Alnylam and Collaborators Discover Key Mechanism for Delivery of RNAi Therapeutics

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has discovered a key mechanism related to the systemic delivery of RNAi therapeutics using lipid nanoparticles (LNPs). The new pre-clinical research was presented at the "Advances in Biopharmaceuticals” Keystone Symposium held January 8-13, 2010 in Midway, Utah, and was performed in collaboration with scientists at the Max Planck Institute of Molecular Cell Biology and Genetics. The new data document a key mechanism for endogenous targeting of LNPs to the liver, provide alternative targeting strategies for the hepatic delivery of RNAi therapeutics, and highlight potential targeting approaches for delivery to non-hepatic tissues and cell types.

"A key achievement this past year was our progress in systemic delivery of RNAi therapeutics, the critical scientific determinant for advancement of this promising new class of medicines to patients,” said Victor Kotelianski, M.D., Ph.D., D.Sc., Senior Vice President, Distinguished Alnylam Fellow. "As noted recently, one dimension of our progress is evidenced by the discovery of novel LNP compositions that have markedly enhanced potency with efficacy achieved at microgram per kilogram dose levels. Today, we’re very pleased to announce our discovery of a key mechanism for systemic delivery by LNPs, a finding that reveals a very promising new frontier for RNAi therapeutics with targeted delivery.”

"We’re very excited about our new findings as they provide critical mechanistic insights for the continued advancement of LNPs as a platform for systemic delivery of RNAi therapeutics,” said Akin Akinc, Ph.D., Associate Director, Research at Alnylam. "Indeed, we have demonstrated that the endogenous protein apolipoprotein E (ApoE) mediates the liver uptake of certain LNPs in a manner that mimics physiologic mechanisms for lipoprotein metabolism. Further, we’ve demonstrated the ability to engineer exogenous targeting of LNPs to yet another liver receptor, pointing to the broader opportunity of targeting LNPs to distinct cell types and tissues beyond the liver.”

The new in vitro and in vivo research findings establish the role of ApoE as an endogenous targeting ligand for neutrally charged ionizable LNPs (iLNPs), but not certain cationic LNPs (cLNPs), and demonstrate an alternative targeting strategy for the hepatic delivery of RNAi therapeutics using the carbohydrate N-acetylgalactosamine (GalNAc) as an exogenous ligand. Data from these studies showed:

• in cultured liver cells, ApoE dramatically enhanced both the cellular uptake and silencing activity of siRNAs formulated in iLNPs;
• in an ApoE knockout mouse model, iLNPs demonstrated a complete loss of activity due to the absence of ApoE as an endogenous targeting ligand;
• however, in vivo activity was found to be fully restored through the addition of an exogenous source of ApoE (recombinant ApoE, or "r-ApoE”) when the protein was pre-mixed with iLNPs prior to their co-administration;
  
  
  • specifically, the data showed that as little as 0.03 mg/kg of r-ApoE was able to fully restore the activity of an siRNA formulated in an iLNP; and,
• alternatively, in the same ApoE knockout model, silencing activity was found to be restored by the use of an exogenous GalNAc ligand that targets the iLNP to the asialoglycoprotein receptor (ASGR) expressed on hepatocytes, with as little as 0.15 mole% GalNAc ligand being sufficient to give near maximal activity.

LNP formulations represent one of several approaches Alnylam is pursuing for systemic delivery of RNAi therapeutics. Additional approaches include novel lipidoid formulations, including cLNPs; mimetic lipoprotein particles (MLPs); siRNA conjugation strategies; and single-stranded RNAi; amongst 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 transthyretin (TTR)-mediated amyloidosis. ALN-VSP and ALN-TTR both utilize a first generation LNP formulation known as stable nucleic acid-lipid particles (SNALP), which contains an ionizable lipid, and is 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. RNAi therapeutics target the cause of diseases by potently silencing specific messenger RNAs (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, TTR amyloidosis, hypercholesterolemia, and Huntington’s disease. 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 and Isis are joint owners of Regulus Therapeutics Inc., a company focused on the discovery, development, and commercialization of microRNA-based therapeutics. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

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 discover and develop novel drug candidates, 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.