Alnylam Pharmaceuticals, Inc., a leading RNAi therapeutics company, announced the publication of new data in the journal Nature Biotechnology by Alnylam scientists and collaborators from Tekmira Pharmaceuticals Corporation, AlCana Technologies, Inc., and The University of British Columbia (UBC). The new study employed a rational design approach for the discovery of novel lipids that can be incorporated into lipid nanoparticles (LNPs) for systemic delivery of RNAi therapeutics. This new research complements the combinatorial chemistry-based approach recently described by Alnylam scientists in the Proceedings of the National Academy of Sciences (PNAS) (Love et al. (January 11, 2010) Proc. Natl Acad. Sci. USA, 10.1073/pnas.0910603106), and highlights the power of using multiple parallel approaches for optimizing LNPs.

"We are very excited by our continued progress in discovering new LNP compositions that provide dramatic improvements in the systemic delivery of RNAi therapeutics," said Victor Kotelianski, M.D., Ph.D., D.Sc., senior vice president, Distinguished Alnylam Fellow. "As compared with our recent paper from our MIT collaboration just last month, this new paper highlights the results of an entirely different approach using rational design for lipid discovery. When formulated with siRNAs, these new lipids form highly potent LNPs that augment Alnylam's platform of second generation LNPs. We believe that these discoveries will define major new opportunities for Alnylam for the advancement of our pipeline."

The new paper (Semple et al., Nature Biotechnology advance online publication, 17 January 2010 (doi:10.1038/nbt.1602)) describes the discovery of a novel lipid, known as "KC2," based on a medicinal chemistry effort to explore the structure-activity relationships in the lipid "DLinDMA," which is used in certain first generation LNPs such as Tekmira's stable nucleic acid-lipid particles (SNALP) formulations. A large number of novel lipids were synthesized to probe the relationship of lipid structure, such as the alkyl chain, linker, and head group moieties, with function as determined by screening for in vivo gene silencing activity. Additional measurements were performed to characterize the ability of the novel lipids to mediate certain physicochemical changes in lipid bilayers consistent with needed disruption of endosomal membranes. In order to explore its suitability for systemic delivery, the novel KC2 lipid was formulated with siRNA in an LNP formulation. Specifically, the in vivo data showed that: gene silencing in rodents was achieved following a single injection at doses as low as 0.01mg/kg; potent and selective silencing of the clinically relevant gene transthyretin (TTR) was achieved at doses as low as 0.1 mg/kg in non-human primates; and, the formulation was found to be well tolerated in both rodents and non-human primates.

"We've been successful in using distinct, albeit complementary strategies for new lipid discovery that has led to the creation of a robust second generation LNP platform for use in Alnylam's systemic delivery efforts," said Antonin de Fougerolles, Ph.D., vice president research. "The novel KC2-containing LNPs described in the current paper demonstrate potent gene silencing efficacy with siRNA at very low microgram per kilogram doses in several species including non-human primates. We fully expect that the significantly improved potency of these second generation LNPs will yield important advantages for advancement of RNAi therapeutics including lowered material requirements, improved therapeutic index, and expanded scope of delivery beyond the liver."

LNP formulations represent one of several approaches Alnylam is pursuing for systemic delivery of RNAi therapeutics. Additional approaches include novel lipidoid formulations, 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-TTR01 for the treatment of TTR-mediated amyloidosis. ALN-VSP and ALN-TTR01 both utilize a first generation SNALP formulation developed in collaboration with Tekmira Pharmaceuticals Corporation.

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.

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.