Alnylam reports further progress on broadening the therapeutic potential of RNAi

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today further progress on the Company's platform efforts in extrahepatic delivery of novel siRNA conjugates, including central nervous system (CNS) and ocular delivery in rat and non-human primates (NHPs). Preclinical results were presented at the Oligonucleotide Therapeutics Society (OTS) 2018 Annual Meeting held September 30 to October 3 in Seattle, WA.

"We are pleased to report on our continued progress on broadening the therapeutic potential of RNAi by demonstrating successful delivery to extrahepatic tissues such as the CNS and eye. The in vivo activity of our novel CNS and ocular siRNA conjugates is consistent across species and targets with potent and highly durable mRNA silencing. As we have seen with liver target gene silencing, we anticipate a highly competitive profile for our siRNA conjugates with increased potency, extended duration of action, and encouraging safety margins," said Kevin Fitzgerald, Ph.D., Senior Vice President, Research at Alnylam. "We are excited to grow the potential universe of tissues, targets, and diseases addressable by RNAi therapeutics, expanding our efforts to reach patients in need of new therapies. We believe that the demonstration of potent, safe, and infrequent dosing may allow us to develop innovative RNAi therapeutics directed to these new targets."

In NHP studies, a single intrathecal (IT) injection of a siRNA conjugate targeting the ubiquitously expressed β-catenin mRNA transcript resulted in broadly distributed target gene silencing across the brain and spinal cord. Robust and durable silencing of β-catenin mRNA was observed after a single dose at day 31 post injection. Specifically, a single 72 mg dose (approximately 24 mg/kg) resulted in over 80 percent target silencing in the spinal cord and approximately 50 percent silencing across regions of the brain. Widespread distribution of the novel siRNA conjugate was observed across the CNS, including the frontal and temporal cortex, deep brain structures such as basal ganglia and dentate gyrus, cerebellum, brain stem and spinal cord, with evidence for cellular localization in neurons, astrocytes, and microglia. In additional rat studies, further optimization of novel conjugates was reported using siRNAs targeting superoxide dismutase 1 (SOD1), a genetically defined disease gene implicated in amyotrophic lateral sclerosis (ALS). Additional optimization of the conjugate design resulted in an over ten-fold improvement in potency, with a dose as low as 0.07 mg (approximately 0.25 mg/kg) resulting in approximately 50 percent SOD1 silencing across the CNS. In both rat and NHP studies, intrathecal administration of these novel siRNA conjugates was found to be generally well tolerated. Consistent with previous guidance, Alnylam expects to select its first CNS Development Candidate (DC) by the end of 2018 with an initial Investigational New Drug (IND) or equivalent application in late 2019 or early 2020.

Alnylam scientists also presented new preclinical results with novel siRNA conjugates targeting transthyretin (TTR), demonstrating delivery to ocular tissue in rats and NHPs. Efficient and durable silencing of ocular TTR mRNA in rat was achieved following a single intravitreal injection, with siRNAs localizing to the relevant cell types in the eye, retinal pigment epithelium (RPE) and ciliary epithelia (CE), where amyloid deposits can occur in approximately 10 percent of hereditary ATTR (hATTR) amyloidosis patients. The ocular target gene silencing effect was recapitulated in NHPs with approximately 98 percent silencing of TTR mRNA in RPE and near complete knockdown of TTR protein at day 31, as measured in immunohistochemical analyses. In NHP studies, there were no notable safety findings related to administration of ocular siRNA conjugates.

Additional OTS presentations by Alnylam scientists and collaborators included results on:

• Further optimization of the Company's enhanced stabilization chemistry plus (ESC+) conjugate platform
• Safety evaluation of 2'-Fluoro-modified nucleotides embedded in GalNAc-conjugate siRNAs
• Simultaneous silencing of two different gene transcripts with Bis-RNAi conjugates.

For the full breadth of results presented by the Company at OTS please visit the Capella section of the Alnylam website.

We are also pleased to share that Alnylam's publication of results from the APOLLO Phase 3 pivotal trial of patisiran featured in the July 5, 2018 issue of The New England Journal of Medicine has been selected as the OTS "2018 Paper of the Year" - an award designed to honor the year's most impactful paper in the field of oligonucleotide therapeutics.