Alnylam

Alnylam Presents New Clinical and Pre-Clinical Data on RNAi Therapeutics at 10th Oligonucleotide Therapeutics Society (OTS) Meeting

10.14.2014

- Additional Phase 1 Clinical Results with ALN-TTRsc and Results from Pre-Clinical Chronic Toxicology Studies Confirm Clinical Activity and Wide Therapeutic Index -

- ALN-GO1, an RNAi Therapeutic Targeting Glycolate Oxidase (GO) in Development for the Treatment of Primary Hyperoxaluria Type 1 (PH1), Advanced as New Program -

- New Pre-Clinical Research Demonstrates Potential for Needle-Less Administration of RNAi Therapeutics with Inhalation for Knockdown of Liver Targets -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, announced today that it presented new data from multiple clinical and pre-clinical studies at the 10th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held October 12 - 15, 2014 in San Diego. Among multiple presentations, the company presented additional data from its Phase 1 trial with ALN-TTRsc, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with TTR cardiac amyloidosis, showing rapid, dose-dependent, stable, and durable knockdown of serum TTR of up to 96.2%. In addition, Alnylam scientists presented pre-clinical data from a new program, ALN-GO1, an investigational RNAi therapeutic targeting glycolate oxidase (GO) in development for the treatment of primary hyperoxaluria type 1 (PH1), showing efficacy in rodent disease models. Finally, new pre-clinical research was presented demonstrating that delivery of Enhanced Stabilization Chemistry (ESC)-GalNAc-siRNA conjugates to the lung achieves similar plasma exposure, efficacy, and duration of liver gene silencing as achieved by subcutaneous delivery. This finding opens up the possibility for needle-less administration of RNAi therapeutics via inhalation for knockdown of liver disease genes.

"Our Phase 1 study of ALN-TTRsc was the first to demonstrate clinical activity and tolerability for RNAi therapeutics using our proprietary GalNAc-conjugate delivery platform that enables subcutaneous administration with a wide therapeutic index. These new data extend our previous presentation by including results from a 7.5 mg/kg cohort where we observe a mean max TTR knockdown of 87.9%. In addition, we have now completed our chronic toxicology studies with ALN-TTRsc, including 6-month rat and 9-month non-human primate studies, which confirmed the wide safety margin established in previous, shorter duration studies. Importantly, we believe these new toxicology results provide additional de-risking for our broader GalNAc-conjugate platform, where we continue to see favorable tolerability results in pre-clinical and clinical studies across an increasing number of programs," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "We are currently conducting a Phase 2 trial of ALN-TTRsc in ATTR patients with TTR cardiac amyloidosis, and we look forward to sharing initial data at a meeting to be held during the American Heart Association meeting on November 15. We remain on track to initiate an open-label extension (OLE) study with ALN-TTRsc in the coming weeks, and expect to begin enrolling patients in our Phase 3 trial in TTR cardiac amyloidosis by the end of this year."

Updated data were presented from the Phase 1 trial of ALN-TTRsc performed in healthy volunteers. Initial results were presented at the Heart Failure Society of America 17th Annual Scientific Meeting in September 2013, and showed robust, consistent, and statistically significant (p < 0.01) knockdown of serum TTR protein levels of up to 94%. The new results include TTR knockdown data for an additional cohort (N=6) receiving doses of 7.5 mg/kg, showing a mean max TTR knockdown of 87.9% and a maximum TTR knockdown of 96.2%. As described before, ALN-TTRsc was generally well tolerated with mild or moderate injection site reactions as the most frequent adverse event, consistent with results from previous cohorts. In addition to the updated clinical data, results from new pre-clinical toxicology data with ALN-TTRsc were presented. Data from 6-month toxicology studies in rats and 9-month toxicology studies in non-human primates (NHPs) showed that chronic dosing with ALN-TTRsc was generally well tolerated. In the 6-month rat study, the No Observed Adverse Effect Level (NOAEL) for ALN-TTRsc was determined to be 30 mg/kg, with adverse findings observed at the 100 mg/kg dose including hepatocyte vacuolation with associated minor increases in liver transaminases (less than or equal to 1.6 times control animals); all were reversed after a three-month non-dosing recovery period. The NOAEL in the rat 6-month study was unchanged from that determined in a previously conducted 6-week study, showing the absence of any cumulative toxicologic effects. In the 9-month NHP study, all doses - including the top dose of 200 mg/kg - were generally well tolerated with no meaningful changes in any hematology and laboratory parameters. The NOAEL will be determined upon completion of histopathology, but is expected to be greater than or equal to 200 mg/kg. The completion of these toxicology studies enables the advancement of ALN-TTRsc into a Phase 3 clinical trial, which is expected to begin by the end of this year, and supports the potential filing of the drug candidate's New Drug Application (NDA). ALN-TTRsc is currently being evaluated in an open-label, multi-dose pilot Phase 2 clinical trial in ATTR patients with TTR cardiac amyloidosis. Alnylam expects to present initial results from the Phase 2 study at a meeting to be held during the American Heart Association meeting in November.

