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Alnylam Pharmaceuticals (ALNY)'s Gene Therapy Shows Strong Efficacy Data in Phase 1 Study  
9/23/2013 6:53:11 AM

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Alnylam Reports Positive Clinical Results – with up to 94% Knockdown of Serum Transthyretin (TTR) – for ALN-TTRsc, a Subcutaneously Delivered RNAi Therapeutic for the Treatment of TTR-Mediated Amyloidosis (ATTR)

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (ALNY), a leading RNAi therapeutics company, announced today positive interim results from its Phase I clinical trial of ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting the transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR). The data are being presented today at the Heart Failure Society of America 17th Annual Scientific Meeting being held September 22 – 25, 2013 in Orlando, Fla. Results show that ALN-TTRsc administration led to robust, consistent, and statistically significant

“These new ALN-TTRsc results are a major milestone in our ATTR program, as well as our entire pipeline of RNAi therapeutics. Specifically, we have demonstrated robust, up to 94% knockdown of circulating TTR with a very encouraging safety profile. We believe this level of consistent TTR knockdown is exceptional and unmatched, and we now aim to advance ALN-TTRsc in future clinical studies with the goal of achieving approximately 90% TTR knockdown to maximize clinical efficacy,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “These new data support our belief that ALN-TTRsc has the potential to be an important therapeutic for the treatment of familial amyloidotic cardiomyopathy (FAC) – a disease for which there are no approved therapies. With these results in hand, we are well positioned for continued execution on this program, which includes the initiation of a pilot Phase II study in FAC patients by the end of this year, and – assuming positive results – start of a pivotal Phase III trial with ALN-TTRsc by the end of 2014.”

ATTR is caused by mutations in the TTR gene which cause abnormal TTR amyloid protein deposits to accumulate in various tissues including peripheral nerves and heart, resulting in 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) affects at least 40,000 people worldwide. ALN-TTRsc, which is being developed for the treatment of FAC, is a subcutaneously administered RNAi therapeutic that comprises an siRNA conjugated to a GalNAc ligand that enables receptor-mediated delivery to the liver. ALN-TTRsc is the first GalNAc-siRNA – and the first subcutaneously delivered systemic RNAi therapeutic – to enter clinical development stages. Alnylam is also developing ALN-TTR02, an intravenously administered RNAi therapeutic targeting TTR for the treatment of ATTR patients with FAP.

The Phase I trial of ALN-TTRsc is being conducted in the U.K. as a randomized, double-blind, placebo-controlled, single- and multi-dose, dose-escalation study, enrolling up to 40 healthy volunteer subjects. The primary objective of the study is to evaluate the safety and tolerability of single and multiple doses of subcutaneously administered ALN-TTRsc. Secondary objectives include assessment of clinical activity of the drug as measured by serum TTR levels. In an initial single-ascending dose phase of the study, subjects (n=16) received subcutaneous doses of placebo or ALN-TTRsc from 1.25 to 10 mg/kg. In the multiple-ascending dose phase of the study, subjects (n=12) received 10 subcutaneous doses of placebo or ALN-TTRsc from 2.5 to 10 mg/kg. Upon completion of this Phase I trial, the company expects to start a pilot Phase II clinical study of ALN-TTRsc in FAC patients in late 2013 and, assuming positive results, plans to start a pivotal Phase III trial with ALN-TTRsc in FAC patients in 2014.

Interim data from the 28 subjects enrolled and analyzed in this study to date showed that single- and multi-dose administration of ALN-TTRsc resulted in rapid, dose-dependent, consistent, and durable knockdown of serum TTR levels. In the multi-dose cohorts (n=12), there was a statistically significant knockdown of serum TTR at doses of 2.5 mg/kg (p ** p ***p p values from ANCOVA models including baseline TTR and dose groups as factors

Analysis of the TTR knockdown in humans as compared to results obtained in non-human primates showed a closely correlated, essentially one-to-one relationship on a mg/kg basis (r2=0.83, p

In this study as reported to date, single and multiple doses of ALN-TTRsc were found to be generally safe and well tolerated. There were no significant adverse events associated with drug at doses through 10.0 mg/kg. All adverse events were deemed mild or moderate in severity. Injection site reactions were observed in a minority of subjects receiving ALN-TTRsc (24%) or placebo (14%). These were reported as being clinically mild and consisted of transient erythema associated in a minority of cases with edema and/or pain. In all cases, these reactions were self-limiting and resolved within approximately two hours of onset. There were no study discontinuations, flu-like symptoms, or changes in cytokines, C-reactive protein (CRP), liver function tests, renal function, or hematologic parameters.

“I am very encouraged by these new clinical activity and safety data with ALN-TTRsc. Specifically, I am impressed with the potent, rapid, and durable knockdown as well as the favorable safety profile observed to date,” said Professor Philip N. Hawkins, National Amyloidosis Centre, Division of Medicine, and University College London Medical School, Royal Free Hospital. “Clearly, the ability of this RNAi therapeutic to achieve a consistent, approximately 90% knockdown of TTR sets a new benchmark that I believe has the potential to translate into meaningful clinical benefit for patients. I very much look forward to the continued advancement of RNAi therapeutics in clinical trials for the treatment of ATTR – both FAP and FAC – as there are currently very few options for patients suffering from this debilitating, progressive disease.”

