Alnylam Reports Positive Phase II Data for Patisiran (ALN-TTR02), an RNAi Therapeutic Targeting Transthyretin (TTR) for the Treatment of TTR-Mediated Amyloidosis (ATTR), and Initiates Phase III Trial

Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, announced today the achievement of positive clinical results from its Phase II trial of patisiran (ALN-TTR02), an RNAi therapeutic targeting the transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR). The data are being presented at the IXth International Symposium on Familial Amyloidotic Polyneuropathy (ISFAP) being held in Rio de Janeiro, Brazil, November 10 – 13. Results showed that multiple doses of patisiran led to robust and statistically significant knockdown of serum TTR protein levels of up to 96%, with mean levels of TTR knockdown exceeding 85%. Knockdown of TTR, the disease-causing protein in ATTR, was found to be rapid, dose dependent, and durable, and similar activity was observed toward both wild-type and mutant protein. In addition, patisiran was found to be generally safe and well tolerated in this study. The company also announced today the initiation of the APOLLO Phase III trial of patisiran in ATTR patients with FAP, with the study now open for enrollment.

“These new data confirm what we have seen consistently with our patisiran program, namely that we can achieve robust knockdown of circulating wild-type and mutant TTR. Specifically, in this Phase II study, we demonstrated up to 96% knockdown of TTR, the disease-causing protein in ATTR, and established a dose and dose regimen for evaluation in our Phase III trial. Knockdown of circulating TTR is expected to result in improved clinical outcomes for patients with ATTR based on data from FAP 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,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “In addition, we continue to be very encouraged with the safety profile of patisiran which has now been extended with this experience in ATTR patients and with multi-dose regimens. By all accounts, these new data are consistent with our earlier experience from pre-clinical and Phase I clinical studies showing excellent translation of RNAi therapeutics, and support our belief that patisiran has the potential to be best-in-class for the treatment of ATTR patients with polyneuropathy.”

The Phase II study with patisiran in ATTR polyneuropathy patients (n=29) was an open-label, multi-center, multi-dose, dose-escalation trial to evaluate the safety and tolerability of two doses of patisiran and to demonstrate clinical activity based on serial measurement of circulating serum levels of wild-type and mutant TTR. Patients received two doses of patisiran in 5 cohorts with doses ranging from 0.01 to 0.30 mg/kg, using either a once-every-four-week or once-every-three-week dosing regimen. The international study included 10 sites in Portugal, France, Sweden, Germany, Spain, Brazil, and the U.S. Interim results from the Phase II study were presented at the 2013 Biennial Meeting of the Peripheral Nerve Society, held June 29 – July 3.

The new data from 28 patients enrolled and currently analyzed showed that multiple doses of patisiran resulted in rapid, dose-dependent, and durable knockdown of serum TTR levels. As compared with the lowest dose group of 0.01 mg/kg, there was a statistically significant knockdown of serum TTR at doses of 0.15 mg/kg (p<0.05) and 0.30 mg/kg (p<0.001). The study results support further evaluation of patisiran at the 0.30 mg/kg dose administered once every three weeks. With this dose and regimen, mean TTR knockdown at nadir of 83.8% and 86.7% was observed following the first and second doses, respectively, with maximum TTR knockdown of up to 96.0%. A more detailed summary of TTR knockdown data is provided in the table below.

A number of additional analyses were performed in this first-ever multi-dose study of patisiran in ATTR patients. First, a proprietary mass spectrometry method was used to measure serum levels of wild-type and mutant V30M proteins. These results showed 1:1 correspondence in knockdown of mutant and wild-type TTR (r²=0.95, p<0.001), with essentially superimposable pharmacodynamic effects toward both protein species. Of interest, patients on TTR stabilizer therapy (specifically tafamidis or diflunisal) showed significantly increased baseline levels of serum TTR; regardless, patisiran administration resulted in a similar degree of TTR knockdown in these patients. These results confirm the absence of any interference by TTR stabilizer drugs with the pharmacologic activity of patisiran, and also demonstrate that RNAi-mediated knockdown of TTR is achieved independent of baseline TTR serum levels. Finally, and as expected, serum TTR knockdown was highly correlated with a reduction in circulating levels of retinol binding protein (RBP) (r²=0.89, p<0.001) and vitamin A (r²=0.90, p<0.001).

Multiple doses of patisiran were found to be generally safe and well tolerated in this study. The majority of the adverse events were mild or moderate. There were no abnormalities seen in liver function tests, renal function, or hematologic parameters. There were two serious adverse events. As previously reported, an episode of self-limiting cellulitis of the arm occurred as a result of drug extravasation at the infusion site in a patient with poor intravenous access. In addition, an episode of nausea and vomiting occurred in a patient with autonomic involvement due to disease; this patient discontinued the study after one dose. The most common adverse event reported was a mild or moderate infusion-related reaction (IRR) which occurred in 10.3% (3/29) of patients overall; this adverse event was managed with a prolonged intravenous infusion and was not associated with any patient discontinuations. Notably, no IRRs were reported among 12 patients who received 0.30 mg/kg once every three weeks, 9 of whom received their infusion with a proprietary micro-dosing regimen administered over 70 minutes.

