Alnylam Reports Positive Phase II Data for ALN-TTR02, an RNAi Therapeutic Targeting Transthyretin (T

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

- Interim Results in ATTR Patients Show up to 93% Knockdown of TTR with Activity toward Both Wild-Type and Mutant TTR -

- Multiple Doses of ALN-TTR02 Generally Safe and Well Tolerated with Once-Every-Four-Week and Once-Every-Three-Week Dosing Regimens -


CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (NAS: ALNY) , a leading RNAi therapeutics company, announced today the achievement of positive clinical results from its Phase II trial of ALN-TTR02, an RNAi therapeutic targeting the transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR). The data were presented today at the 2013 Biennial Meeting of the Peripheral Nerve Society, held June 29 - July 3 in St. Malo, France. Interim results show that multiple doses of ALN-TTR02 led to robust and statistically significant (p<0.001) knockdown of serum TTR protein levels of up to 93%. 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, ALN-TTR02 was found to be generally safe and well tolerated in this study.

"These new ALN-TTR02 results are a major milestone in our TTR program, where - for the first time in ATTR patients - we have demonstrated robust knockdown of up to 93% of circulating wild-type and mutant TTR in a multi-dose study. The clinical relevance of lowering circulating TTR has been demonstrated in ATTR patients who have benefited from the elimination of mutant TTR through liver transplantation. In addition, we are very encouraged with the continued safety profile of ALN-TTR02 which has now been extended with this experience in ATTR patients and with multi-dose regimens," said Jared Gollob, M.D., Vice President, Clinical Research at Alnylam. "This Phase II trial continues in patients receiving a once-every-three-week dosing regimen and we plan to share the complete data set at the International Symposium on Familial Amyloidotic Polyneuropathy in Rio de Janeiro this November."

"I am very encouraged by these new clinical activity and safety data with ALN-TTR02, an RNAi therapeutic for the treatment of ATTR. Specifically, I am impressed with the potent, rapid, and durable knockdown of both mutant and wild-type TTR, which is important since TTR protein reduction in patients with ATTR has the potential to delay or even reverse disease progression with associated clinical benefits," said Professor David Adams, M.D., Ph.D., Neurology Department Head at CHU de Bicetre (APHP), Le Kremlin-Bicetre Cedex, France. "I very much 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 debilitating, progressive disease."

The Phase II trial with ALN-TTR02 is 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. To date, 25 patients in eight cohorts have been dosed in the study, and all patients for the final cohort have been scheduled for dosing. The international study is being conducted at 10 sites in Portugal, France, Sweden, Germany, Spain, Brazil, and the U.S.

Data from the first 19 patients enrolled and analyzed in this study showed that multiple doses of ALN-TTR02 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<0.01) and 0.30 mg/kg (p<0.001). At 0.30 mg/kg administered once every four weeks, mean TTR knockdown at nadir of 82.6% and 84.8% was observed following the first and second doses, respectively, and maximum TTR knockdown was up to 90.8%. At 0.30 mg/kg administered once every three weeks, mean TTR knockdown at nadir of 83.1% and 87.4% was observed following the first and second doses, respectively, and maximum TTR knockdown was up to 92.8%.

Summary of ALN-TTR02 Clinical Activity Results

Dose Group (mg/kg)       N         Dose 1         Dose 2
              Max TTR KD (%)        

TTR KD @ Nadir
(Mean % ± SD)

        Max TTR KD (%)        

TTR KD @ Nadir
(Mean % ± SD)

0.01 q4w       4+         37.8         20.1 ± 13.2         34.4         32.9 ± 2.3
0.05 q4w       3         58.0         48.4 ± 16.2         58.5         46.9 ± 15.0
0.15 q4w       3         81.7         74.5 ± 6.8***         86.0         77.0 ± 7.8**
0.30 q4w       6^         87.5         82.6 ± 5.9***         90.8         84.8 ± 10.5***
0.30 q3w       3         83.8         83.1 ± 1.1***         92.8         87.4 ± 5.9***

