Alnylam and Collaborators Publish Clinical Trial Results with RNAi Therapeutics Targeting Transthyretin (TTR) for the Treatment of TTR-Mediated Amyloidosis (ATTR) in the New England Journal of Medicine

– Represents the Journal’s First Ever Publication of Clinical Trial Results with an RNAi Therapeutic –

– Results from Phase I Trials of ALN-TTR01 and ALN-TTR02 Demonstrate Rapid, Dose-Dependent, Durable, and Specific Knockdown of TTR, the Disease-Causing Protein in ATTR –

Business Wire

CAMBRIDGE, Mass.--(BUSINESS WIRE)--

Alnylam Pharmaceuticals, Inc. (ALNY), a leading RNAi therapeutics company, announced today the publication of complete study results from Phase I trials with ALN-TTR01 and ALN-TTR02 in the New England Journal of Medicine. The paper, titled “Safety and Efficacy of RNAi Therapy for Transthyretin Amyloidosis” (Coelho et al., N Engl J Med 2013;369:819-29), shows that RNAi therapeutics targeting transthyretin (TTR) achieved rapid, dose-dependent, durable, and specific knockdown of TTR, the disease-causing protein in TTR-mediated amyloidosis (ATTR). These results document the most robust proof of concept for RNAi therapy in man to date, including knockdown of serum TTR protein levels of up to 94% after just a single dose of drug.

“Our ATTR program is the lead effort in our ‘Alnylam 5x15’ product development and commercialization strategy, which is focused on advancing innovative RNAi therapeutics toward genetically defined targets for the treatment of diseases with high unmet medical need. Our overall clinical trial experience with RNAi therapeutics for the treatment of ATTR now includes a Phase I trial with ALN-TTR01, Phase I and II trials with ALN-TTR02, and a Phase I trial with ALN-TTRsc, a subcutaneously administered RNAi therapeutic utilizing our proprietary GalNAc conjugate delivery platform,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “The Phase I studies of ALN-TTR01 and ALN-TTR02 demonstrate key human proof of concept for RNAi therapeutics targeting TTR but also for liver-expressed target genes in general, and we are thrilled to be publishing these landmark data in the New England Journal of Medicine. Notably, this is the first time that clinical results with an RNAi therapeutic have been published in the Journal, and we are proud to be associated with this milestone as we lead the clinical translation of RNAi therapeutics as a whole new class of innovative medicines.”

“This new paper describes our clinical trial experience with ALN-TTR01 and ALN-TTR02, which utilize first- and second-generation lipid nanoparticle formulations, respectively. Relative to ALN-TTR01, the results for ALN-TTR02 showed exceptional improvement in potency, without any apparent loss in tolerability, thus documenting the important advances made by Alnylam scientists and collaborators on systemic delivery of RNAi therapeutics. Indeed, with ALN-TTR02 we achieved very robust effects, including up to 94% reduction of serum TTR and a nearly 80% level of suppression sustained at one month with just a single dose. Further, ALN-TTR02 was also found to be generally safe and well tolerated,” said Jared Gollob, M.D., Vice President, Clinical Research at Alnylam. “Knockdown of circulating TTR is expected to result in improved clinical outcomes for patients with ATTR based on data from patients receiving liver transplants. Further, evidence from other systemic amyloidotic diseases shows that as little as a 50% reduction of the disease-causing protein can result in disease improvement or stabilization. Accordingly, we believe the findings published today in the New England Journal of Medicine suggest that the robust, sustained knockdown of TTR levels observed in our clinical trials with ALN-TTR02 may ameliorate the course of disease in patients with ATTR.”

ALN-TTR01 and ALN-TTR02 are systemically delivered RNAi therapeutics using first- and second-generation lipid nanoparticle (LNP) formulations, respectively, that encapsulate an identical siRNA targeting both wild-type and mutant TTR mRNA. The ALN-TTR01 Phase I trial enrolled participants from July 2010 through September 2011, and the ALN-TTR02 Phase I trial enrolled participants from March through May 2012. Both trials were designed as multi-center, randomized, single-blind, placebo-controlled, dose-ranging studies in patients with ATTR (n=32) – in the case of ALN-TTR01, or in healthy adult volunteers (n=17) – in the case of ALN-TTR02. The primary objective of each study was to evaluate the safety and tolerability of a single dose of ALN-TTR01 or ALN-TTR02. In addition, preliminary clinical activity of each drug was evaluated based on measurements of serum TTR protein levels.

