Levacetylleucine for AT
(2026)Objective
To assess the safety and efficacy of oral levacetylleucine (N-acetyl-L-leucine) for the neurological manifestations of ataxia-telangiectasia in paediatric and adult patients.
Study Summary
• Consistent supportive benefit on FDA f-SARA (−0·57, 95% CI −0·92 to −0·23; p=0·001), ICARS (−2·84, 95% CI −4·87 to −0·81; p=0·003), and investigator CGI-I (−0·4, 95% CI −0·7 to −0·02; p=0·02); subgroup analysis showed uniform benefit across age, gender, and disease severity.
• Safe and well-tolerated: 40% AE rate on levacetylleucine vs 35% on placebo, no treatment-related serious adverse events, no deaths, and no discontinuations for adverse events.
Intervention
Oral levacetylleucine (N-acetyl-L-leucine) granules for suspension: 4 g/day (≥35 kg) or weight-tiered ≈0·1 g/kg/day (<35 kg) two to three times daily for 12 weeks per crossover period.
Inclusion Criteria
Age ≥4 years; genetically confirmed ataxia-telangiectasia; SARA score 7–34; gait subtest 2–7 or 9-hole peg test with dominant hand in 20–150 sec; weight ≥15 kg.
Study Design
Arms: Levacetylleucine → placebo (n=36) versus Placebo → levacetylleucine (n=37) in a 12+12-week double-blind crossover, allowing each patient to serve as their own control.
Patients per Arm: 36 (levacetylleucine→placebo) vs 37 (placebo→levacetylleucine); 73 total randomised and analysed
Outcome
• Secondary: f-SARA −0·57 (p=0·001), ICARS −2·84 (p=0·003), investigator CGI-I −0·4 (p=0·02); EQ-5D-5L/Y showed improvements in mobility, pain, self-care, and usual activities.
• Safety: 54 AEs in 29 (40%) on levacetylleucine vs 75 AEs in 25 (35%) on placebo; only 3 drug-related AEs (all mild-moderate and transient: diarrhoea, eczema, insomnia); no related SAEs, no deaths.
Clinical Question
In paediatric and adult patients with genetically confirmed ataxia-telangiectasia, does 12 weeks of oral levacetylleucine (N-acetyl-L-leucine) improve neurological status, functioning, and quality of life compared with placebo?
Bottom Line
In this first positive phase 3 trial in ataxia-telangiectasia, levacetylleucine produced a statistically significant and clinically meaningful improvement in SARA (treatment effect −1·88 points, 95% CI −2·70 to −1·06; p<0·0001) over 12 weeks with a favourable safety profile and no treatment-related serious adverse events.
Major Points
- First completed positive phase 3 RCT for any therapy in ataxia-telangiectasia, a rare autosomal-recessive neurodegenerative disorder with no approved treatments.
- 73 patients (47 paediatric, 26 adult) across 10 sites in 6 countries received 12 weeks of oral levacetylleucine and 12 weeks of matching placebo in a crossover design; 70 completed both periods.
- Primary SARA outcome: mean change −1·92 with levacetylleucine vs −0·14 with placebo (linear mixed model treatment effect −1·88, 95% CI −2·70 to −1·06; p<0·0001), exceeding the 1–1·5 point clinically meaningful threshold.
- Supportive secondary results: FDA f-SARA −0·57 (p=0·001), ICARS −2·84 (p=0·003), and investigator CGI-I −0·4 (p=0·02); subgroup benefit was consistent across age, disease-onset group, weight-based dose, and gender.
- Patients randomised to levacetylleucine→placebo deteriorated by 1·81 SARA points during period 2 washout, mirroring the drug's expected pharmacokinetic effect.
- 81% of exit interviews (57/70) reported neurological improvement on levacetylleucine; 66% described the changes as meaningful for everyday life.
- Safety: 54 AEs in 29 patients (40%) on levacetylleucine vs 75 AEs in 25 patients (35%) on placebo; only 3 drug-related AEs (mild diarrhoea, mild eczema, moderate insomnia), no treatment-related serious adverse events and no deaths.
- Weight-tiered oral dosing (2 g/day for 15–<25 kg, 3 g/day for 25–<35 kg, 4 g/day for ≥35 kg) as granules for suspension in water, orange juice, or almond milk was well tolerated.
Study Design
- Study Type
- Randomised Controlled Trial (Phase 3, crossover)
- Randomization
- Yes
- Blinding
- Double-blind (participants, investigators, assessors, sponsor, families)
- Sample Size
- 73
- Follow-up
- Two consecutive 12-week treatment periods (24 weeks total); open-label extension ongoing
- Centers
- 10
- Countries
- Germany, Slovakia, Spain, Switzerland, UK, USA
Primary Outcome
Definition: Mean change from baseline in SARA (Scale for the Assessment and Rating of Ataxia) total score after each 12-week treatment period
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| −0·14 (SD 2·38) | −1·92 (SD 2·81) | N/A (linear mixed-effects model) (−2·70 to −1·06) | <0·0001 |
Limitations & Criticisms
- Small sample (n=73) reflecting a rare disease population; crossover design increases power but cannot fully exclude carry-over effects despite the observed washout deterioration.
- Short 12-week per-period exposure; effects on ataxia-telangiectasia hallmarks such as immunological defects and cancer risk cannot be assessed in this timeframe.
- Symptomatic entry criteria excluded children younger than 4 years, asymptomatic patients, and those with advanced disease unable to complete functional assessments — limiting generalisability at both extremes of the disease.
- Predominantly White North American and European population (75% White); ethnic/racial diversity was scarce.
- No validated biomarker or surrogate endpoint for ataxia-telangiectasia to corroborate the clinical improvement.
- Secondary endpoints reported without multiplicity adjustment, so p-values are hypothesis-generating rather than confirmatory.
- Not all functional scales are formally validated in paediatric populations.
- Industry-sponsored (IntraBio); the sponsor collaborated on design but had no role in data collection, analysis, interpretation, or writing per the disclosures.
Citation
Lancet Neurol. 2026 Jul;25(7):633-644