Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial
12 affiliations
- 1Department of Pediatrics, University of Cologne, Cologne, Germany; Third Department of Paediatrics, 'Attikon' University General Hospital, Chaidari, Attica, Greece; Medical School, National and Kapodistrian University of Athens, Athens, Attica, Greece; Department of Child Neurology, Justus Liebig University, Giessen, Germany. Electronic address: [email protected]
- 2Department of Neurology, University Hospital Bern (Inselspital), Switzerland
- 3Respiratory Support and Sleep Service Unit, Royal Papworth NHS Hospital, Cambridge, UK
- 4Department of Pediatric Neurology, National Institute of Children's Diseases, Comenius University in Bratislava, Bratislava, Slovak Republic
- 5Department of Pediatric Neurology, University Hospital La Paz, Madrid, Spain
- 6Department of Neurology, P J Safarik University, Kosice, Slovak Republic; Department of Neurology, University Hospital of Louis Pasteur, Kosice, Slovak Republic
- 7Department of Child Neurology, Justus Liebig University, Giessen, Germany
- 8Children's Clinical Research Team, University of Nottingham, Nottingham, UK
- 9Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA
- 10Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
- 11UTHealth Houston, Houston, TX, USA
- 12Department of Pediatrics, University of Cologne, Cologne, Germany
Abstract
BACKGROUND: Ataxia-telangiectasia is a rare, autosomal recessive neurodegenerative disorder. Levacetylleucine (N-acetyl-L-leucine) has been shown to be efficacious for the treatment of neurological manifestations and to have a disease-modifying effect in lysosomal storage disorders such as Niemann-Pick disease type C. We aimed to assess the safety and efficacy of levacetylleucine for paediatric and adult patients with ataxia-telangiectasia. METHODS: In this phase 3, randomised, double-blind, placebo-controlled crossover trial, participants were enrolled across ten research hospitals in Germany, Slovakia, Spain, Switzerland, the UK, and the USA. Eligible patients aged 4 years or older with genetically confirmed ataxia-telangiectasia were randomly assigned (1:1) using interactive response technology to receive two or three times daily orally administered levacetylleucine or a matching placebo over two consecutive 12-week treatment periods (patients weighing 35 kg or more received 4 g per day of orally administered levacetylleucine or a matching placebo three times per day and patients weighing less than 35 kg received weight-tiered doses two or three times per day based on approximately 0·1 g/kg per day). All participants, investigators, and assessors were blinded to group assignment. The primary outcome was the mean change on the Scale for the Assessment and Rating of Ataxia (SARA), assessed at baseline and at the end of each 12-week treatment period of levacetylleucine or placebo. Safety and efficacy analyses were done in all randomly assigned patients who received at least one dose of study medication, and a linear mixed-effects model was used to account for data missing at random. The trial is registered with ClinicalTrials.gov, NCT06673056, and CTIS, 2024-517706-29; the open-label extension phase is ongoing. FINDINGS: Between March 18, 2025 and June 30, 2025, 77 participants with a genetically confirmed diagnosis of ataxia-telangiectasia were screened for inclusion. Four patients were excluded (not meeting inclusion criteria) and 73 were enrolled and randomly assigned (36 to levacetylleucine followed by placebo and 37 to placebo followed by levacetylleucine. 73 patients were included in the primary analysis and safety sets. 38 (52%) of 73 patients were female and 35 (48%) were male; 55 (75%) of 73 patients were White. 47 (64%) of 73 were younger than 18 years and 26 (36%) were aged 18 years or older. The mean change in the SARA total score with levacetylleucine was -1·92 (SD 2·81) versus -0·14 (2·38) with placebo (linear mixed model treatment effect -1·88 [SD 0·41], 95% CI -2·70 to -1·06; p<0·0001). 54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo. No treatment-related serious adverse events or deaths occurred. INTERPRETATION: Levacetylleucine showed a significant and clinically meaningful improvement in functioning and was safe and well-tolerated, providing a favourable benefit-risk profile for the treatment of ataxia-telangiectasia. An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective and disease-modifying effects. FUNDING: IntraBio.
