Alnylam Announces Positive Initial Phase 2 Data with Revusiran (ALN-TTRsc), an Investigational RNAi Therapeutic Targeting Transthyretin (TTR) for the Treatment of TTR Cardiac Amyloidosis, with up to 98.2% Knockdown of Serum TTR in Patients

Nov 14,2014

- Revusiran Found to be Generally Well Tolerated in Patients with Advanced Cardiac Disease -

- After Five Weeks of Treatment, No Significant Changes in Exploratory Clinical Measurements Observed -

-Data Support Advancement of Revusiran to Phase 3 Clinical Trial;
On Track to Start by Year End -

- Company to Host Conference Call at 8:00 a.m. ET Today to Discuss Data -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today positive initial Phase 2 data with revusiran (ALN-TTRsc), an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR cardiac amyloidosis. Initial results are being presented this weekend to clinicians convening during the American Heart Association meeting held in Chicago, including a meeting of the Association of Black Cardiologists. In the pilot Phase 2 study, revusiran was found to be generally well tolerated in TTR cardiac amyloidosis patients. Revusiran demonstrated clinical activity with an up to 98.2% knockdown of serum TTR - the disease causing protein. This included similar knockdown effects toward wild type and mutant TTR protein within V122I patients, who represent the most common genotype associated with inherited forms of TTR cardiac amyloidosis. In the five week course of treatment, there were no significant changes observed in a number of exploratory clinical measurements. Revusiran utilizes Alnylam's proprietary GalNAc-conjugate delivery platform that enables subcutaneous delivery of RNAi therapeutics with a wide therapeutic index.

"Our pilot Phase 2 study was designed to evaluate the tolerability and initial clinical activity of revusiran in patients with TTR cardiac amyloidosis. These initial results demonstrate that revusiran is generally well tolerated in patients with significant disease burden. In addition, we continue to be impressed with the level of knockdown - up to 98.2% - achieved with revusiran toward both mutant and wild-type TTR. In fact, this level of knockdown is the greatest ever reported for an RNAi therapeutic in clinical studies. As would be expected with the short treatment duration of five weeks, there were no significant changes in the exploratory clinical measurements performed," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "We look forward to further evaluation of revusiran in our Phase 2 open-label extension (OLE) study that is now enrolling patients who participated in the Phase 2 study. We believe long-term dosing with revusiran could provide us with important data on tolerability, in addition to the potential for activity toward clinical endpoints. We plan on sharing data from the OLE study about once annually, beginning in 2015. In addition, having now concluded favorable regulatory discussions in the U.S. and Europe, we expect to begin our Phase 3 trial in TTR cardiac amyloidosis before year's end."

TTR-mediated amyloidosis (ATTR) is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene. These mutations cause misfolding of the protein and the formation of amyloid fibrils that deposit in tissues. One of the clinical manifestations of ATTR is familial amyloidotic cardiomyopathy (FAC), in which TTR amyloid deposition in the heart leads to cardiac wall thickening and heart failure. In addition, wild-type TTR can accumulate as amyloid deposits in the heart of elderly people in a disease known as senile systemic amyloidosis (SSA). 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.

The revusiran pilot Phase 2 study was aimed at evaluating the safety, tolerability, pharmacodynamic, and preliminary clinical activity of revusiran in patients with FAC and SSA. This trial was conducted as an open-label, multi-dose study. Revusiran was administered initially as daily subcutaneous doses for five days and then once weekly for five weeks at doses of 5.0 mg/kg or 7.5 mg/kg, for a total of 10 doses. The primary objective of the study was to evaluate the safety and tolerability of revusiran. The secondary objectives were to assess the clinical activity of revusiran toward serum levels of TTR and characterize the drug's pharmacokinetic profile. In addition, a number of exploratory clinical measurements were performed at baseline and days 42 and 90 after start of dosing.

The initial Phase 2 results presented were from 26 patients, including 14 diagnosed with FAC and 12 with SSA. Results being presented are from a data cutoff date of October 3, 2014. Revusiran was found to be generally well tolerated in both FAC and SSA patients. The most common adverse event was injection site reactions (ISR) that occurred in 23% of patients. These were all mild in severity and were similar to the ISRs observed and previously reported in the revusiran Phase 1 study. The next most common adverse event was a low incidence of transient mild liver function test (LFT) changes (15%) that, in all cases, resolved without discontinuing therapy. In 3 of 4 patients, these elevations appeared to be clinically insignificant and were less than 1.5 times the upper limit of normal (ULN). One patient had an approximate 4-fold elevation in liver transaminases that was deemed a serious adverse event (SAE) and mild in severity; this event resolved during continued dosing. There was also a low incidence (15%) of mild, transient, and clinically insignificant monocytosis (increase in percentage monocyte count), which occurred in 4 individuals with elevated baseline monocytosis. There were no discontinuations and no significant changes in renal function or any other laboratory chemistry or hematologic parameters.

