updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development – including at least two programs in Phase 3 and five to six programs with human proof of concept – by the end of 2015. 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 ALN-TTRsc 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, its expectations regarding the EXPLORE trial, the timing of regulatory filings for ALN-AS1, and the potential therapeutic opportunities for ALN-AS1, as well as its expectations regarding its “Alnylam 5×15″ product strategy, and its plans regarding commercialization of RNAi therapeutics, including ALN-AS1, 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.

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