U.S. — Levacetylleucine (Aqneursa) improved neurological symptoms and functioning in adults and children with ataxia-telangiectasia in a phase III, randomized, crossover trial. Drugmaker IntraBio submitted an application to the FDA in March to expand the levacetylleucine label to include ataxia-telangiectasia, with a decision expected by September 19.

The trial's primary endpoint was the mean 12-week change in Scale for the Assessment and Rating of Ataxia (SARA) scores from baseline among 73 adult and pediatric ataxia-telangiectasia patients. SARA scores range from 0 to 40, where 0 indicates no ataxia and 40 indicates severe ataxia. A 1-point change in SARA score is considered clinically meaningful.

At 12 weeks, oral levacetylleucine treatment resulted in a -1.88 point improvement in SARA scores compared with placebo. The mean change in SARA scores was -1.92 points for the levacetylleucine group and -0.14 points for the placebo group. The difference in SARA scores between levacetylleucine and placebo had a P-value less than 0.001. Levacetylleucine also demonstrated improvements in quality of life compared with placebo. Subgroup analyses indicated that neurologic symptoms improved with levacetylleucine across all demographics.

Martakis and colleagues stated, "Levacetylleucine showed a significant and clinically meaningful improvement in functioning and was safe and well-tolerated, providing a favorable benefit-risk profile for the treatment of ataxia-telangiectasia." An open-label extension phase of this trial is ongoing to investigate potential long-term, neuroprotective, and disease-modifying effects. Overall, 54 adverse events occurred in 29 patients who received levacetylleucine, while 75 adverse events occurred in 25 patients on placebo. Two patients experienced three treatment-emergent adverse events related to levacetylleucine: diarrhea, eczema, and insomnia. All adverse events related to levacetylleucine were transient. The trial recorded no treatment-related discontinuations, serious adverse events, or deaths. The safety profile observed in this trial was consistent with results from the phase III trial of levacetylleucine for Niemann-Pick disease type C, for which it was approved in 2024.

The trial was conducted at 11 sites across six countries and enrolled 73 patients. Patients were randomly assigned to receive weight-based doses of oral levacetylleucine or placebo two to three times daily. Participants spent 12 weeks on their first assigned treatment before switching to the opposite treatment for another 12 weeks. "As the trial was a crossover design, in which each patient received levacetylleucine and placebo and therefore served as their own control, no stratification by age was done," Martakis said.

Quality of life assessments in adults showed a decrease in patient-reported moderate to severe mobility problems, and pain and discomfort with levacetylleucine, along with an increase in the ability to perform usual activities. Pediatric patients also demonstrated improvements in mobility and self-care with the treatment.

Why It Matters

Ataxia-telangiectasia is a rare inherited disorder caused by variants in the ATM gene, which results in progressive degeneration of the cerebellum, central nervous system, and immune system, leading to cognitive and physical decline and premature death. Bart van de Warrenburg, MD, PhD, and Michèl Willemsen noted that therapeutic options for ataxia-telangiectasia have been largely supportive despite advances in understanding the disease's pathophysiology. This trial provides evidence that a pharmacological intervention can produce clinically meaningful symptomatic improvement in the disorder. Martakis' group concluded that levacetylleucine demonstrated a favorable benefit-risk profile for treatment.

The phase III trial involved 73 patients, with most being under 18 years old and diagnosed with the condition before age two. The trial excluded patients younger than age four, asymptomatic patients, and those with advanced disease who could not reliably complete functional assessments. Eligible patients had genetically confirmed ataxia-telangiectasia and SARA scores between 7 and 34 points. The FDA's decision on the label expansion application for levacetylleucine to include ataxia-telangiectasia is anticipated by September 19.