Alnylam and Collaborators at MIT Report New Pre-clinical Research on Systemic Delivery of RNAi Therapeutics

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, and collaborators from the David H. Koch Institute for Integrative Research at the Massachusetts Institute of Technology (MIT) today announced the publication of new data in the journal Proceedings of the National Academy of Sciences (PNAS) describing further advancements in discovery and development of novel "lipidoid” formulations for the systemic delivery of RNAi therapeutics. Lipidoids are lipid-like materials discovered for the delivery of RNAi therapeutics, and were originally described by Alnylam and MIT collaborators (Akinc et al., Nature Biotechnology, 26: 561-569, 2008). In particular, the new research findings demonstrate the discovery of new lipidoid materials that facilitate significantly improved in vivo potency for RNAi therapeutics.

"We are very encouraged with the substantial progress we and our collaborators have made with lipid nanoparticles (LNPs) based on novel lipid-like materials such as lipidoids,” said Victor Kotelianski, M.D., Ph.D., D.Sc., Senior Vice President, Distinguished Alnylam Fellow. "To our knowledge, these new LNP formulations facilitate endogenous liver gene silencing at doses that are orders-of-magnitude lower than those required by previously described siRNA delivery approaches, thereby setting a new standard in potency for the systemic delivery of RNAi therapeutics. In addition, the current study is the first to report on the simultaneous and highly specific RNAi-mediated silencing of as many as five liver targets in vivo, serving as proof of principle that multiple genes involved in similar or divergent biological pathways can be silenced with a single administration of a single drug product. From a therapeutic standpoint, this could enable novel pharmaceutical strategies, where silencing of multiple targets could achieve an enhanced level of efficacy.”

The new pre-clinical data describe a formulation based on a lipidoid known as "C12-200” that was shown to:

• enable gene silencing in vivo in rodents at doses below 0.01 mg/kg;
• demonstrate complete, rapid, and durable gene silencing in rodents as soon as 24 hours with protein levels returning to baseline within 20 to 35 days;
• specifically inhibit expression of as many as five target genes simultaneously after a single injection of an LNP formulation in rodents; and,
• demonstrate potent and selective silencing of the clinically relevant gene transthyretin (TTR) at doses as low as 0.03 mg/kg in non-human primates.

"We are excited by the delivery performance of these new formulations,” said Daniel Anderson, Ph.D. of the David H. Koch Institute for Integrative Cancer Research at MIT. "This work demonstrates that doses measured in micrograms per kilogram can provide potent gene silencing with RNAi in several species including primates. This greatly improved efficacy allows us to dramatically decrease the dose levels of LNPs, thereby widening the therapeutic index, and also opens the door to formulations that can simultaneously inhibit multiple genes or pathways.”

Lipidoid formulations represent one of several approaches Alnylam is pursuing for systemic delivery of RNAi therapeutics. Additional approaches include other lipid nanoparticles formulations, mimetic lipoprotein particles (MLPs), siRNA conjugation strategies, and single-stranded RNAi, among others. Alnylam is currently enrolling patients in a Phase I clinical program with its systemic RNAi therapeutic ALN-VSP for the treatment of liver cancers. In addition, Alnylam intends to initiate a Phase I trial in the first half of 2010 for an additional systemic RNAi therapeutic, ALN-TTR for the treatment of TTR-mediated amyloidosis. ALN-VSP and ALN-TTR both utilize a first generation lipid nanoparticle formulation known as stable nucleic acid-lipid particles (SNALP), developed in collaboration with Tekmira Pharmaceuticals Corp.

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 RNAs (siRNAs), 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 applying its therapeutic expertise in RNAi to address significant medical needs, many of which cannot effectively be addressed with small molecules or antibodies, the current major classes of drugs. Alnylam is leading the translation of RNAi as a new class of innovative medicines with peer-reviewed research efforts published in the world’s top scientific journals including Nature, Nature Medicine, and Cell. The company is leveraging these capabilities to build a broad pipeline of RNAi therapeutics; its most advanced program is in Phase II human clinical trials for the treatment of respiratory syncytial virus (RSV) infection and is partnered with Cubist and Kyowa Hakko Kirin. In addition, the company is developing RNAi therapeutics for the treatment of a wide range of disease areas, including liver cancers, hypercholesterolemia, Huntington’s disease, and TTR amyloidosis. The company’s leadership position in fundamental patents, technology, and know-how relating to RNAi has enabled it to form major alliances with leading companies including Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, and Cubist. To reflect its outlook for key scientific, clinical, and business initiatives, Alnylam established "RNAi 2010” in January 2008 which includes the company’s plan to significantly expand the scope of delivery solutions for RNAi therapeutics, have four or more programs in clinical development, and to form four or more new major business collaborations, all by the end of 2010. Alnylam is a joint owner of Regulus Therapeutics, a joint venture focused on the discovery, development, and commercialization of microRNA therapeutics. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit http://www.alnylam.com.

About the Koch Institute

The MIT Center for Cancer Research (CCR) has changed its name to the David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute – pronounced "coke”) effective March 2008. This name change is linked to generous funding received in support of the creation of a new building and endeavor, to be completed by the year 2010, to house expanded and innovative cancer research at MIT. Note that all CCR facilities and faculty members have been incorporated into the Koch Institute.

Alnylam Forward-Looking Statement

Various statements in this release concerning Alnylam’s future expectations, plans and prospects, 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 the company’s ability to successfully demonstrate efficacy and safety of its drug candidates in human clinical trials, as well as those risks more fully discussed in the "Risk Factors” section of its most recent quarterly report on Form 10-Q on file with the Securities and Exchange Commission. 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.