Amylyx Begins Phase 1 LUMINA Study of CAPN2-Targeting Agent for ALS

Sabrina Paganoni, MD, PhD

Dosing has begun for a new phase 1, placebo-controlled study (NCT06665165) testing Amylyx Pharmaceuticals’ AMX0114, investigational antisense oligonucleotide (ASO) targeting calpain-2 (CAPN2), in patients with amyotrophic lateral sclerosis (ALS). Dubbed LUMINA, the randomized study is expected to have early cohort data expected this year.¹

The trial, expected to enroll 48 patients with ALS across North America, randomly assigns participants 3:1 to receive AMX0114 or placebo by intrathecal administration once every 4 weeks for a total of up to 4 doses. Primarily designed to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of the agent, LUMINA also includes other secondary outcomes like change in calpain-2 levels, neurofilament light (NfL) levels, and other pharmacodynamic biomarkers of ALS.

AMX0114 is a unique therapy, one of the few currently in development targeting CAPN2. Calpain-2, a member of the calpain family of calcium-dependent cysteine proteases, has emerged as a promising therapeutic target in ALS due to its involvement in key pathological processes associated with the disease. Calpains, particularly calpain-2, are known to mediate proteolytic cleavage of various cellular substrates, including cytoskeletal proteins and enzymes, contributing to neuronal degeneration when dysregulated. In ALS, aberrant calpain activation has been implicated in motor neuron injury, axonal degeneration, and neuroinflammation—key drivers of disease progression.

"ALS is a devastating and fatal neurodegenerative disease with limited treatment options, underscoring the urgent need for new therapeutic approaches that target the underlying mechanisms driving ALS progression,” principal investigator Sabrina Paganoni, MD, PhD, investigator at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, said in a statement.¹ "AMX0114 represents a potential therapeutic approach to inhibiting one of the fundamental drivers of axonal degeneration. Dosing the first participant in LUMINA is a step toward a potential treatment option for people living with ALS and their loved ones."

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Eligible participants must be adults aged 18 or older with a diagnosis of clinical definite or probable ALS, confirmed by an experienced physician. Symptom onset must have occurred within 24 months of the study’s start. Those on riluzole or edaravone must maintain a stable regimen for at least 30 days before beginning the study and throughout its duration. Female participants of childbearing potential must use effective birth control during the trial and for 60 days afterward, while male participants must practice contraception with female partners and abstain from sperm donation for at least 90 days post-trial.

Exclusion criteria include advanced respiratory impairment (SVC < 75%), abnormal liver or kidney function, or any significant unstable medical condition unrelated to ALS that may affect safety or compliance. Women who are pregnant, breastfeeding, or planning pregnancy are excluded, as are individuals with psychiatric instability, cognitive impairment, or substance abuse that might impair consent or adherence. Participants cannot have tracheostomies, contraindications to lumbar punctures, prior hypersensitivity to the study drug, or a history of investigational therapy such as gene therapy, stem cell therapy, or ASOs within 30 days of the study.

"AMX0114 targets calpain-2, which has been found to be an important contributor to axonal degeneration and studied over decades of research as a potential target for the treatment of ALS and other neurodegenerative diseases. In preclinical studies, AMX0114 showed improved neuronal survival and reductions in extracellular NfL levels across multiple disease models," Camille L. Bedrosian, MD, chief medical officer at Amylyx, said in a statement.¹ "We are excited to progress AMX0114 into the clinic for people with ALS as we work to advance a potential therapy for this relentlessly progressive, fatal disease."

AMX0114 is Amylyx’ second generation therapy behind AMX0035. AMX0035, formerly marketed as Relyvrio, was approved by the FDA as a treatment for ALS but was voluntarily withdrawn from the market in April 2024 after data from a follow-up confirmatory trial did not confirm the therapy’s clinical benefit. Known as the PHOENIX trial (NCT05021536), results from the study showed no difference in the primary end point of ALS Functional Rating Scale between AMX0035-treated and placebo-treated patients over a 48-week period (P = .667).^2,3

REFERENCES
1. Amylyx Pharmaceuticals Announces First Participant Dosed in Phase 1, Multiple Ascending Dose LUMINA Trial of AMX0114 in People Living with Amyotrophic Lateral Sclerosis. News release. Amylyx Pharmaceuticals. April 9, 2025. Accessed April 10, 2025. https://www.biospace.com/press-releases/amylyx-pharmaceuticals-announces-first-participant-dosed-in-phase-1-multiple-ascending-dose-lumina-trial-of-amx0114-in-people-living-with-amyotrophic-lateral-sclerosis
2. Amylyx Pharmaceuticals Announces Formal Intention to Remove RELYVRIO®/ALBRIOZA™ from the Market; Provides Updates on Access to Therapy, Pipeline, Corporate Restructuring, and Strategy. News Release. Amylyx Pharmaceuticals. Published April 4, 2024. Accessed April 10, 2025. https://www.businesswire.com/news/home/20240404501040/en/Amylyx-Pharmaceuticals-Announces-Formal-Intention-to-Remove-RELYVRIO%C2%AEALBRIOZA%E2%84%A2-from-the-Market-Provides-Updates-on-Access-to-Therapy-Pipeline-Corporate-Restructuring-and-Strategy
3. Amylyx Pharmaceuticals announces topline results from global phase 3 PHOENIX trial of AMX0035 in ALS. News release. March 8, 2024. Accessed April 10, 2025. https://www.amylyx.com/news/amylyx-pharmaceuticals-announces-topline-results-from-global-phase-3-phoenix-trial-of-amx0035-in-als