“We are in the midst of very exciting times at Alnylam, with a steady flow of pre-clinical and clinical data that reflect the strong potential of RNAi therapeutics as an emerging class of innovative medicines. These new Phase I clinical results with ALN-TTRsc establish human translation for RNAi therapeutics that utilize our GalNAc-siRNA conjugate delivery platform. This platform enables subcutaneous dose administration with a wide therapeutic index and has now become our primary approach for execution on our ‘Alnylam 5x15’ product strategy,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “Importantly, we believe these new results demonstrate an unmatched level of efficacy for RNA therapeutics with a consistent, approximately 90% target gene knockdown via subcutaneous dose administration, in addition to a very promising safety profile. As a result, we believe these data are very meaningful not only for the continued advancement of ALN-TTRsc, but also for the continued execution on our entire ‘Alnylam 5x15’ product strategy. Through this strategy, we believe that we are building a compelling opportunity for shareholder value creation with a modular and reproducible approach for development and, ultimately, commercialization of innovative medicines for genetically defined diseases.”

In 2012, Alnylam entered into an exclusive alliance with Genzyme, a Sanofi company, to develop and commercialize RNAi therapeutics, including ALN-TTR02 and ALN-TTRsc, for the treatment of ATTR in Japan and the broader Asian-Pacific region. Alnylam plans to develop and commercialize the ALN-TTR program in North and South America, Europe, and rest of the world.

Conference Call Information

Management will discuss these Phase I clinical data with ALN-TTRsc on Monday, September 23, 2013 at 8:00 a.m. ET. A slide presentation will also be available on the News & Investors page of the company’s website, www.alnylam.com, to accompany the conference call. To access the call, please dial 877-312-7507 (domestic) or 631-813-4828 (international) five minutes prior to the start time and refer to conference ID 68228737. A replay of the call will be available beginning at 11:00 a.m. ET on Monday, September 23, 2013. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 68228737.

About Transthyretin-Mediated Amyloidosis

Transthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited, progressively debilitating, and fatal disease caused by mutations in the TTR gene. TTR protein is produced primarily in the liver and is normally a carrier for retinol binding protein. 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) affects at least 40,000 people worldwide. FAP patients have a life expectancy of five to 15 years from symptom onset, and the only treatment options for early stage disease are liver transplantation and tafamidis (approved in Europe). The mean survival for FAC patients is approximately 2.5 years, and there are no approved therapies. There is a significant need for novel therapeutics to treat patients who have inherited mutations in the TTR gene.

About 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. Research findings demonstrate potent and durable target gene silencing, as well as a wide therapeutic index, with subcutaneously administered GalNAc-siRNAs from multiple “Alnylam 5x15” programs.

About RNA Interference (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 toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: 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 familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; and ALN-CC5, an RNAi therapeutic targeting the C5 component of the complement pathway for the treatment of complement-mediated diseases, amongst other programs. As part of its “Alnylam 5x15TM” strategy, the company expects to have five RNAi therapeutic products for genetically defined diseases in clinical development, including programs in advanced stages, on its own or with a partner by the end of 2015. Alnylam has additional partnered programs in clinical or development stages, including ALN-RSV01 for the treatment of respiratory syncytial virus (RSV) infection and ALN-VSP for the treatment of liver cancers. The company’s leadership position on RNAi therapeutics and intellectual property have enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, Ascletis, Monsanto, Genzyme, and The Medicines Company. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam has also formed Alnylam Biotherapeutics, a division of the company focused on the development of RNAi technologies for applications in biologics manufacturing, including recombinant proteins and monoclonal antibodies. Alnylam’s VaxiRNA™ platform applies RNAi technology to improve the manufacturing processes for vaccines; GlaxoSmithKline is a collaborator in this effort. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 100 peer-reviewed papers, including many in the world’s top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, and Cell. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

About “Alnylam 5x15™”

The “Alnylam 5x15” strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics toward genetically defined targets for the treatment of diseases with high unmet medical need. Products arising from this initiative share several key characteristics including: a genetically defined target and disease; the potential to have a major impact in a high unmet need population; the ability to leverage the existing Alnylam RNAi delivery platform; the opportunity to monitor an early biomarker in Phase I clinical trials for human proof of concept; and the existence of clinically relevant endpoints for the filing of a new drug application (NDA) with a focused patient database and possible accelerated paths for commercialization. By the end of 2015, the company expects to have five such RNAi therapeutic programs in clinical development, including programs in advanced stages, on its own or with a partner. The “Alnylam 5x15” programs include: 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 familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; and ALN-CC5, an RNAi therapeutic targeting the C5 component of the complement pathway for the treatment of complement-mediated diseases, amongst other programs. Alnylam intends to focus on developing and commercializing certain programs from this product strategy itself in North and South America, Europe, and other parts of the world; these include ALN-TTR, ALN-AT3, ALN-AS1, and ALN-CC5, amongst other programs.

Alnylam Forward-Looking Statements

Various statements in this press release concerning Alnylam’s future expectations, plans and prospects, including without limitation, Alnylam’s expectations regarding its “Alnylam 5x15” product strategy, Alnylam’s views with respect to the potential for RNAi therapeutics, including ALN-TTRsc, its expectations regarding the reporting of data from its ALN-TTRsc clinical trials, its expectations with respect to the timing and success of its clinical trials for ALN-TTRsc, and its expectations regarding the potential market opportunity for ALN-TTRsc, 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, including ALN-TTRsc, 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 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 Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on August 9, 2013 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.

Contact:

Alnylam Pharmaceuticals, Inc.

Cynthia Clayton, 617-551-8207

Vice President, Investor Relations and

Corporate Communications

or

Spectrum

Amanda Sellers (Media), 202-955-6222 x2597

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