Alnylam and Collaborators Publish Results from Phase I Clinical Trial and Extension Study with ALN-V

Alnylam and Collaborators Publish Results from Phase I Clinical Trial and Extension Study with ALN-VSP, an RNAi Therapeutic for the Treatment of Liver Cancer

- Results Published in Cancer Discovery Document Most Comprehensive Human Experience To Date for RNAi Therapeutics Delivered with Lipid Nanoparticles (LNPs) -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (NAS: ALNY) , a leading RNAi therapeutics company, and collaborators announced today the publication of complete study results from a Phase I trial with ALN-VSP, a systemically delivered RNAi therapeutic for the treatment of advanced solid tumors with liver involvement. The paper, titled "First-in-Man Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement" appears as an OnlineFirst publication in the journal Cancer Discovery (Tabernero et al.,Cancer Discovery CD-12-0429; Published OnlineFirst January 2013). The study results document anti-tumor activity for ALN-VSP in a heavily pre-treated and advanced patient population, including a complete response in an endometrial cancer patient who had multiple hepatic metastases. In addition, this study provided proof of RNAi mechanism in man based on molecular analysis of biopsy samples from patients. Finally, in this study - the most comprehensive study of a systemically administered RNAi therapeutic to date - chronic dosing of ALN-VSP for up to 26 months was found to be generally safe and well tolerated.

"Our ALN-VSP Phase I clinical trial defines the most comprehensive human experience for RNAi therapeutics delivered with lipid nanoparticle formulations. Results from this study highlight safety and tolerability of multiple doses of ALN-VSP, proof of RNAi activity in man, and evidence for anti-tumor activity in a very advanced, heavily pre-treated cancer patient population," said Jared Gollob, M.D., Vice President, Clinical Research at Alnylam. "We are encouraged by the anti-tumor activity observed in this study in multiple patients who achieved stable disease or better; this includes a patient with endometrial cancer metastatic to the liver who achieved a complete response. Results from the extension study also give us increased confidence in long-term chronic dosing for RNAi therapeutics delivered with lipid nanoparticle formulations, as patients received an average of over 11 months of treatment overall, including one patient who received treatment for over two full years."

ALN-VSP is a systemically delivered RNAi therapeutic using first-generation lipid nanoparticle (LNP) or "SNALP" delivery technology that comprises two siRNAs targeting two genes critical for the growth and development of cancer cells: vascular endothelial growth factor (VEGF) and kinesin spindle protein (KSP). The ALN-VSP Phase I trial was designed as a multi-center, open-label, dose-escalation study in patients with advanced solid tumors with liver involvement who failed to respond to or had progressed after standard treatment. A total of 41 patients were enrolled. The primary objective was to evaluate the safety, tolerability, and pharmacokinetics of intravenously administered ALN-VSP given every two weeks. Other secondary and exploratory objectives included: assessment of tumor response using Response Evaluation Criteria for Solid Tumors (RECIST); quantitation of change in tumor blood flow and vascular permeability as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI); and, analysis of pharmacodynamic effects of ALN-VSP on tumors as measured in patients electing to proceed with voluntary pre- and post-treatment biopsies.

Results of the Phase I study in 41 patients were previously presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in 2011 and demonstrated proof of RNAi mechanism based on liver biopsy samples and disease control (stable disease or better after first two months) in 13/31 (42%) patients treated at doses greater than or equal to 0.4 mg/kg. ALN-VSP was generally safe and well tolerated up to a dose of 1.0 mg/kg. The most common adverse events were grade 1-2 fatigue (24% of patients), nausea (17% of patients) and fever (17% of patients), with no clear dose relationship. There were also no dose-dependent changes in liver function tests. Grade 2 infusion-related reactions were observed in 15% of patients, or 3% of total doses administered; these reactions responded to slowing of the infusion of drug, and no patients discontinued therapy because of an infusion reaction. Dose-limiting toxicities included: liver failure and death in one patient with extensive hepatic metastases involving greater than 70% of liver mass and prior splenectomy/partial hepatectomy at 0.7 mg/kg; transient grade 3 thrombocytopenia in two patients at 1.25 mg/kg; and grade 3 hypokalemia in one patient at 1.5 mg/kg.

The ALN-VSP extension study was designed to enable continued dosing with ALN-VSP in patients who had achieved stable disease or better after completing four months of treatment on the Phase I trial. Patients enrolled onto the extension study were permitted to receive bi-weekly ALN-VSP at the same dose level that they had been safely treated with in the Phase I study until disease progression or unacceptable toxicity; a total of seven patients were enrolled. The primary objective was to collect long-term safety data. The secondary objective was to assess tumor response.

