Alnylam’s Preclinical Data Supports CNS Delivery of RNA Interference Therapies


Cambridge, Massachusetts-based Alnylam Pharmaceuticals reported preclinical results that supports advancement of its RNA interference (RNAi) therapeutics for central nervous system disorders into the clinic.

The company indicated that it had delivered its novel small interfering RNA (siRNA) conjugates into the central nervous system (CNS). The data was presented at the TIDES: Olignonucleotide and Peptide Therapeutics 2018 Annual Meeting held in Boston this week. The study was performed on rats. A single intrathecal injection of a siRNA conjugate had broad distribution across the brain and spinal cord regions.

RNAi is a natural cellular process where genes can be silenced—turned off. Alnylam is focused on using the technology to treat various diseases caused by lack of appropriate proteins or excess proteins. They have particular potential for preventing or reversing neurodegenerative diseases caused by dominantly inherited genes, such as Alzheimer’s, Huntington’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS).

Alnylam expects to select its first CNS-targeted development candidate this year and file its first investigational new drug (IND) or equivalent in late 2019 or early 2020, with possibly one or more INDs per year after that.

“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, Alynylam’s senior vice president, Research, in a statement. “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.”

On May 3, Alnylam provided its first-quarter financials. For a company with no products on the market, it has $1.6 billion in cash and investments. Revenues for the quarter were $21.9 million, compared to $19 million in the same quarter the year before. The revenues came from its alliance with Sanofi Genzyme and with The Medicines Company.

On the other hand, the company has a number of pipeline products, with one awaiting U.S. Food and Drug Administration (FDA) approval. That is patisiran, an investigational RNAi treatment for hereditary ATTR amyloidosis. It is also being evaluated by the European Medicines Agency (EMA).

It also has ALN-TTRsc02, also for ATTR amyloidosis, which is in Phase I trials, and givosiran for acute hepatitis porphyrias (AHPs). It recently completed enrollment of the first 30 patients of givorsiran in the ENVISION Phase III trial. In addition, it has lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1 (PH1), and several other programs.

The patisiran approval is expected in mid-2018, with a PDUFA date of August 11. If approved, the company has plans to launch the drug in the U.S. shortly afterwards. One issue that could face the company is competition from Pfizer’s tafamidis. Pfizer recently released positive data on its Phase III trial of TTR amyloidosis patients with cardiomyopathy. Not much data was made available, but it did show a 50 percent reduction in mortality and a 40 percent cut in hospitalizations.

Stephen Simpson, writing for Seeking Alpha, notes, “Although these results do suggest that tafamidis could be competitive in the cardiomyopathy and hybrid TTR markets (which wasn’t expected before), it seems unlikely to me that the drug will play much of a role in neuropathy—unlike Alnylam’s drug patisiran, which has been shown to reverse symptoms, tafamidis largely leads to just a slower progression for neuropathy patients. Interestingly, patisiran has also been shown to be more effective when given to polyneuropathy patients previously on stabilizers like tafamidis.”

He goes on to note that Alnylam has a lot going on. “Between Alnylam’s controlled drugs and its partnerships with Sanofi (which controls fitusiran, an RNAi drug for hemophilia in pivotal studies) and The Medicines Co. (which controls inclisiran, an RNAi drug for cholesterol in pivotal studies), Alnylam could be looking at six FDA approvals over the next three to four years.”

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