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Alnylam and Collaborators Present New Clinical Data for Patisiran, an RNAi Therapeutic Targeting Transthyretin (TTR) in Development for the Treatment of TTR-Mediated Amyloidosis (ATTR)

Companies mentioned in this article: Alnylam Pharmaceuticals, Inc.

CAMBRIDGE, Mass. -- (BUSINESS WIRE) -- Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, and collaborators announced today new clinical data for patisiran (ALN-TTR02), an RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of TTR-mediated amyloidosis (ATTR). These data are being presented at the International Symposium on Amyloidosis (ISA) held April 27 – May 1, 2014 in Indianapolis, Indiana. First, the company presented updated Phase 2 results in patients with Familial Amyloidotic Polyneuropathy (FAP) confirming robust TTR knockdown of up to 96% with a mean TTR knockdown of approximately 80%. Further, Alnylam presented preliminary results from the open-label extension (OLE) study with patisiran in patients that were enrolled in the Phase 2 study. Preliminary results from the OLE study showed that multiple doses of patisiran achieved sustained knockdown of serum TTR protein levels at the 80% target level through 168 days. Moreover, OLE results showed a favorable tolerability profile with up to eight doses administered. Finally, the company presented results of a natural history, cross-sectional analysis study of 283 FAP patients aimed at measuring the rate of neuropathy progression and its correlation with disease severity. These results provide support for Alnylam’s Phase 3 APOLLO trial where patisiran is being evaluated for its potential efficacy and safety in the FAP indication.

“We continue to make strong progress in our patisiran development program, which is focused on making a difference in the lives of ATTR patients with polyneuropathy. Several highlights from our efforts are being presented at ISA, including updated Phase 2 study results, initial data from our Phase 2 OLE study, and results from a natural history study of neuropathy progression in FAP. Notably, our initial results from the Phase 2 OLE confirm a sustained TTR knockdown at the 80% target level through up to 168 days. Further, we are very encouraged by the tolerability data, especially the significant reduction in infusion reactions due to the use of our proprietary micro-dosing regimen. With this early update on the OLE study, we still expect to present clinical endpoint data results later this year consistent with our external guidance,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “Another notable highlight is the presentation of FAP natural history study results. This cross-sectional analysis evaluated the neuropathy progression rate in a multinational population of patients with FAP, and demonstrates a rapid progression in NIS and a high correlation of this measurement with disease severity. Moreover, these results give us confidence that our APOLLO Phase 3 trial of patisiran in FAP patients is robustly powered to show the potential impact of TTR lowering on the mNIS+7 endpoint used in that study.”

Alnylam presented updated results from its Phase 2 study of patisiran, which was conducted in 29 patients with FAP where patients received two doses of drug administered as an intravenous infusion. As previously reported at the International Society of Familial Amyloidotic Polyneuropathy (ISFAP) meeting in November 2013, patisiran demonstrated a rapid, dose-dependent, and durable knockdown of serum TTR of up to 96% and an average TTR knockdown of approximately 80%. The updated data included results from an additional patient dosed in the study and follow up TTR knockdown data from other patients.

The company also presented initial results from its Phase 2 OLE study with patisiran. The OLE study is enrolling patients that were treated in the Phase 2 study and is designed to evaluate the long-term safety and tolerability of patisiran administration. The OLE study is also measuring a number of clinical endpoints every six months, including the modified composite Neuropathy Impairment Score, termed "mNIS+7"; this score is also the primary endpoint of the Phase 3 APOLLO trial of patisiran in FAP. Further, serum TTR levels are being measured following the first dose and then pre-dose every six to twelve weeks; since TTR levels are measured pre-dose, the results are a conservative estimate of TTR knockdown achieved over time with repeat dosing. Of the 29 patients eligible for enrollment, 25 have been enrolled to date and an additional two patients are expected to be enrolled by the end of May; the results from 23 patients are currently evaluable for analysis based on a data cut-off as of April 3, 2014.

