Clinical Perspectives on Promising Phase 1 Data of CAPN2-Targeting Therapy AMX0114 for ALS

The drug pipeline for amyotrophic lateral sclerosis (ALS) has expanded significantly in the last decade, with several different types of molecules and mechanisms starting to come into play. Among these include Amylyx’s AMX0144, an investigational antisense oligonucleotide (ASO) targeting calpain-2 (CAPN2), a therapeutic target known for its potential in motor neuron injury and axonal degeneration.

Recently positive findings from a phase 1 study, dubbed LUMINA (NCT06665165), testing AMX0144 in patients with ALS were presented at the 36th International Symposium on ALS/MND (MNDA) held from December 5-7 in San Diego, California. The study features those within 24 months of first ALS symtpmsom onset who have a slow vital capacity of at least 65%. Coming into the study, patients are allowed to be on FDA-approved treatments for ALS for at least 30 days prior to baseline visit.

To better learn about the positive safety findings and the promise behind AMX0144, NeurologyLive^® reached out to ALS expert and study investigator Sabrina Paganoni, MD, PhD. Paganoni, investigator at the Sean M. Healey & AMG Center for ALS at Mass General Brigham, provided perspective on how this agent differs from marketed therapies or others in development, as well as advances in the field have led to the conversations around CAPN2-targeted treatments. Furthermore, she spoke on some of the lingering needs within the ALS community outside of treatments.

NeurologyLive: As a CAPN2-targeting agent, how unique is AMX0114 to the ALS landscape and what advantages does it offer?

Sabrina Paganoni, MD, PhD: Building on recent breakthroughs enabled by antisense oligonucleotides (ASOs) driven by specific genetic mutations, there is tremendous promise and excitement in extending antisense technology to all forms of ALS. The LUMINA trial is among the first to pursue that goal, and if successful, it could open an entirely new therapeutic avenue for a broad range of people living with ALS. The study is grounded in mechanistic data, with a robust biological rationale for silencing CAPN2 and is further strengthened by translational efforts designed to track drug effects using cutting-edge biomarkers.

Calpain-2 is a protein that plays a role in nerve damage and degeneration by cleaving important structural proteins, such as neurofilament light chain (NfL) and alpha II-spectrin (SBDP-145). AMX0114 targets calpain-2 and by reducing the activity of this protein we hope to be able to help address nerve damage. Importantly, calpain-2 seems to be active in both sporadic and familial forms of ALS, suggesting that this approach could be relevant for different forms of the disease.

Describe the phase 1 preliminary findings - what stands out from a safety standpoint?

The early safety and tolerability data presented at the 36th International Symposium on ALS/MND represent a step forward in advancing this carefully designed drug development program. These preliminary findings suggest an encouraging safety profile at the dose studied in the first cohort of 12 participants, with no treatment-related serious adverse events or serious neurological adverse events reported to date. Based on these findings, the second cohort testing a higher dose is now enrolling in Canada and will enroll in the U.S. soon.

How have your experiences with previous molecules (mainly AMX0035) helped shape your clinical trials and approach with AMX0114?

The experiences gained from previous trials have been instrumental in refining the clinical development strategy for AMX0114. The LUMINA trial leverages a biomarker-driven approach combined with comprehensive monitoring of safety within an efficient multiple ascending dose design. The focus on biomarkers not only enhances our ability to understand target engagement and biological impact, but also has the potential to pave the way toward more personalized therapeutic strategies in ALS.

In general, what are some of the biggest unmet needs for the ALS community (outside of just therapeutics)?

Beyond the development of effective therapeutics, the ALS community faces several unmet needs that are critical for improving patient care and outcomes. One major need is the enhancement of care coordination and support services for people living with ALS and their families. Many individuals with ALS experience complex physical and emotional challenges that require a multidisciplinary approach, and we need to continue to expand access to specialized care. Additionally, there is a pressing need for increased funding and resources dedicated to research, as well as advocacy efforts aimed at raising awareness about ALS. Critical research efforts include the development of biomarkers to enable earlier diagnosis, identify subgroups, track progression, and detect response to treatment. These efforts are on the critical path to truly effective and personalized treatments for ALS.