Levacetylleucine Shows Promising Safety and Efficacy in Treating Ataxia-Telangiectasia: Phase 3 Trial Findings

Highlight

• Levacetylleucine (N-acetyl-L-leucine) significantly improved neurological function in patients with ataxia-telangiectasia, measured by the Scale for the Assessment and Rating of Ataxia (SARA).
• The randomized, double-blind, placebo-controlled crossover design enrolled 73 genetically confirmed patients aged 4 years and older across six countries.
• Levacetylleucine was well-tolerated with no treatment-related serious adverse events reported, supporting its favorable safety profile.
• An ongoing open-label extension phase aims to evaluate potential long-term neuroprotective and disease-modifying effects.

Study Background

Ataxia-telangiectasia (A-T) is a rare, autosomal recessive neurodegenerative disorder characterized by progressive cerebellar ataxia, immunodeficiency, cancer predisposition, and telangiectasia. Neurological decline in A-T significantly impairs motor function, balance, and coordination, contributing to substantial morbidity and reduced quality of life. Currently, no approved disease-modifying therapies exist for A-T, leaving a critical unmet medical need for effective treatment options to slow or improve neurological deficits.

Levacetylleucine (N-acetyl-L-leucine), a modified amino acid derivative, has shown efficacy in ameliorating neurological symptoms in lysosomal storage disorders like Niemann-Pick disease type C, suggesting potential for use in other neurodegenerative diseases. This clinical trial aimed to rigorously evaluate the safety and efficacy of levacetylleucine in pediatric and adult patients with genetically confirmed A-T.

Study Design

This phase 3, randomized, double-blind, placebo-controlled crossover trial enrolled participants aged 4 years or older with genetically confirmed ataxia-telangiectasia at ten specialized research hospitals across Germany, Slovakia, Spain, Switzerland, the UK, and the USA. Using interactive response technology, 73 eligible patients were randomly assigned in a 1:1 manner to receive either levacetylleucine followed by placebo or placebo followed by levacetylleucine.

Participants received oral levacetylleucine or matching placebo for two consecutive 12-week periods. Dosing was weight-based: patients ≥35 kg were given 4 g per day divided into three doses, while those <35 kg received approximately 0.1 g/kg/day split into two or three doses.

The primary efficacy endpoint was the mean change in the Scale for the Assessment and Rating of Ataxia (SARA) score, assessed at baseline and after each 12-week treatment period. The SARA is a well-validated clinical scale measuring ataxia severity, with higher scores indicating worse impairment. The trial maintained blinding for participants, investigators, and outcome assessors throughout the study.

Statistical analysis employed a linear mixed-effects model, accounting for any data missing at random. Safety assessments included adverse event recording and routine clinical monitoring. The trial is registered under ClinicalTrials.gov NCT06673056 and CTIS 2024-517706-29.

Following the crossover trial, an ongoing open-label extension phase aims to further evaluate the prolonged effects of levacetylleucine.

Key Findings

Between March and June 2025, 77 patients were screened; 4 were excluded for ineligibility, and 73 enrolled participants were randomized—36 to levacetylleucine first, 37 to placebo first. Of these, 52% were female, 75% White, and 64% younger than 18 years.

After 12 weeks of levacetylleucine treatment, patients showed a mean reduction in SARA score of 1.92 points (standard deviation 2.81), compared to a 0.14 point reduction (SD 2.38) under placebo. The linear mixed-effects model estimated a treatment effect of -1.88 (SD 0.41) with a 95% confidence interval ranging from -2.70 to -1.06, achieving high statistical significance (p < 0.0001). This indicates a clinically meaningful improvement in neurological function with levacetylleucine compared to placebo.

Regarding safety, 54 adverse events were reported in 29 patients during levacetylleucine administration, compared to 75 events in 25 patients receiving placebo. Importantly, no treatment-related serious adverse events or deaths occurred, underscoring levacetylleucine’s tolerability.

The trial demonstrated a robust benefit-risk profile for levacetylleucine in treating A-T neurological symptoms.

Expert Commentary

This rigorous phase 3 crossover trial provides compelling evidence supporting levacetylleucine as a promising therapeutic agent for neurodegenerative symptoms of ataxia-telangiectasia. The statistically and clinically significant improvement in SARA scores suggests meaningful functional benefit in diverse patient populations, including children and adults.

The crossover study design strengthens internal validity by allowing within-subject comparison, minimizing inter-patient variability. The trial’s multinational scope and inclusion of a broad age range enhance generalizability.

A notable strength is the favorable safety profile, as the absence of serious adverse events supports the agent’s feasibility for long-term use. However, the relatively short 12-week treatment periods limit conclusions about sustained disease-modifying effects. The ongoing open-label extension will be critical to determine whether levacetylleucine can attenuate neurodegeneration progression over time.

Mechanistically, levacetylleucine’s exact neuroprotective pathways remain incompletely understood but may involve modulation of neuronal metabolism and cellular stress responses, warranting further preclinical and biomarker studies.

Limitations include the lack of active comparator and dependence on a single clinical scale; future studies incorporating additional functional and biomarker endpoints could provide complementary insight.

Current clinical guidelines do not include disease-modifying therapies for A-T, thus this evidence could inform future recommendations pending replication and long-term data.

Conclusion

Levacetylleucine represents a promising therapeutic advance for patients with ataxia-telangiectasia. This phase 3 trial evidences significant and clinically meaningful improvement in ataxia severity alongside a strong safety profile. These findings address a critical unmet need for effective treatments targeting neurological dysfunction in this rare disorder.

Pending longer-term data from the ongoing extension study, levacetylleucine may become an important component of A-T management, potentially modifying the disease course and improving patients’ motor function and quality of life.

Further research is warranted to clarify mechanisms, optimize dosing, and establish comparative effectiveness with emerging therapies.

Funding and Trial Registration

The trial was funded by IntraBio. It is registered on ClinicalTrials.gov (NCT06673056) and the Clinical Trials Information System (CTIS 2024-517706-29). An open-label extension phase is currently ongoing to investigate the long-term effects of levacetylleucine treatment.

References

1. Martakis K, Bremova-Ertl T, Bolton C, et al. Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial. Lancet Neurol. 2026 Jul;25(7):633-644. PMID: 42309084.
2. Schmahmann JD. Ataxia-telangiectasia: Molecular basis and clinical aspects. Nat Rev Neurol. 2020;16(9):555-568.
3. Bremova-Ertl T, et al. N-acetyl-L-leucine for lysosomal storage disorders: a review of emerging clinical evidence. Orphanet J Rare Dis. 2023;18(1):89.