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Alnylam Advances New Innovations in RNAi Therapeutics

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The research was presented at the 11th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held October 11 - 14, 2015, in Leiden, Netherlands. First, the company presented data on its Bis-RNAiTM platform that enables simultaneous knockdown of two distinct disease genes with a single, subcutaneously administered molecular entity. Further, the company presented data on its ReversirTM platform. Reversir molecules enable tailored control of RNAi pharmacology with rapid reversal of target gene silencing effects. The company believes that these new platform technologies greatly expand the universe of opportunities for RNAi therapeutics.

"At Alnylam we strive to pioneer new breakthroughs in RNAi. Today, we're announcing development of two new platform technologies that we believe broaden the opportunities for RNAi therapeutics as a whole new class of medicines. With Bis-RNAi, we've developed an approach for the simultaneous knockdown of two distinct target genes with a single, subcutaneously administered molecular entity. We can imagine meaningful applications of Bis-RNAi in many clinical indications, including those in our Cardio-Metabolic and Hepatic Infectious Disease Strategic Therapeutic Areas," said Rachel Meyers, Senior Vice President of Research at Alnylam. "With our Reversir platform, we now have a tool for control of RNAi pharmacology that enables rapid reversal of target gene silencing. We believe that tailored pharmacology is a highly desired attribute for precision medicines. We look forward to the advancement of new pipeline programs based on these platforms as early as next year."

In a poster presentation entitled "Bis-RNAiTM Conjugates for Simultaneous Silencing of Two Transcripts," Alnylam scientists described a novel approach whereby a single molecular entity consisting of two linked siRNAs conjugated to a GalNAc moiety can simultaneously achieve robust silencing of two different mRNA transcripts. Multiple Bis-RNAi designs were evaluated to determine the effects of linker structure and GalNAc ligand placement on in vivo activity. In rodent and non-human primate studies, a Bis-RNAi tool compound targeting transthyretin (TTR) and Factor VII (FVII) achieved similar levels of target gene knockdown as that observed with a "parent" mixture consisting of the individual siRNAs at a 1:1 ratio. In addition, the duration of silencing effects for the Bis-RNAi compound was found to be similar to that of the individual siRNAs in the parent mixture. Furthermore, the Bis-RNAi constructs were found to lack immune activity as measured in both an in vitro human whole blood assay and in an in vivo mouse model, with cytokine profiles comparable to the parent mixture and untreated controls. Alnylam believes that there are many potential clinical applications for the Bis-RNAi platform, including in the company's Cardio-Metabolic and Hepatic Infectious Disease STArs, and expects to advance its first Development Candidate from this platform in 2016.

In a second presentation entitled "Reversirs for Rapid and Potent Reversal of siRNA Silencing Activity," the company shared key scientific data characterizing the development of its Reversir platform. Reversir molecules are GalNAc-conjugated, single-stranded oligonucleotide constructs that are designed to recognize and bind to the complimentary RISC-bound antisense strand of an siRNA, leading to rapid and complete reversal of RNAi-mediated target gene silencing activity in vivo. Studies were performed in mice using a GalNAc-siRNA targeting Factor IX (FIX) and Reversir constructs designed to specifically reverse the FIX siRNA silencing activity. Specifically, a single subcutaneous dose of the FIX siRNA led to robust FIX knockdown of approximately 80% that was sustained for over 4 weeks. When a single subcutaneous dose of the Reversir molecule was administered on day 8, FIX knockdown was rapidly reversed, with levels returning to baseline within one week. A preliminary rat toxicology study showed that Reversir constructs are generally well tolerated with no significant findings to date, including lack of changes in body weight gain or serum chemistry. Alnylam believes that its Reversir platform can be deployed across existing and future pipeline programs to enable tailored control of RNAi pharmacology for precision medicines, and expects to advance initial Development Candidates from this platform in 2016