Alnylam Demonstrates Continued Commitment to Transthyretin-Mediated Amyloidosis Patients with Advancement of ALN-TTRsc02, an Investigational RNAi Therapeutic with Potential for Low Volume, Once Quarterly, Subcutaneous Dose Regimen


- In Pre-clinical Studies, ALN-TTRsc02 Achieves Potent Knockdown of Serum TTR of Up to 99% and Multi-Month Durability After a Single Subcutaneous Dose -

- ALN-TTRsc02 Becomes the Company's Most Potent and Durable RNAi Therapeutic Discovered to Date -

- Company Guides to File Investigational New Drug (IND) or IND-Equivalent in Early 2016, Present Clinical Data in Late 2016, and Initiate a Phase 3 Study in 2017 -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it presented key pre-clinical data and provided program guidance for ALN-TTRsc02, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis). The new data were presented at the 11th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held October 11 - 14, 2015, in Leiden, Netherlands. In pre-clinical studies, including those in non-human primates (NHPs), ALN-TTRsc02 achieved potent and highly durable knockdown of serum TTR of up to 99% with multi-month durability achieved after just a single dose, supportive of a potentially once quarterly dose regimen. Based on these pre-clinical data, ALN-TTRsc02 is the most potent and durable investigational RNAi therapeutic discovered at Alnylam to date. The company is currently conducting Investigational New Drug (IND)-enabling studies and plans to file an IND or IND-equivalent in early 2016 with initial data in late 2016. Assuming positive clinical results, Alnylam expects to initiate a Phase 3 study for ALN-TTRsc02 in 2017.

"Alnylam is fully committed to improving the lives of patients with ATTR amyloidosis, and we believe that our investigational ALN-TTRsc02 program, if successful, has the potential to provide an important therapeutic option for the management of their disease. ALN-TTRsc02 is a logical extension of our overall TTR program, as we're deploying our second generation 'ESC' GalNAc conjugate technology to achieve a best-in-class profile with the potential for a low volume, once quarterly subcutaneous dose regimen," said Eric Green, Vice President, General Manager, TTR Program. "We continue to make excellent progress with patisiran and revusiran, both of which are in Phase 3 studies for the treatment of ATTR amyloidosis, and we now plan to work closely with regulatory authorities to diligently bring ALN-TTRsc02 to patients and the market as an additional option in the future."

ALN-TTRsc02 utilizes the company's Enhanced Stabilization Chemistry (ESC)-GalNAc-siRNA conjugate delivery platform, which enables high potency and durability with a very wide therapeutic index. Clinical data from other RNAi therapeutic programs in Alnylam's pipeline that utilize ESC-GalNAc technology have demonstrated robust efficacy and the potential for a dosing regimen that is monthly, quarterly, or possibly, in certain cases, bi-annually.

In a presentation titled, "Enhanced Pharmacologic Activity and Durability Demonstrated with an ESC GalNAc-siRNA Targeting Transthyretin," Alnylam scientists presented data characterizing the development of ALN-TTRsc02. First, a series of ESC-GalNAc-siRNAs targeting TTR were screened for knockdown activity in transgenic mice and NHPs. These and other data led to selection of the Development Candidate (DC) for ALN-TTRsc02. In pharmacodynamic studies, ALN-TTRsc02 achieved potent and durable knockdown of serum TTR in transgenic mice and NHPs. In NHPs, a single subcutaneous dose at 1 mg/kg led to TTR knockdown of up to 99% with sustained knockdown of more than 50% for greater than 84 days. Monthly subcutaneous dosing at 1 mg/kg achieved sustained TTR knockdown of up to 99% with mean maximal effects greater than 95%. Data were also shown comparing TTR knockdown activity of ALN-TTRsc02 to that of revusiran, a late-stage, investigational RNAi therapeutic targeting TTR that utilizes Alnylam's first generation Standard Template Chemistry (STC)-GalNAc-siRNA conjugate technology. The results showed that ALN-TTRsc02 has a markedly superior TTR knockdown profile compared to revusiran. Finally, in initial rat toxicology studies, ALN-TTRsc02 was found to be generally well tolerated with no significant adverse events at doses as high as 100 mg/kg. Alnylam believes that these data, combined with the improved profile of ESC-GalNAc conjugates in humans compared to NHPs - as evidenced by clinical data from other Alnylam pipeline programs - may allow for a low dose, low volume, once quarterly subcutaneous dose regimen.

Genzyme Alliance

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 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 Transthyretin-Mediated Amyloidosis

Transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis) 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 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-TTRsc02 for the treatment of TTR-mediated amyloidosis, its expectations with respect to the expected timing of regulatory filings, including its plan to file an IND or IND equivalent for ALN-TTRsc02, expectations regarding the reporting of clinical data with ALN-TTRsc02, the expected initiation of a Phase 3 trial for ALN-TTRsc02, its expectations regarding its STAr pipeline growth strategy, and its plans regarding commercialization of RNAi therapeutics, including ALN-TTRsc02, 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.

Alnylam Pharmaceuticals, Inc.
Michael Mason, 617-551-8327
Vice President, Finance and Treasurer
Liz Bryan (Media), 202-955-6222 x2526

Source: Alnylam Pharmaceuticals, Inc.

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