Evan Mizerak, on Developing an ASO Targeting CAPN2 for ALS


The lead of preclinical research at Amylyx Pharmaceuticals discussed the literature supporting AMX0114’s target and its upcoming trial design.

“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.

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
Related Videos
Akshay Sharma, MBBS, a bone marrow transplant physician at St. Jude Children’s Research Hospital
M. Peter Marinkovich, MD, on Bringing RDEB Treatment to the Local Level
Caspian Oliai, MD, MS, the medical director of the UCLA Bone Marrow Transplantation Stem Cell Processing Center
Frederick “Eric” Arnold, PhD
Genovefa (Zenia) Papanicolaou, MD, an infectious diseases specialist at Memorial Sloan Kettering Cancer Center
Jeffrey Chamberlain, PhD, on Exciting New Research at MDA 2024
Alan Beggs, PhD, on Challenges in Therapeutic Development for Rare Diseases
Akshay Sharma, MBBS, a bone marrow transplant physician at St. Jude Children’s Research Hospital
PJ Brooks, PhD
John DiPersio, MD, PhD, the director of the Center for Gene and Cellular Immunotherapy at Washington University School of Medicine
© 2024 MJH Life Sciences

All rights reserved.