Evan Mizerak, on Developing an ASO Targeting CAPN2 for ALS

“Calpain-2 is a calcium dependent cysteine protease, it's part of a family of calpains... But Calpain-2 is the one that has the most robust evidence in the literature for having a connection to neurodegeneration. And so essentially, when there's a calcium influx into the axon precipitated by neuronal injury, that causes aberrant overactivation of calpain-2, which results in axonal transport deficits, and ultimately, denervation. And so that's kind of the pathophysiological connection of the protein to ALS pathophysiology.”

Amylyx Pharmaceuticals is developing an antisense oligonucleotide (ASO) targeting the gene encoding calpain-2 (CAPN2), termed AMX0114, with the hope of affecting axonal degeneration in amyotrophic lateral sclerosis (ALS). The company is currently tying up investigational new drug (IND)-enabling studies and aims to initiate a first-in-human trial in the fourth quarter of 2024.

The design of the single ascending dose/multiple ascending dose study was presented at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida, by Joshua Cohen, co-chief executive officer and cofounder, Amylyx.

CGTLive® spoke with Evan Mizerak, lead, preclinical research, Amylyx, to learn more about AMX0114 and the CAPN2 target. He discussed the body of scientific literature supporting CAPN2 as a target in ALS, including evidence of hyperactivity of CAPN2 in disease relevant tissue, attenuated disease symptoms in mice models with CAPN2 modulation, and even a possible role in cleaving and processing neurofilament.

Click here to view more coverage of the 2024 MDA Conference.

REFERENCE

Cohen J, Miller R, Pesko J, et al.Next Steps in Development for AMX0114: An Antisense Oligonucleotide Targeting Calpain-2, a Critical Effector of Axonal Degeneration. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Orlando, FL. Poster #M199