Levacetylleucine for AT
Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial
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.
Design
Study Type: Randomised Controlled Trial (Phase 3, crossover)
Randomization: 1
Blinding: Double-blind (participants, investigators, assessors, sponsor, families)
Enrollment Period: March 18, 2025 – June 30, 2025
Follow-up Duration: Two consecutive 12-week treatment periods (24 weeks total); open-label extension ongoing
Centers: 10
Countries: Germany, Slovakia, Spain, Switzerland, UK, USA
Sample Size: 73
Analysis: Linear mixed-effects model in all patients who received at least one dose (n=73); permuted 4-patient block randomisation via centralised interactive response technology (Medpace)
Inclusion Criteria
- Age ≥4 years
- Genetically confirmed diagnosis of ataxia-telangiectasia
- SARA total score 7–34 at screening
- Gait subtest of the SARA scale within the 2–7 range, or able to perform the 9-hole peg test with the dominant hand in 20–150 seconds
- Weight ≥15 kg at screening
- Written informed consent by patient, parent, caregiver, or legal representative
Exclusion Criteria
- Not meeting the SARA range or functional test criteria above
- Advanced disease state precluding reliable completion of functional assessments
- Asymptomatic ataxia-telangiectasia (not eligible under this symptomatic protocol)
- Use of prohibited concomitant medication (monitored by regular urine analyses to confirm adherence)
- Detailed inclusion/exclusion list in trial appendix (pp 2–3)
Arms
| Field | Levacetylleucine → Placebo | Control |
|---|---|---|
| Intervention | Oral levacetylleucine (N-acetyl-L-leucine) granules for suspension: 4 g/day divided TID (≥35 kg) or weight-tiered ≈0·1 g/kg/day BID–TID (<35 kg) for 12 weeks (period 1), then matching placebo for 12 weeks (period 2) | Matching placebo granules (same colour, taste, appearance, solubility) for 12 weeks, then crossover to levacetylleucine 4 g/day TID or weight-tiered ≈0·1 g/kg/day for 12 weeks |
| Duration | 24 weeks (two 12-week periods, back-to-back) | 24 weeks (two 12-week periods, back-to-back) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Mean change from baseline in SARA (Scale for the Assessment and Rating of Ataxia) total score after each 12-week treatment period | Primary | −0·14 (SD 2·38) | −1·92 (SD 2·81) | N/A (linear mixed-effects model) | <0·0001 |
| FDA functional SARA (f-SARA, axial 4-item) | Secondary | −0·10 (SD 1·02) | −0·65 (SD 1·16) | 0·001 | |
| ICARS (International Cooperative Ataxia Rating Scale) | Secondary | −1·69 (SD 6·09) | −4·22 (SD 7·77) | 0·003 | |
| Investigator Clinical Global Impression of Improvement (CGI-I) | Secondary | −0·2 (SD 0·6) | −0·6 (SD 0·8) | 0·02 | |
| SCAFI composite (8MWT, 9HPT-D, 9HPT-ND, PATA) | Secondary | 0·04 (SD 0·24) | 0·06 (SD 0·28) | Not significant | |
| Caregiver CGI-I | Secondary | −0·2 (SD 0·8) | −0·2 (SD 0·8) | Not tested | |
| EQ-Visual Analogue Scale (quality of life) | Secondary | −0·3 (SD 19·2) | 1·3 (SD 15·5) | ||
| Exit interviews reporting neurological improvement | Secondary | 57 (81%) of 70 responders reported improvement on levacetylleucine; 46 (66%) called changes meaningful to daily life; 29 (41%) noted safety-related functional gains | |||
| Any treatment-emergent AE | Adverse | 29 (40%) on levacetylleucine vs 25 (35%) on placebo (54 vs 75 events) | |||
| Infections and infestations | Adverse | 15 (21%) vs 13 (18%) | |||
| Cough | Adverse | 6 (8%) vs 2 (3%) | |||
| Fall | Adverse | 3 (4%) vs 2 (3%) | |||
| Upper respiratory tract infection | Adverse | 3 (4%) vs 3 (4%) | |||
| Pyrexia | Adverse | 3 (4%) vs 2 (3%) | |||
| Diarrhoea | Adverse | 2 (3%) vs 4 (6%) | |||
| Vomiting | Adverse | 1 (1%) vs 4 (6%) | |||
| Abdominal pain | Adverse | 1 (1%) vs 3 (4%) | |||
| Gastrointestinal disorders (SOC) | Adverse | 5 (7%) vs 10 (14%) | |||
| Injury, poisoning, procedural complications (SOC) | Adverse | 7 (10%) vs 5 (7%) | |||
| Drug-related AEs (all mild or moderate, transient) | Adverse | Diarrhoea (mild), eczema (mild), insomnia (moderate) — 3 events in 2 patients on levacetylleucine | |||
| Treatment-related serious AEs | Adverse | 0 | |||
| Deaths | Adverse | 0 | |||
| Discontinuations due to AE | Adverse | 0 (three unrelated SAE withdrawals: T-cell acute leukaemia, diffuse large B-cell lymphoma, lower respiratory tract infection) | |||
Subgroup Analysis
Prespecified subgroup analyses of the primary SARA endpoint showed consistent benefit across paediatric vs adult, age at disease onset, disease severity, weight-based dose group, and gender, with no evidence of heterogeneity of treatment effect.
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.
Funding
IntraBio (industry sponsor); the funder collaborated on study design only, with no role in data collection, analysis, interpretation, or manuscript writing.
Based on: Levacetylleucine for AT (Lancet Neurology, 2026)
Authors: Martakis K, Bremova-Ertl T, Bolton C, et al.
Citation: Lancet Neurol. 2026 Jul;25(7):633-644
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