Alnylam Pharmaceuticals reports significant progress in discovery of novel technologies for systemic delivery of RNAi therapeutics

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, and collaborators from the Massachusetts Institute of Technology (MIT), The University of British Columbia (UBC), AlCana Technologies, Inc., and Tekmira Pharmaceuticals Corporation, presented results from multiple ongoing research efforts regarding the discovery of novel technologies for the systemic delivery of RNAi therapeutics. A total of 12 oral presentations and posters were presented at the International Liposome Research Days and Lipids, Liposomes & Membrane Biophysics meeting held at UBC in Vancouver, Canada, August 4-8, 2010. Among many new research achievements, Alnylam scientists described the discovery of a new lipid called "MC3" that has been formulated with siRNAs into novel lipid nanoparticles (LNPs) that achieve effective in vivo gene silencing activity at single-digit microgram per kilogram dose levels.

“Combinatorial Development of Biomaterials and Synthetic siRNA Delivery Systems”

"As is evidenced by the numerous high-quality presentations at this leading scientific meeting on liposome research, we and our collaborators continue to make very significant progress in advancing the discovery of novel and improved technologies for the systemic delivery of RNAi therapeutics. The breadth of presentations from Alnylam scientists and external research collaborators at MIT, AlCana, and UBC, together with our partnership and manufacturing agreement with Tekmira, exemplify the strength of Alnylam's leadership in RNAi delivery," said Kevin Fitzgerald, Ph.D., Senior Director, Research at Alnylam. "A key highlight emerging from this meeting is the discovery of our novel 'MC3' family of lipids and their superior performance in vivo when formulated into LNPs. Indeed, these formulations achieve effective gene silencing with single-digit microgram per kilogram dose levels, a result that sets a completely new industry benchmark for RNAi delivery."

Several oral presentations were made at the meeting describing scientific progress on the mechanistic understanding and potency improvements with LNP-based delivery of RNAi therapeutics. In particular, the discovery of a new lipid called MC3 was detailed; when formulated with siRNAs, MC3-containing ionizable LNPs (iLNPs) exhibited in vivo gene silencing potencies with ED₅₀ levels in the single-digit microgram per kilogram range. As with other iLNPs, MC3-based LNP formulations achieved in vivo gene silencing activity in an apolipoprotein E (ApoE)-dependent manner. Further, presentations included an update on the applications of "C12-200" lipidoid-based cationic LNP (cLNP) formulations that achieve highly potent in vivo gene silencing efficacy in a non-ApoE-dependent manner. Additional findings related to the rational design of novel cationic and ionizable lipids that demonstrate improved properties for systemic delivery of RNAi therapeutics were also reported. Finally, results were presented related to the translation of LNPs into clinical development, including Alnylam's ALN-VSP and ALN-TTR programs developed in collaboration with Tekmira, which utilize an LNP formulation referred to as stable nucleic acid lipid particle (SNALP). In particular, real-time stability studies showed the ability of achieving stable formulations for at least two years at 2^oC to 8^oC storage conditions.

Oral presentations given at the meeting included the following:

• "Progress on LNP-Mediated Delivery of RNAi Therapeutics," by Martin Maier, Ph.D., Senior Director, Drug Discovery at Alnylam;
• "Progress in the Development of LNP Delivery Systems for siRNA: Advancing LNPs to the Clinic," by Mark Tracy, Ph.D., Senior Director, Pharmaceutical Operations at Alnylam;
• "Combinatorial Development of Biomaterials and Synthetic siRNA Delivery Systems," by Professor Daniel Anderson, Ph.D., Department of Chemical Engineering, Harvard-MIT Division of Health Sciences & Technology, David H. Koch Institute for Integrative Cancer Research;
• "Lipid Nanoparticle Delivery Systems for the Systemic Delivery of siRNA," by Pieter Cullis, Ph.D., Professor Biochemistry and Molecular Biology at UBC; and,
• "Rational Design of Cationic Lipids for siRNA Delivery: Identifying Critical Structure/Activity Relationships," by Michael Hope, Ph.D., Chief Scientific Officer of AlCana.

In addition, multiple posters were presented at the meeting providing further updates on the systemic delivery of RNAi therapeutics. Specifically, data were presented describing the discovery of additional novel lipids; the use of small molecules in both cis and trans configurations to enhance LNP-based delivery; targeting-based approaches with LNPs; and, the achievement of extra-hepatic delivery of siRNAs, including to immune cells and prostate cancer tumor xenografts, with LNPs.

Posters presented at the meeting included the following:

• "Development of Targeted LNPs for the Delivery of RNAi Therapeutics," Soma De, Ph.D., Scientist at Alnylam;
• "Synthesis and Evaluation of Bicyclic Ketal-based Cationic Lipids for the Delivery of siRNA via Lipid Nanoparticle Systems," by Muthusamy Jayaraman, Ph.D., Principal Scientist at Alnylam;
• "Influence of Cationic Lipid Composition on Gene Silencing Properties of siRNA in Primary Antigen Presenting Cells," by Genc Basha, Research Associate at UBC;
• "siRNA Knockdown of the Androgen Receptor using Liposomal Nanoparticles to Treat Advanced Prostate Cancer," by Justin B. Lee, Graduate Student at UBC;
• "Reverse Headgroup Lipids: A New Class of Lipids With Enhanced Bilayer Destabilizing Characteristics," by Alex Leung, Graduate Student at UBC;
• "Identification of Small Molecules that Enhance Intracellular Delivery and Function of siRNA Presented in LN in vitro," by Paulo Lin, Postdoctoral Fellow at UBC; and
• "Identification of Small Molecules that Enhance Uptake of Liposomal Nanoparticles in Target Cells," by Chris Tam, Research Associate at UBC.

"The significant progress we are making in the delivery of RNAi therapeutics is certainly clear as demonstrated by the presentations and posters from Alnylam and collaboration scientists," said Laurence Reid, Ph.D., Senior Vice President and Chief Business Officer at Alnylam. "Importantly, Alnylam's exclusive relationships with key research efforts at MIT, UBC, and AlCana enable discovery of new delivery technologies - including intellectual property and know-how - that expand our overall RNAi therapeutics platform. Of course, advances in our RNAi platform strengthen the value we deliver to our existing partners and also form the foundation for Alnylam's future partnerships."