**p < 0.01 vs. 0.01 mg/kg group; p values from ANCOVA models including baseline TTR as covariate and dose group as factor

***p < 0.001 vs. 0.01 mg/kg group; p values as above

+ Includes first dose data from additional patient prior to protocol amendment

^ Excludes post-day 28 data from patient that experienced drug extravasation during second infusion

A number of additional analyses were performed in this first-ever study of ALN-TTR02 in ATTR patients. First, a proprietary mass spectrometry method was used to measure serum levels of wild-type and mutant V30M proteins. These results demonstrated an essentially 1:1 knockdown of mutant and wild-type TTR (r2=0.95, p<0.001) with superimposable pharmacodynamic effects toward both protein species. Furthermore, a similar degree of TTR knockdown was observed in patients on concurrent TTR stabilizer therapy (specifically, tafamidis or diflunisal) compared to those who received ALN-TTR02 alone. These results demonstrate the absence of any interference by TTR stabilizer drugs with the pharmacologic activity of ALN-TTR02. Finally, and as expected, serum TTR reductions were highly correlated with parallel changes in retinol binding protein (RBP) (r2=0.85, p<0.001) and vitamin A levels (r2=0.84, p<0.001).

Multiple doses of ALN-TTR02 were found to be generally safe and well tolerated. There were no significant adverse events or discontinuations associated with drug up through 0.30 mg/kg. There were no abnormalities in liver function tests, renal function, or hematologic parameters. Adverse events included a mild infusion-related reaction that occurred in one patient who was able to complete dosing with slowing of the infusion rate. An episode of self-limiting cellulitis of the arm, a serious adverse event, occurred as a result of drug extravasation at the infusion site in a patient with poor intravenous access. In the ongoing dosing in patients at 0.30 mg/kg once every three weeks using a reduced and simplified pre-medication regimen, there have been no reports to date of any infusion-related reactions. The new pre-medication regimen includes a reduced steroid dose administered prior to ALN-TTR02 infusion.

Alnylam intends to present the final data from this ALN-TTR02 Phase II study at the IXth International Symposium on Familial Amyloidotic Polyneuropathy (ISFAP) to be held in Rio de Janeiro, Brazil, November 10 - 13, 2013. In addition, the company remains on track to initiate in mid-2013 an open-label extension (OLE) study of ALN-TTR02 for patients treated in the Phase II study. The ALN-TTR02 OLE study will include a number of clinical endpoint measurements, such as neuropathy impairment score, or "NIS," with initial data expected to be presented in 2014. In addition, the company intends to start a Phase III pivotal trial for ALN-TTR02 in familial amyloidotic polyneuropathy (FAP) patients by the end of 2013.

"We are in the midst of a very exciting time at Alnylam, with a steady flow of pre-clinical and clinical data that reflect the strong potential of RNAi therapeutics as innovative medicines. These data points support our ongoing 'Alnylam 5x15' product strategy, where we are advancing RNAi therapeutics toward genetically defined targets for diseases with limited treatment options for patients and their caregivers," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "These ALN-TTR02 data presented today demonstrate robust and durable knockdown of serum TTR, as well as safety and tolerability in a multi-dose study in ATTR patients. By all accounts, these 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 ALN-TTR02 will be best-in-class for the treatment of ATTR patients with polyneuropathy. Assuming continued success in the Phase II study, these results position us well for continued execution on our program, which includes initiation in the next few months of our open label extension study that will include clinical endpoint measurements and the start of our Phase III trial by year's end."

Alnylam has 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 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 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 the C5 component of the complement pathway 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, and Cell. 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 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 the C5 component of the complement pathway 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, and ALN-AS1; the company will seek global development and commercial alliances for other programs.

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 ALN-TTR02, its expectations regarding the reporting of data from its ALN-TTR02 clinical trials, its expectations with respect to the timing and success of its clinical trials for ALN-TTR02, 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 discover and develop novel drug candidates and delivery approaches, successfully demonstrate the efficacy and safety of its drug candidates, including ALN-TTR02, 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 current report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 7, 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.



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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