Objective: To assess the efficacy, safety, and tolerability of levacetylleucine in people with CACNA1A disorders.

Background: CACNA1A disorders refer to a range of rare, progressive, neurological and neurodevelopmental disorders with pathogenic mutations in the calcium voltage-gated channel subunit alpha1 A (CACNA1A) gene. The gene is primarily expressed in neurons and plays a critical role in calcium-ion signaling. Levacetylleucine enters enzyme-controlled pathways to correct metabolic dysfunction, improve energy production, and normalize lysosomal calcium levels, thereby stabilizing inter-ion calcium signaling. Clinical trials of levacetylleucine in disorders featuring ataxia, cognitive impairment, and epilepsy, such as Niemann-Pick disease type C, GM2 gangliosidoses, and ataxia-telangiectasia have demonstrated an improvement in neurological signs and symptoms, and levacetylleucine was shown to be safe and well-tolerated.

Method: IB1001-304 will enroll participants ≥4 years with a genetically confirmed diagnosis of CACNA1A disorder. Participants will be assessed during three study periods: a baseline period, after which they will be randomized (1:1) to receive treatment with levacetylleucine or placebo for 12-weeks during the first intervention period (Period 1). Following Period 1, participants will crossover to receive the opposite treatment for 12-weeks during a second intervention period (Period 2). An Extension Phase will be planned to allow participants who participated in the trial to have further access to levacetylleucine. Treatment will be administered orally, and participants will receive a total daily dose of 2-4 g/day based on weight-tiered doses.

Results: The primary efficacy endpoint will be the Scale for the Assessment and Rating of Ataxia. Secondary endpoints include Spinocerebellar Ataxia Function Index, quality of life (EQ-5D-5L for participants ≥18 years and EQ-5D-Y for participants <18 years), Neurology Quality of Life-Upper Extremity Function, and Clinical Global Impression of Improvement. Safety assessments include adverse event incidence and severity.

Conclusion: CACNA1A disorders are a group of neurological disorders with no approved treatments. IB1001-304 will evaluate the efficacy and safety of levacetylleucine in improving neurological signs and symptoms, functioning, and quality of life in people with CACNA1A disorders.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-phase-3-multinational-randomized-placebo-controlled-double-blind-crossover-trial-ib1001-304-evaluating-levacetylleucine-in-cacna1a-disorders/