"We are pleased to share a number of new advances from our research efforts. First, we are announcing a new program, ALN-GO1, for the treatment of primary hyperoxaluria type 1 (PH1), an ultra-orphan disease where a defect in glyoxylate metabolism in the liver results in oxalate deposition in the kidney and leads to end-stage renal disease. Pre-clinical data in rodent models of PH1 show that ALN-GO1, an ESC-GalNAc conjugate siRNA targeting glycolate oxidase (GO), achieves robust knockdown of liver GO and substantial reduction in urinary oxalate levels. We plan to identify an ALN-GO1 Development Candidate in mid-2015 and expect to file an investigational new drug application in 2016," said Rachel Meyers, Ph.D., Vice President of Research and RNAi Lead Development at Alnylam. "We are also excited about our work demonstrating the potential for inhalational delivery of GalNAc-siRNA conjugates. Specifically, our new pre-clinical results show that delivery of GalNAc-siRNA conjugates to the lung achieves a comparable level and duration of hepatic target gene knockdown to that observed with subcutaneous injection. We believe that this could allow for the potential development of RNAi therapeutics that employ a needle-less, non-invasive dosing paradigm."

Alnylam scientists and collaborators presented pre-clinical data from the new program, ALN-GO1, in development for the treatment of PH1. PH1 is an autosomal recessive disorder of glyoxylate metabolism, where hepatic detoxification of glyoxylate is impaired due to mutation of the AGXT gene, which encodes the liver peroxisomal alanine-glyoxylate aminotransferase (AGT) enzyme, resulting in excessive oxylate production. Excess oxalate in PH1 patients is unable to be fully excreted by the kidneys leading to the formation of recurrent kidney stones and the deposition of calcium oxalate crystals in the kidneys and urinary tract. Renal damage is caused by a combination of tubular toxicity from oxalate, nephrocalcinosis, and renal obstruction by stones. Compromised kidney function exacerbates the disease as oxalate is released into systemic circulation where it may accumulate and crystalize in bones, eyes, skin, heart, and central nervous system, leading to severe illness and death. About 50% of patients will have kidney failure by age 15, and about 80% will have end stage renal disease by age 301. The prevalence of PH1 reported in Europe ranges from 1 to 9 per million. Higher values are reported in specific populations with a high rate of consanguinity. Many patients are diagnosed under the age of 10 years2. Current treatment options are very limited and although combined organ transplantation of liver and kidneys has been successful, this is risky and limited due to organ availability. The enzyme glycolate oxidase (GO) works upstream of AGT to oxidize glycolate to glyoxylate. Human genetics show that a loss of function mutation in the production of GO results in a 20-fold increase in the amount of glycolate in urine, but no other clinical symptoms, suggesting that knockdown of GO may starve the disrupted pathway of glyoxylate and thereby reduce the oxalate burden in patients with PH1. A panel of ESC-GalNAc-siRNA conjugates targeting GO were screened in vitro for their ability to silence the GO mRNA. The most potent of these were further evaluated in vivo with subcutaneous dosing, and an ESC-GalNAc-siRNA targeting GO was identified that yielded a single-dose ED50 of 1.25 mg/kg and a multi-dose ED50 of 0.3 mg/kg. In addition, this compound demonstrated therapeutic efficacy in rodent models of PH1, as indicated by a significant decrease in levels of urinary oxalate of up to 79%. As noted above, Alnylam plans to select a Development Candidate for ALN-GO1 by mid-2015 and to file an investigational new drug (IND) application in 2016.