Preliminary results showed that the TTR knockdown observed following the first dose in the OLE study closely matched TTR knockdown shown in the Phase 2 study, with essentially superimposable pharmacodynamic effects. Moreover, repeat dosing of patisiran led to a sustained TTR knockdown of approximately 80% through up to day 168, equivalent to up to eight doses of drug, as measured in pre-dose blood samples. These data provide the first clinical evidence of sustained, RNAi-mediated TTR knockdown in FAP patients beyond two doses of patisiran. Repeat dosing of patisiran was found to be well tolerated, with minimal adverse events. Importantly, the incidence of infusion-related reactions (IRR) was found to be significantly reduced to 2% in patients from the Phase 2 and Phase 2 OLE studies receiving study drug with a proprietary micro-dosing regimen, as compared with an incidence of 15% in patients receiving a standard infusion (p=0.03). All other reported adverse events were mild to moderate, and there were no changes in liver function tests, renal function, or hematological parameters. Consistent with earlier guidance, Alnylam continues to plan on reporting initial clinical endpoint data from the OLE study in late 2014. Specifically, the company expects to have 6-month mNIS+7 data from approximately 20 patients at that time. The company intends to provide recurrent updates from the OLE study at least annually thereafter.

“These preliminary clinical activity and safety data from the OLE study with patisiran are promising. In particular, the potent, rapid, and durable knockdown of TTR achieved by patisiran, which is now confirmed to be sustained with multi-dosing, is important since TTR protein reduction in patients with ATTR may have the potential to delay or even reverse disease progression with associated clinical benefit. It is also encouraging to see the favorable tolerability profile for multiple dose administration of patisiran, including the clear reduction in the occurrence of infusion reactions with micro-dosing,” said David Adams, Head of Department of Neurology and Coordinator of the French Reference Center for FAP (NNERF)/APHP/CHU Bicêtre/France. “I very much look forward to participating in the continued clinical advancement of this RNAi therapeutic, including the ongoing Phase 2 OLE and APOLLO Phase 3 studies, as there are currently few options for our FAP patients suffering from this debilitating, progressive, and life-threatening disease.”

Finally, Alnylam and collaborators announced today the results of a 283-patient natural history study of patients with FAP. The aim of the study was to characterize neuropathy severity and rate of progression in a multinational population of FAP patients. The retrospective cross-sectional analysis showed a change in the NIS rate of 14.3 points per year, consistent with the rate of 11.6 points per year observed in the placebo arm of the diflunisal Phase 3 trial, which included both V30M and non-V30M FAP patients. This change in NIS rate corresponds to a change in the mNIS+7 rate of approximately 17.8 points per year. Results demonstrated that NIS is highly correlated with Polyneuropathy Disability (PND) Score (p<0.0001 by ANOVA) and FAP Stage (p<0.0001 by ANOVA). NIS was also shown to be associated with TTR genotype, with the early-onset V30M population exhibiting a significantly lower median NIS compared to late-onset V30M or non-V30M patients (p<0.001). The results of the natural history study provide a solid foundation for the conduct of the ongoing Phase 3 APOLLO trial of patisiran, which is aimed at establishing the efficacy and safety of patisiran in ATTR patients with FAP.

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 approved 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. 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 LNP Technology

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

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 the Genzyme Collaboration

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 obtains the right to access Alnylam’s current “5x15” and future genetic medicines pipeline in the rest of the world (ROW), including co-development/co-commercialization and/or global product rights for certain programs. In the case of patisiran, Alnylam will advance the product in North America and Western Europe, while Genzyme will advance the product in the ROW.

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 5x15TM” 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), 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 TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; 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, The Medicines Company, and Genzyme, a Sanofi company. 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, 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™” and Genetic Medicines

The “Alnylam 5x15” strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics as genetic medicines. Alnylam’s genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of diseases with high unmet medical need. These programs share several key characteristics including: a genetically defined target and disease expressed in the liver; the potential to have a major impact in a high unmet need population; the ability to leverage the existing Alnylam RNAi platform with clinically proven delivery to the liver; the opportunity to monitor an early biomarker in Phase 1 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. 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 “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 TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) in development for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 in development for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) in development for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 in development for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 in development for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; and other programs yet to be disclosed. In 2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product geographic alliance on Alnylam’s genetic medicine programs. 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 ALN-TTRsc in North America and Europe.

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 patisiran for the treatment of ATTR, its expectations regarding its "Alnylam 5x15" product strategy, its expectations with respect to the design, timing, and success of its clinical trials, including its Phase 3 APOLLO study, its expectations regarding the reporting of data from its clinical trials, 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 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 Annual Report on Form 10-K 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.


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