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BibTeX
@article{martakis2026safety,
title = {{Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial}},
author = {Κyriakos Martakis and Tatiana Brémovà-Ertl and Clare Bolton and Tomas Foltan and María del Mar García Romero and Matthias Gautschi and Vladimír Haň and Andreas Hahn and Miriam Kolníková and Ouliana Panagioti and Susan Perlman and Manish Prasad and Jeremey Schmahmann and Matěj Škorvánek and Nivedita Thakur and Moritz Thiel and Franziska Hoche},
journal = {The Lancet Neurology},
year = {2026},
month = jun,
doi = {10.1016/s1474-4422(26)00158-4},
url = {https://doi.org/10.1016/s1474-4422(26)00158-4},
note = {CC BY},
}
RIS
TY - JOUR
TI - Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial
AU - Κyriakos Martakis
AU - Tatiana Brémovà-Ertl
AU - Clare Bolton
AU - Tomas Foltan
AU - María del Mar García Romero
AU - Matthias Gautschi
AU - Vladimír Haň
AU - Andreas Hahn
AU - Miriam Kolníková
AU - Ouliana Panagioti
AU - Susan Perlman
AU - Manish Prasad
AU - Jeremey Schmahmann
AU - Matěj Škorvánek
AU - Nivedita Thakur
AU - Moritz Thiel
AU - Franziska Hoche
PY - 2026
DA - 2026/06/17
JO - The Lancet Neurology
DO - 10.1016/s1474-4422(26)00158-4
UR - https://doi.org/10.1016/s1474-4422(26)00158-4
AB - BACKGROUND: Ataxia-telangiectasia is a rare, autosomal recessive neurodegenerative disorder. Levacetylleucine (N-acetyl-L-leucine) has been shown to be efficacious for the treatment of neurological manifestations and to have a disease-modifying effect in lysosomal storage disorders such as Niemann-Pick disease type C. We aimed to assess the safety and efficacy of levacetylleucine for paediatric and adult patients with ataxia-telangiectasia. METHODS: In this phase 3, randomised, double-blind, placebo-controlled crossover trial, participants were enrolled across ten research hospitals in Germany, Slovakia, Spain, Switzerland, the UK, and the USA. Eligible patients aged 4 years or older with genetically confirmed ataxia-telangiectasia were randomly assigned (1:1) using interactive response technology to receive two or three times daily orally administered levacetylleucine or a matching placebo over two consecutive 12-week treatment periods (patients weighing 35 kg or more received 4 g per day of orally administered levacetylleucine or a matching placebo three times per day and patients weighing less than 35 kg received weight-tiered doses two or three times per day based on approximately 0·1 g/kg per day). All participants, investigators, and assessors were blinded to group assignment. The primary outcome was the mean change on the Scale for the Assessment and Rating of Ataxia (SARA), assessed at baseline and at the end of each 12-week treatment period of levacetylleucine or placebo. Safety and efficacy analyses were done in all randomly assigned patients who received at least one dose of study medication, and a linear mixed-effects model was used to account for data missing at random. The trial is registered with ClinicalTrials.gov, NCT06673056, and CTIS, 2024-517706-29; the open-label extension phase is ongoing. FINDINGS: Between March 18, 2025 and June 30, 2025, 77 participants with a genetically confirmed diagnosis of ataxia-telangiectasia were screened for inclusion. Four patients were excluded (not meeting inclusion criteria) and 73 were enrolled and randomly assigned (36 to levacetylleucine followed by placebo and 37 to placebo followed by levacetylleucine. 73 patients were included in the primary analysis and safety sets. 38 (52%) of 73 patients were female and 35 (48%) were male; 55 (75%) of 73 patients were White. 47 (64%) of 73 were younger than 18 years and 26 (36%) were aged 18 years or older. The mean change in the SARA total score with levacetylleucine was -1·92 (SD 2·81) versus -0·14 (2·38) with placebo (linear mixed model treatment effect -1·88 [SD 0·41], 95% CI -2·70 to -1·06; p<0·0001). 54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo. No treatment-related serious adverse events or deaths occurred. INTERPRETATION: Levacetylleucine showed a significant and clinically meaningful improvement in functioning and was safe and well-tolerated, providing a favourable benefit-risk profile for the treatment of ataxia-telangiectasia. An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective and disease-modifying effects. FUNDING: IntraBio.
SN - 1474-4422
SN - 1474-4465
ER -