Next Steps in Development for AMX0114: An Antisense Oligonucleotide Targeting Calpain-2, a Critical Effector of Axonal Degeneration


Clinical Trials

Poster Number: M199


Joshua Cohen, Amylyx Pharmaceuticals, Inc., Ryan Miller, Amylyx Pharmaceuticals, Inc., John Pesko, Amylyx Pharmaceuticals, Inc., Sabrina Paganoni, MD, PhD, Sean M. Healey and AMG Center for ALS & the Neurological Clinical Research Institute, Jeremy Shefner, MD, Barrow Neurological Institute, Leonard van den Berg, MD, PhD, Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Justin Klee, Amylyx Pharmaceuticals, Inc., Amanda Hayden, Amylyx Pharmaceuticals, Inc., Lahar Mehta, Amylyx Pharmaceuticals, Inc.

Axonal degeneration has been recognized as a key early contributor to the clinical presentation and pathogenesis of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Activation of the calcium-dependent protease calpain-2 is proposed as a critical effector of axonal degeneration. We have developed AMX0114, an antisense oligonucleotide (ASO) targeting the gene encoding calpain-2 (CAPN2). AMX0114 has shown efficacious and robust target mRNA and protein knockdown in in vitro experiments and Investigational New Drug-enabling studies are underway.

Describe preliminary Single Ascending Dose (SAD)/Multiple Ascending Dose (MAD) design for first-in-human study to evaluate safety and tolerability as well as pharmacokinetic (PK) and pharmacodynamic (PD) signals of activity of AMX0114.

Both SAD and MAD studies will enroll participants with ALS from centers in the United States, Europe, and Canada. Adaptive dose escalation will be based on safety, tolerability, PK, and PD markers of disease progression. Participants completing the SAD study will have the option to enroll in the MAD study after a washout period, and an open-label extension will be available for participants completing the MAD study. Outcome measures will include incidence of adverse events and serious adverse events, and clinical measures of efficacy including the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised and Slow Vital Capacity. PD measures will include neurofilament light chain (a substrate of calpain) and other markers of calpain proteolytic activity.

Results from the SAD/MAD study will inform subsequent investigations of AMX0114 in ALS.

AMX0114 targets a key early contributor to ALS pathogenesis and will be evaluated in first-in-human studies in 2024. A more detailed study design will be shared during MDA 2024.