Background: Axonal degeneration is increasingly recognized as an early contributor to amyotrophic lateral sclerosis (ALS), shaping both pathogenesis and clinical presentation. Calpain-2, a calcium-dependent cysteine protease, has emerged as a key effector of this process, with growing evidence implicating its role in ALS progression. To modulate this pathway, Amylyx developed AMX0114, an antisense oligonucleotide (ASO) inhibitor of calpain-2.
Objectives: LUMINA (NCT06665165) is an ongoing phase 1 randomized, double-blind, placebo-controlled, multiple ascending dose trial evaluating AMX0114 in individuals with ALS. The trial is designed to assess the safety, tolerability, and pharmacokinetics (PK) of AMX0114, as well as its biological activity through pharmacodynamic (PD) and clinical outcome measures.
Methods: LUMINA will enroll a total of ~48 participants at ~15 sites in Canada and the United States. Participants are randomized 3:1 to receive AMX0114 or placebo by intrathecal administration once every four weeks for a total of up to 4 doses. Eligible individuals include adults (≥18 years) with clinically definite or clinically probable ALS (as defined by El Escorial criteria) and symptom onset within the past 24 months.
Primary endpoints of the study include the incidence of adverse events (AEs), serious AEs, and dose-limiting toxicities. Secondary and tertiary endpoints include PK measurements (plasma and cerebrospinal fluid [CSF] levels of AMX0114), ALS-related and target engagement PD biomarkers (e.g., neurofilament light chain [NfL], spectrin breakdown product 145 [SBDP-145]), and functional measures of ALS progression (e.g., ALS Functional Rating Scale-Revised score).
Results and Conclusions: LUMINA is the first-in-human study of AMX0114, a novel investigational ASO targeting calpain-2 in adults with ALS. Cohort 1 enrollment is complete, and evaluation of safety, tolerability, PK/PD, and clinical outcomes is ongoing. Preliminary data from Cohort 1 will be presented at the meeting.