Results of the ALN-TTR01 Phase I study demonstrated a dose-dependent reduction in serum TTR levels with a statistically significant mean reduction of 38% at approximately day 7 to 10 in the 1.0 mg/kg group (p

Results of the ALN-TTR02 Phase I study demonstrated substantial knockdown of serum TTR in all participants receiving doses of 0.15 to 0.50 mg/kg. Knockdown was rapid, potent, and durable, with highly significant changes, as compared to placebo (p2=0.83) and vitamin A levels (r2=0.86). Furthermore, a single 0.4 mg/kg dose of an siRNA targeting PCSK9 in the identical LNP formulation showed no effect on serum TTR levels in a separate Phase I trial in healthy volunteers, showing that the effect of ALN-TTR02 on TTR suppression was specific to the TTR siRNA. To confirm the RNAi mechanism of action for TTR knockdown, a 5’ RACE (rapid amplification of cDNA ends) assay was performed on blood samples – processed to isolate liver-derived exosomes – obtained from participants in the 0.3 mg/kg group. The predicted TTR mRNA cleavage product was absent in the pre-dose samples and present in each of the post-dose samples, consistent with the RNAi mechanism. ALN-TTR02 administered as a 60-minute infusion was found to be generally safe and well tolerated, with no serious adverse events or discontinuations in the study related to ALN-TTR02 and no significant adverse events associated with drug up through 0.30 mg/kg. A moderate acute infusion reaction was observed in one subject receiving ALN-TTR02 at 0.50 mg/kg (overall incidence of 7.7%) who was able to complete dosing with slowing of the infusion rate. There were no changes in liver function tests or other laboratory parameters including C-reactive protein and cytokines.

In addition to the clinical results described above, the new paper describes a number of important pre-clinical findings in non-human primates. First, the interrelationship of TTR knockdown in non-human primates and in humans was evaluated, and revealed a closely correlated, essentially superimposable pharmacodynamic effect in the two species at the same mg/kg dose. These results demonstrate that the non-human primate is a predictive species for RNAi therapeutic clinical activity. Also, the results of extended dosing in the non-human primate were described, and showed a sustained pharmacodynamic effect – with no evidence of tachyphylaxis – toward TTR knockdown with increasing nadir effects upon repeat dose administration.

“RNAi therapeutics represent a novel and exciting approach for ATTR patients and have great potential to make a meaningful impact in the treatment of this devastating disease. The ability of RNAi therapeutics to suppress production of hepatic TTR and to reduce circulating levels of both mutant and non-mutant TTR has the potential to delay or even reverse disease progression with associated clinical benefits in patients with ATTR,” said Teresa Coelho, M.D., Director, Unidade Clinica de Paramiloidose, and lead author on the paper. “I am very encouraged with these published data and other more recent data with ALN-TTR02. I look forward to the continued advancement of RNAi therapeutics in clinical trials for the treatment of ATTR, as there are currently few options for patients suffering from this progressive and debilitating genetic disease.”

Alnylam is currently advancing ALN-TTR02 in a Phase II study which is designed as an open-label, multi-center, multi-dose, dose-escalation trial to evaluate the safety and tolerability of two doses of ALN-TTR02 and to demonstrate clinical activity based on serial measurement of circulating serum levels of wild-type and mutant TTR. The study was designed to treat up to 30 ATTR polyneuropathy patients with ALN-TTR02 administered at doses of 0.01 to 0.30 mg/kg, using either a once-every-four-week or once-every-three-week dosing regimen. Interim results, presented at the 2013 Biennial Meeting of the Peripheral Nerve Society, held June 29 – July 3, 2013 in St. Malo, France, showed that multiple doses of ALN-TTR02 led to robust and statistically significant (p

Alnylam is also advancing ALN-TTRsc, a subcutaneously administered RNAi therapeutic targeting TTR for the treatment of ATTR. The company recently announced top-line results from a Phase I study in healthy adult volunteers, in which ALN-TTRsc achieved robust and statistically significant (p

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.

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 LNP Technology

Alnylam has licenses to Tekmira LNP intellectual property for use in RNAi therapeutic products using LNP technology.

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 porphyria including 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 complement component C5 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, Cell, and the New England Journal of Medicine. 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 porphyria including 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 complement component C5 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.

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-TTR01, ALN-TTR02, and ALN-TTRsc, its views regarding the predictive nature of non-human primate data with RNAi therapeutics towards human data, its expectations regarding the reporting of data from its ALN-TTR02 and ALN-TTRsc clinical trials, its expectations with respect to the timing and success of its clinical trials for ALN-TTR02 and ALN-TTRsc, and its expectations regarding the potential market opportunity for ALN-TTR02 and 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-TTR02 and 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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