Revusiran demonstrated clinical activity in TTR cardiac amyloidosis patients as measured by knockdown of serum TTR, the disease-causing protein. Specifically, administration of revusiran resulted in potent, rapid, and durable knockdown of serum TTR of up to 98.2%, with a mean maximum knockdown of 87.2% +/- 9.1%. Using a mass spectrometric assay capable of measuring the V122I mutant TTR, a similar level of knockdown was observed for wild-type and mutant TTR in V122I patients. In particular, there was a strong correlation of knockdown of the wild-type protein and the V122I mutant protein (r2=0.79, p less than 0.0001). Further, a similar degree of TTR knockdown was observed in both FAC and SSA patients. After five weeks of treatment in this small study population, there were no significant changes observed in the exploratory clinical measurements performed, including 6-minute walk distance (6-MWD), modified body mass index (mBMI), echocardiogram and cardiac MRI, circulating cardiac biomarkers including NT-proBNP and troponin, and questionnaires to assess cardiomyopathy symptoms and quality of life. Alnylam expects to present the full data set from this Phase 2 trial in early 2015.

"TTR cardiac amyloidosis represents a significant unmet medical need with no approved therapies, and I believe that revusiran holds promise as a potential new treatment option for patients. I am very encouraged by these initial Phase 2 results, showing a favorable tolerability profile, in addition to potent and rapid knockdown of circulating levels of serum TTR, the disease-causing protein," said Julian Gillmore, M.D., Ph.D., of the National Amyloidosis Centre, University College London. "I look forward to continuing to work with Alnylam as they advance this investigational agent in clinical development."

Alnylam has also initiated its Phase 2 open-label extension (OLE) study of revusiran. All patients who completed dosing in the Phase 2 trial are eligible to be enrolled in the OLE study. Revusiran will be administered at a fixed subcutaneous dose of 500 mg, with once-daily dosing for the first five days followed by weekly dosing thereafter. The study is designed to evaluate the tolerability and clinical activity of revusiran with long-term dosing for up to two years. In addition to data on mortality, hospitalization, general tolerability, and knockdown of serum TTR, the study will assess a number of clinical endpoints every six months. These include the same exploratory clinical measures used in the pilot Phase 2 trial noted above, as well as additional measures of amyloid burden including technetium imaging of the heart and quantitation of amyloid in abdominal fat pad aspirates. The company expects to present results from the revusiran Phase 2 OLE study at least once annually starting in 2015. Finally, Alnylam has now completed its meetings with regulatory authorities from the U.S. and EU regarding the design of a Phase 3 trial for revusiran in TTR cardiac amyloidosis, and expects to initiate the study by the end of the year. The company will provide details on the design of this study when it announces the start of the Phase 3 trial.

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. In the case of revusiran, Alnylam and Genzyme are co-developing and co-commercializing the investigational RNAi therapeutic in North America and Western Europe, while Genzyme is developing and commercializing revusiran in the rest of world.

Conference Call Information

Alnylam management will discuss these initial Phase 2 results with revusiran (ALN-TTRsc), for the treatment of TTR cardiac amyloidosis in a webcast conference call on Friday, November 14 at 8:00 a.m. ET. A slide presentation will also be available on the News & Investors page of the company's website,, 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 35351048. A replay of the call will be available beginning at 11:00 a.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 35351048.

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 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) targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); revusiran (ALN-TTRsc) 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 targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5 targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1 targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-HBV targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection; ALN-TMP targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3 targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; ALN-AGT targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia; ALN-GO1 targeting glycolate oxidase (GO) for the treatment of primary hyperoxaluria type 1 (PH1); ALN-HDV targeting the hepatitis delta virus (HDV) genome for the treatment of HDV infection; ALN-PDL targeting programmed death ligand 1 (PD-L1) for the treatment of chronic liver infections; 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 revusiran 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

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 revusiran (ALN-TTRsc) for the treatment of FAC, its expectations with respect to timing of regulatory filings and the reporting of initial data from its Phase 2 OLE clinical trial for revusiran, the expected start of a Phase 3 trial for revusiran, and, the potential therapeutic opportunities for revusiran, as well as its expectations regarding its "Alnylam 5x15" product 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 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.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and
Corporate Communications
Spectrum (Media)
Liz Bryan, 202-955-6222 x2526

Source: Alnylam Pharmaceuticals, Inc.

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