Rare Disease Report

Preclinical Data Exhibits CNS Delivery of RNAi Therapeutics

MAY 08, 2018
Mathew Shanley
This morning, it was announced that Alnylam Pharmaceuticals has achieved delivery of novel small interfering RNA (siRNA) conjugates to the central nervous system (CNS) and intends to advance a pipeline of investigational RNAi therapeutics into clinical development.

Initial results from preclinical studies conducted in rats were presented at the TIDES: Oligonucleotide and Peptide Therapeutics 2018 Annual Meeting in Boston, as part of a plenary talk titled “Delivering on RNAi Therapeutics: Patisiran and Beyond.”

Data from the trial showed that a single intrathecal injection of a novel siRNA conjugate resulted in broad distribution across the brain and spinal cord regions. In all key anatomical regions of the brain and spinal cord, robust and highly durable silencing of a disease target gene transcript was seen, and specificity of the silencing effect was confirmed with a subsequent siRNA conjugate targeting an independent gene transcript universally expressed in the CNS.

“Over the past 15 years, Alnylam has advanced conjugate-based delivery of investigational RNAi therapeutics with multiple transformative discoveries, paving the way for development of a whole new class of innovative medicines,” said Kevin Fitzgerald, Ph.D., Senior Vice President, Research at Alnylam in a press release.  “We have now applied our learnings, including additional chemistry advances, to enable delivery of siRNAs beyond the liver to the CNS, where there are a large number of unmet needs well suited for RNAi therapeutics. As we begin to advance our CNS pipeline, initial efforts are focused on genetically validated CNS targets, use of biomarkers for initial proof-of-concept, and disease settings with high unmet need and a definable path to regulatory approval and patient access.”

The company utilized its enhanced stabilization chemistry (ESC) platform with the novel siRNA conjugates, and further modifications are expected to enable broad CNS delivery and efficient uptake in neuronal cells.

“We believe the robust potency, durability, and tolerability of liver-targeted RNAi therapeutics in Alnylam's broader clinical pipeline set a strong foundation for the future development of investigational CNS-targeted RNAi therapeutics, where we expect to select our first development candidate later this year,” continued Fitzgerald.

RNAi therapeutics have the potential to prevent or reverse rare neurodegenerative diseases caused primarily by inherited genes where there are no existing treatment options, like Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). In April of this year, Alnylam presented data proving that its 2 leading products – givosiran and patisiran – yield positive results in acute hepatic porphyrias (AHPs) and hereditary amyloidosis (hATTR), as well.

Alnylam intends to complete selection of its first CNS-targeted development candidate (DC) in 2018, and is then expected to file its first investigational new drug (IND) or IND equivalent sometime between late 2019 and early 2020. The company anticipates the potential for one or more INDs per year thereafter.

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