“I am very encouraged by these clinical activity and safety data with patisiran, an RNAi therapeutic for the treatment of ATTR. In particular, the potent, rapid, and durable knockdown of both mutant and wild-type TTR achieved by patisiran is important since TTR protein reduction in patients with ATTR has the potential to delay or even reverse disease progression with associated clinical benefit,” said Ole Suhr, M.D., Adjunct Professor in the Department of Public Health and Clinical Medicine, Umea University in Sweden, and an investigator in Alnylam’s ATTR clinical trials. “I very much look forward to participating in the continued clinical advancement of this RNAi therapeutic, including the ongoing Phase II open-label extension study and the recently initiated APOLLO Phase III trial, as there are currently few options for our patients suffering from this debilitating, progressive disease.”

Alnylam is currently enrolling patients in a Phase II open-label extension (OLE) study with patisiran. Eligible patients treated in the Phase II study can enroll in the OLE study, where they will receive patisiran at a dose of 0.30 mg/kg every three weeks for up to two years. The primary objective of this study is to evaluate the long-term safety and tolerability of patisiran administration. In addition, the study will measure a number of clinical endpoints every six months. This includes measurement of a modified composite Neuropathy Impairment Score, termed “mNIS+7,” which is an evaluation of muscle weakness, sensory and autonomic function, and nerve conductance across a 304-point scale, where neuropathy progression leads to an increased score over time. A number of additional clinical endpoints will be assessed, including: quality of life; timed 10-meter walk test to evaluate mobility; modified body mass index as a measure of nutritional status; level of disability; and nerve fiber density in skin biopsies. In addition, serum TTR levels will be measured. Initial data from the OLE study are expected to be presented in 2014, with periodic updates thereafter approximately once a year.

Alnylam also announced today that it has initiated the APOLLO Phase III study of patisiran. The APOLLO Phase III trial is a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of patisiran in ATTR patients with FAP. The primary endpoint of the study is the difference in the change in mNIS+7 between patisiran and placebo at 18 months. Secondary endpoints include: the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score; NIS-weakness; modified BMI; timed 10-meter walk; and the COMPASS-31 autonomic symptom score. The trial is designed to enroll up to 200 FAP patients with a baseline NIS in the range of 10 to 100, which represents patients with Stage 1 or Stage 2 disease. Patients will be randomized 2:1, patisiran:placebo, with patisiran administered at 0.30 mg/kg once every three weeks for 18 months. The study was designed with 90% power to conservatively detect as little as a 37.5% difference in change in mNIS+7 between treatment groups, with a two-sided alpha of 0.05. The placebo mNIS+7 progression rate was derived from an Alnylam analysis of natural history data from 283 FAP patients. Alnylam has obtained protocol assistance for the patisiran Phase III study from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) and has completed its End-of-Phase II meeting with the U.S. Food and Drug Administration (FDA). All patients completing the APOLLO Phase III study will be eligible to enroll in a Phase III OLE study.

“We are very pleased to be announcing today that we have initiated our APOLLO Phase III trial, which is now open for enrollment. As the company’s first ever Phase III study, this is a very significant milestone in our history and also for the entire field of RNAi therapeutics. Further, initiation of our Phase III trial with patisiran highlights continued execution on our ‘Alnylam 5x15’ product development and commercialization strategy, which is focused on advancing RNAi therapeutics toward genetically defined targets for the treatment of diseases with high unmet medical need,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “The APOLLO study aims to evaluate the efficacy and safety of patisiran for the treatment of ATTR patients with FAP. Importantly, the study design has been supported by an analysis of FAP patient natural history data collected over the last several years. Further, we believe our discussions with the FDA and EMA support the use of this single, global study for marketing authorization. We will now focus on enrollment of FAP patients in the Phase III trial as a top priority for Alnylam, fulfilling our commitment to bring this potential novel therapy to patients and their caregivers.”

In 2012, Alnylam entered into an exclusive alliance with Genzyme, a Sanofi company, to develop and commercialize RNAi therapeutics, including patisiran 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 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: 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 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-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; 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; and, ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease, amongst other programs. As part of its “Alnylam 5x15” 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, the 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.

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: patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR in development for the treatment of ATTR in patients with familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) in development for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) in development for the treatment of porphyria including acute intermittent porphyria (AIP); ALN-CC5, an RNAi therapeutic targeting complement component C5 in development for the treatment of complement-mediated diseases; ALN-PCS, an RNAi therapeutic targeting PCSK9 in development for the treatment of hypercholesterolemia; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 in development for the treatment of beta-thalassemia and iron-overload disorders; and, ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) in development for the treatment of AAT deficiency liver disease, 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.

Alnylam Forward-Looking Statements

Various statements in this 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 patisiran (ALN-TTR02), its expectations with respect to the timing, execution, and success of its clinical trials for ALN-TTR02 and its expectations regarding the use of a single, global Phase III study of ALN-TTR02 for marketing authorization, and its expectations regarding the potential market opportunity for ALN-TTR02, 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 manage operating expenses, 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 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.

Photos/Multimedia Gallery Available: http://www.businesswire.com/multimedia/home/20131110005028/en/