New paper documents discovery of novel lipids, including MC3

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, and collaborators announced today the publication of a scientific paper documenting the discovery of novel lipids used in second generation lipid nanoparticles (LNPs) for systemic delivery of RNAi therapeutics. These results were published in a paper titled "Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo" (DOI: 10.1002/anie.201203263) in the journal Angewandte Chemie International Edition. The findings describe the rational design, synthesis, and evaluation of novel lipids, including MC3, that have led to the discovery of Alnylam's proprietary second generation LNP platform for systemic delivery of RNAi therapeutics. This research was conducted in collaboration with scientists from AlCana Technologies, Inc. and the University of British Columbia (UBC).

"This new paper documents the work performed by Alnylam, AlCana, and UBC scientists leading to the discovery of novel lipids, including MC3, that demonstrate remarkably improved in vivo potency for systemic delivery of RNAi therapeutics. In addition, our results have led to the identification of a key structural feature of novel ionizable lipids, specifically the pKa of the amino group of the lipid, required for optimal in vivo efficacy," said Muthiah Manoharan, Ph.D., Senior Vice President, Drug Discovery. "The MC3 lipid and resulting second generation LNPs have now advanced into clinical stages of evaluation. These novel LNPs exhibit significant improvements in potency and broadened therapeutic index for RNAi therapeutics, as evidenced by our recent human data with ALN-PCS, and also define Alnylam's LNP platform for advancement of ALN-TTR02 and potentially other 'Alnylam 5x15' programs."

The results published in this new paper reveal key insights for optimizing systemic delivery of RNAi therapeutics with LNPs. The findings describe a comprehensive structure-activity relationship (SAR) study resulting in the design, synthesis, and evaluation of over 50 novel lipids. In an earlier study a particular lipid, DLin-KC2-DMA, was identified as a highly potent cationic lipid when incorporated into LNP encapsulating siRNA targeting the factor VII (FVII) mRNA (Semple, et al., Rational design of cationic lipids for siRNA delivery, Nat. Biotechnol. 28, 172-176; 2010); the researchers used this lipid as the starting point for their SAR study. The resulting data demonstrated a close relationship between the apparent acid dissociation constant, or pKa, of the ionizable amino lipid head groups present in the LNPs and their ability to elicit potent hepatic gene silencing in vivo. This effect of the pKa is likely due to enhanced endosomal release of the siRNA in the cytoplasm where it can harness the RNAi pathway. In this new paper, an LNP formulation based on DLin-MC3-DMA - or simply MC3 - was identified as one of the most potent lipids.

Earlier this year, the United States Patent and Trademark Office (USPTO) issued a Notice of Allowance of claims for a patent application which covers the MC3 lipid; the patent has now been issued (U.S. Patent No. 8,158,601). This patent includes 30 claims covering composition of matter and formulations of MC3, as well as methods of using these compositions and formulations, and recognizes the novelty of the MC3 lipid for systemic delivery of RNAi therapeutics.

Alnylam's proprietary MC3 LNP delivery platform is being utilized in development programs as part of the company's "Alnylam 5x15™" product strategy including: ALN-TTR02, an RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of severe hypercholesterolemia; and potentially other programs.

Source: Alnylam Pharmaceuticals, Inc.

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