Alnylam Initiates Phase 1 Clinical Trial for ALN-AS1, an Investigational RNAi Therapeutic Targeting Aminolevulinic Acid Synthase 1 (ALAS1) for the Treatment of Acute Hepatic Porphyrias, Including Acute Intermittent Porphyria (AIP)

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, announced today that it has initiated a Phase 1 clinical trial with 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). The Phase 1 trial of ALN-AS1 will be conducted initially in AIP patients who are asymptomatic "high excreters" (ASHE). These ASHE subjects have a defined mutation in the porphobilinogen deaminase (PBGD) gene and elevated urinary levels of aminolevulinic acid (ALA) and porphobilinogen (PBG), but do not have a current history of porphyria attacks or disease activity. Subsequently, the trial is designed to enroll AIP patients who experience recurrent porphyria attacks. The company expects to present initial clinical data from this trial in early 2016.

"We believe ALN-AS1 has the potential to be a transformative therapy for patients with acute hepatic porphyrias, a group of ultra-rare monogenic diseases with enormous unmet medical need, and we're excited to now advance this innovative investigational medicine to the clinic. Our Phase 1 study aims to obtain data on safety and tolerability in addition to potential clinical activity in ASHE subjects and AIP patients with recurrent attacks," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam. "We're encouraged by the potential for ALN-AS1 to make a difference in the lives of people afflicted with acute hepatic porphyrias. In pre-clinical studies performed in rodent models of AIP, we have shown that subcutaneous administration of ALN-AS1 results in complete suppression of the toxic heme biosynthesis intermediates that cause disease symptoms and pathology. We very much look forward to the advancement of ALN-AS1 in the clinic and expect to share initial data from the Phase 1 trial in early 2016."

"Patients with AIP often present with acute, and at times recurrent attacks that are characterized by severe abdominal pain, neuropathy, neuropsychiatric manifestations, and, in very severe cases, paralysis and respiratory failure. Novel therapies are needed for porphyria patients who suffer from recurrent attacks. These patients can spend a significant number of days in the hospital every month and have a very poor quality of life," said Eliane Sardh, M.D., Ph.D., Senior Physician at the Porphyria Centre Sweden and the Centre for Inherited Metabolic Diseases and Department of Endocrinology, Metabolism and Diabetes at Karolinska University Hospital in Stockholm, Sweden. "I am encouraged with the pre-clinical data to date with ALN-AS1, which I believe support the potential for an RNAi therapeutic as a novel therapeutic option for patients with AIP and other acute hepatic porphyrias."

ALN-AS1 is a subcutaneously administered, investigational RNAi therapeutic that employs Alnylam's ESC-GalNAc delivery technology. ESC-GalNAc-siRNA conjugates are designed to achieve targeted delivery of RNAi therapeutic 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 ALN-AS1 led to rapid, dose-dependent, and long-lasting knockdown of the ALAS1 mRNA in the liver of 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 production of ALA and PBG, the toxic heme intermediates in AIP. Pre-clinical studies with RNAi therapeutics targeting ALAS1 have been published by Alnylam and collaborators previously (Yasuda et al., Proc Natl Acad Sci USA 2014;111(21):7777-7782).

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 subjects. The primary objective of Part A and Part B 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 urinary 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 and other disease symptoms, use of hematin and pain medications, number and duration of hospitalizations, and quality of life.

"Patients afflicted with acute hepatic porphyrias, such as AIP, can suffer from severe and recurrent attacks that are potentially life-threatening and that can result in a markedly decreased ability to lead a normal functioning life. Current treatment options are limited, especially for patients with recurrent attacks that often require monthly hospitalizations for administration of hematin and pain management," said Desiree LyonCo-Founder and Executive Director of the American Porphyria Foundation. "Today is an important step forward for our patient community, as ALN-AS1, a promising investigational medicine for the treatment of acute hepatic porphyrias, has entered clinical testing. I am so pleased with Alnylam's commitment to make a difference in the lives of our patients."

In addition to the Phase 1 trial, Alnylam and clinicians from the American Porphyria Consortium and The European Porphyria Network are currently enrolling patients in the EXPLORE trial, a prospective observational study of patients with acute hepatic porphyrias - including 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 acute hepatic porphyrias that suffer from recurrent attacks.

In January 2014, Alnylam and Genzyme, a Sanofi company, formed an alliance to accelerate and expand the development and commercialization of RNAi therapeutics across the world. The alliance is structured as a multi-product geographic alliance in the field of rare diseases. Alnylam retains product rights in North America and Western Europe, while Genzyme obtained the right to access certain programs in Alnylam's current and future Genetic Medicines pipeline, including ALN-AS1, in the rest of the world. In certain defined instances, Genzyme has co-development/co-commercialization and/or global product rights. Genzyme's rights are structured as an opt-in that is triggered upon achievement of human proof-of-principle.

About ALN-AS1

Alnylam is developing 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. ALN-AS1 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. ALN-AS1 has the potential to be a prophylactic approach for the prevention of recurrent attacks, as well as for the treatment of acute porphyria attacks.

About Acute 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. Acute 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 acute hepatic porphyria 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 heme intermediates that precipitate disease symptoms. Patients with one of the acute 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 approved treatment for acute attacks is hematin (Panhematin® or Normosang®), a preparation of heme derived from human blood. Hematin requires administration through a large vein or a central intravenous line and is associated with a number of complications including thrombophlebitis or coagulation abnormalities. While hematin is not approved for prophylactic use (i.e., the prevention of acute attacks), it is often used in this manner in patients who experience recurrent attacks. Chronic administration of hematin has been found to result in renal insufficiency, iron overload, systemic infections (due to the requirement for central venous access) and, in some instances, tachyphylaxis.

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. Alnylam's pipeline of investigational RNAi therapeutics is focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline of RNAi therapeutics for the treatment of rare diseases; Cardio-Metabolic Disease, with a pipeline of RNAi therapeutics toward genetically validated, liver-expressed disease targets for unmet needs in cardiovascular and metabolic diseases; and Hepatic Infectious Disease, with a pipeline of RNAi therapeutics that address the major global health challenges of hepatic infectious diseases. In early 2015, Alnylam launched its "Alnylam 2020" guidance for the advancement and commercialization of RNAi therapeutics as a whole new class of innovative medicines. Specifically, by the end of 2020, Alnylam expects to achieve a company profile with 3 marketed products, 10 RNAi therapeutic clinical programs - including 4 in late stages of development - across its 3 STArs. The company's demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. 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 about Alnylam's pipeline of investigational RNAi therapeutics, please visit

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 acute hepatic porphyrias, its expectations regarding the reporting of data from its ALN-AS1 clinical studies, its expectations regarding the potential market opportunity for ALN-AS1, 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 be replicated or continue to occur in other subjects or in additional studies or otherwise 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.