Results from the extension study were previously presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in 2012 and demonstrated that chronic dosing with ALN-VSP up to 1.0 mg/kg was generally safe and well tolerated in this setting. On average, patients received bi-weekly treatments for 11.3 months. An endometrial cancer patient achieved a complete response (CR) after 20 months of treatment at 0.7 mg/kg and remained in remission upon completion of 26 months of therapy. A patient with pancreatic neuroendocrine tumor (PNET) treated at 1.0 mg/kg remained on study with stable disease (SD) for 18 months, and two patients with renal cell carcinoma (RCC) treated at 1.0 mg/kg remained on study with SD for approximately 8-12 months. No new toxicities were reported among the patients enrolled onto the extension study. A PNET patient and an RCC patient who achieved SD at 1.0 mg/kg came off the study after 5.5 and 8.5 months, respectively, for adverse events that included grade 3 elevated alkaline phosphatase or grade 2 fatigue deemed possibly related to study drug. A decrease in spleen volume, likely an on-target anti-KSP effect and not associated with any adverse events, occurred to a greater degree on the extension study than in the Phase I trial and was most pronounced in patients receiving 12 or more doses.

"Both primary liver cancer and metastatic disease of the liver are associated with poor prognosis for patients, and new therapies are clearly needed," said Josep Tabernero, M.D., Chairman of the Medical Oncology Department and Phase I Program at Vall d'Hebron University Hospital in Barcelona, Spain. "This Phase I trial and extension study with ALN-VSP represents, to our knowledge, the most comprehensive clinical trial of a systemically delivered RNAi therapeutic and also the most extensive experience with RNAi therapeutics in cancer. The safety data and anti-tumor activity with ALN-VSP, including a complete response in a patient with multiple liver metastases who had failed multiple prior therapies, are very encouraging and I look forward to the further development of this promising agent."

In 2012, Alnylam and Ascletis Pharmaceuticals (Hangzhou) Co., Ltd., a privately held U.S.-China joint venture pharmaceutical company, formed a strategic collaboration for the development of ALN-VSP in China. Alnylam will retain all rights in the rest of the world, and is eligible to receive milestones and royalties from Ascletis based on product sales.

About Liver Cancers

Cancer affecting the liver, known as either primary or secondary liver cancer, is associated with one of the poorest survival rates in oncology and represents a major unmet medical need affecting a large number of patients worldwide. Primary liver cancer, or hepatocellular carcinoma (HCC), is one of the most common cancers worldwide, with more than 630,000 people diagnosed each year including approximately 350,000 in China. Secondary liver cancer, also known as metastatic liver cancer, is cancer that spreads to the liver from another part of the body due to other common cancers like colon, lung, or breast cancer. Worldwide, more than 500,000 people are diagnosed with secondary liver cancer each year.

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 for the treatment of genetically defined diseases, including ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-AT3 for the treatment of hemophilia and rare bleeding disorders (RBD), ALN-AS1 for the treatment of acute intermittent porphyria, ALN-PCS for the treatment of hypercholesterolemia, and ALN-TMP for the treatment of hemoglobinopathies. As part of its "Alnylam 5x15^TM" 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, and Genzyme. In addition, Alnylam holds a significant 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.

Alnylam Forward-Looking Statements

Various statements in this release concerning Alnylam's future expectations, plans and prospects, including without limitation, statements regarding Alnylam's views with respect to the potential for RNAi therapeutics, including the potential for ALN-VSP, and Alnylam's expectations regarding its "Alnylam 5x15" product strategy, 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 successfully demonstrate the efficacy and safety of its drug candidates and the pre-clinical and clinical results for these product candidates, including ALN-VSP, which may not support further development of such product candidates, both our and Ascletis' ability to successfully advance ALN-VSP resulting in the potential payment of milestones and royalties to us, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials for such product candidates, obtaining, maintaining and protecting intellectual property, obtaining regulatory approval for products, competition from others using technology similar to Alnylam's and others developing products for similar uses, and Alnylam's ability to establish and maintain strategic business alliances, including its collaboration with Ascletis, and new business initiatives, as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's current report on Form 8-K filed with the Securities and Exchange Commission (SEC) on January 14, 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 does not assume any obligation to update any forward-looking statements.

Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and Corporate Communications
or
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Amanda Sellers, 202-955-6222 x2597 (Media)

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