Finally, Alnylam scientists presented new pre-clinical data demonstrating the potential for needle-less administration of ESC-GalNAc-siRNA conjugates via inhalation to achieve knockdown of liver gene targets. In mouse studies, ESC-GalNAc-siRNA conjugates targeting the TTR and Factor VII (FVII) mRNAs were shown to achieve comparable knockdown activity in mouse liver when delivered through use of a Microsprayer® device as compared to subcutaneous injection. In addition, the duration of liver gene knockdown and pharmacokinetics for systemic exposure were found to be similar for GalNAc-siRNA administered to the lung as compared with results obtained from subcutaneous dosing. These data provide proof of concept for inhalation as a needle-less, non-invasive approach for administration of RNAi therapeutics targeting liver disease genes.

About ATTR

Transthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene. TTR protein is produced primarily in the liver and is normally a carrier of vitamin A. Mutations in TTR cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy. ATTR represents a major unmet medical need with significant morbidity and mortality; familial amyloidotic polyneuropathy (FAP) affects approximately 10,000 people worldwide and familial amyloidotic cardiomyopathy (FAC) is estimated to affect at least 40,000 people worldwide. FAP patients have a life expectancy of 5 to 15 years from symptom onset, and the only approved treatment options for early stage disease are liver transplantation, and tafamidis (approved in Europe). FAC is fatal within 2.5 to 5 years of diagnosis and treatment is currently limited to supportive care. Senile systemic amyloidosis (SSA) is a non-hereditary form of TTR cardiac amyloidosis caused by idiopathic deposition of wild-type TTR; its prevalence is generally unknown, but is associated with advanced age. There is a significant need for novel therapeutics to treat patients with TTR amyloid polyneuropathy and/or cardiomyopathy.

About Primary Hyperoxaluria Type 1 and ALN-GO1

Primary Hyperoxaluria Type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism. When this metabolic pathway is impaired in PH1, a loss of function in the enzyme that metabolizes glyoxylate into glycine and pyruvate in the liver results in its conversion to oxylate instead. The enzyme glycolate oxidase (GO) works upstream of this defect to oxidize glycolate to glyoxylate. Human genetics shows that a loss of function mutation in the production of GO results in a 20-fold increase in the amount of glycolate in the urine, but no other clinical symptoms, suggesting that knockdown of GO may starve the disrupted pathway of glyoxylate and thereby reduce the oxalate burden in patients with PH1. Excess oxalate in PH1 patients can cause severe kidney damage through recurrent painful kidney stones and the formation and deposition of calcium oxalate crystals in the kidneys and urinary tract. Compromised kidney function exacerbates the disease as oxalate is released into systemic circulation where it may accumulate and crystalize in bones, eyes, skin, heart, and central nervous system, leading to severe illness and death. Most patients present early in life, and greater than 50% of patients progress to end stage renal disease (ESRD) before the age 30. ALN-GO1 is a subcutaneously administered RNAi therapeutic that silences GO. ALN-GO1 utilizes Alnylam's ESC-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.

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 5x15™" 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; ALN-GO1, an RNAi therapeutic targeting glycolate oxidase (GO) for the treatment of Primary Hyperoxaluria Type 1 (PH1); and other programs yet to be disclosed. As part of its "Alnylam 5x15" 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-TTRsc for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR) and ALN-GO1 for the treatment of Primary Hyperoxaluria Type 1 (PH1), the timing of regulatory filings for ALN-TTRsc and ALN-GO1, the timing of clinical studies, including the reporting of data from clinical studies, the potential therapeutic opportunities for ALN-GO1, the potential for needle-less administration of RNAi therapeutics, as well as its expectations regarding its "Alnylam 5x15" product strategy, and its plans regarding commercialization of RNAi therapeutics, including ALN-TTRsc and ALN-GO1, 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.

1 Oxaloxis & Hyperoxaluria Foundation

2 Mayo Clinic Hyperoxaluria Center Registry

Alnylam Pharmaceuticals, Inc.
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Vice President, Investor Relations and Corporate Communications
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