CAPN2-Targeting Agent AMX0114 Shows Safe Profile in Phase 1 LUMINA Trial of ALS

Recently presented findings from the initial cohort of the phase 1 LUMINA trial (NCT06665165) showed that investigational AMX0114 (Amylyx Pharmaceuticals), was safe and led to no treatment-related serious adverse events (SAEs) in patients with amyotrophic lateral sclerosis (ALS). Based on these data, the company is expected to begin enrollment for the second cohort of participants in Canada later this month and in the U.S. in January.^1,2

LUMINA, a double-blind, placebo-controlled, multiple-ascending dose study, tests the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AMX0114, an investigational antisense oligonucleotide (ASO) targeting calpain-2 (CAPN2). In recent years, Calpain-2 has emerged as a promising therapeutic target in ALS because its dysregulated activation contributes to motor neuron injury, axonal degeneration, and neuroinflammation that drive disease progression.

The safety data, presented at the 36th International Symposium on ALS/MND (MNDA) held from December 5-7 in San Diego, California, included 12 patients in Cohort 1 who had received at least 2 doses of AMX0114 or placebo. At doses of 12.5 mg, the investigational treatment was considered well-tolerated, with no treatment-related SAEs or serious neurological adverse events as of the November 11^th data cut-off.

LUMINA, which began earlier this year, includes a 4-week screening period, followed by a 13-week treatment period, and an 8-week safety follow-up. The fully enrolled study, which features 48 patients with ALS, randomly assigns participants 3:1 to either AMX0114 or placebo every 4 weeks for a total of up to 4 doses. Biomarker data, including change in calpain-2 levels, neurofilament light, and other PD biomarkers of ALS, are expected to be presented in the first half of 2026.

"LUMINA is a first-in-human study, and we are encouraged by these data as we continue to advance AMX0114 as a potential treatment for this rapidly progressive disease with high unmet need. The safety and tolerability analysis allows LUMINA to proceed with its next cohort of participants, which is critical given that this community has no time to wait," trial investigator Sabrina Paganoni, MD, PhD, investigator at the Sean M. Healey & AMG Center for ALS at Mass General Brigham, said in a statement.

To be included in LUMINA, patients must be 18 years of age, have a diagnosis of clinically definite or clinically probable ALS, and be treated within 24 months since onset of first ALS symptom. Furthermore, patients entering the study have slow vital capacity of at least 65%, and are allowed on stable, FDA-approved treatments for ALS for at least 30 days prior to baseline visit.

"We appreciate the partnership with LUMINA sites and participants to achieve complete enrollment of the first cohort. In addition, we are pleased that to date no drug-related SAEs or dose-limiting toxicities were observed, which represent important early steps in this study," Camille L. Bedrosian, MD, chief medical officer at Amylyx, said in a statement. "AMX0114 is designed to inhibit calpain-2, a calcium-activated protease that is one of the fundamental drivers of axonal degeneration and consequent disease progression in ALS. Preclinical studies have demonstrated that treatment with AMX0114 resulted in potent, dose-dependent, and durable reduction in calpain-2 protein levels, translating to improved neuronal survival and reductions in extracellular NfL levels. We look forward to presenting cohort 1 biomarker data at a medical meeting in the first half of next year."

READ MORE: FDA Approves Inebilizumab for AChR- and MuSK-Positive Generalized Myasthenia Gravis

In addition to presenting the preliminary safety of AMX0114, Amylyx also gave presentation characterizing the cerebrospinal fluid (CSF) biomarker signature of calpain-2 activity in ALS and its application in the LUMINA study. The presentation, led by Paganoni and others, highlighted the importance of calpain-2 in ALS, including its effect on axonal degeneration, the mechanistic link to ALS pathways, and the substrate processing of this protein. They noted that calpain-2 cleaves cytoskeletal proteins alpha II-spectrin and NfL resulting in breakdown products that may serve as markers of calpain-2 activity.³

Investigators also presented an analysis on calpain-driven biomarkers, such as spectrin breakdown product 145 (SBDP-145) assay that may help with the qualification and CSF characterization of ALS. The analysis featured 107 CSF samples, 47 from the NEALS Biorepository and 60 from the Target ALS Biorepository, testing CSF SBDP-145 levels using an ELISA assay (Biomatik). Of these samples, 42 were health controls (HC), 44 had sporadic ALS, and 9 had familial ALS.

Overall, results revealed that levels of SBDP-145 were significantly higher in CSF from people living with ALS (combining both sporadic and familial) relative to controls (P = .0029). All told, this showed that SBDP-145 is a calpain-specific breakdown product and may serve as a biochemical marker of neuronal injury. Furthermore, the findings also demonstrated that calpain-induced fragments of rNfL are similar to white matter as NfL fragments detected in ALS CSF.

REFERENCES
1. Amylyx Pharmaceuticals Announces New Safety and Tolerability Cohort 1 Data of AMX0114 in ALS from First-in-Human LUMINA Trial. News release. December 5, 2025. Accessed December 17, 2025. https://investors.amylyx.com/news-releases/news-release-details/amylyx-pharmaceuticals-announces-new-safety-and-tolerability
2. Paganoni S, Kett L, Bowser R, et al. A Phase 1, Multicenter, Randomized, Placebo-Controlled Multiple Ascending Dose Study to Evaluate the Safety and Tolerability of AMX0114 in Amyotrophic Lateral Sclerosis (LUMINA). Presented at: 36th International Symposium on ALS/MND (MNDA); December 5-7; San Diego, California. CLT-14
3. Bowser R, An J, Kett L, et al. Characterizing the CSF Biomarker Signature of Calpain-2 Activity in ALS and Its Application in the Phase 1 Trial. Presented at: 36th International Symposium on ALS/MND (MNDA); December 5-7; San Diego, California.