Modified Amino Acid Improves Neurologic Symptoms in Rare Genetic Disorder

Levacetylleucine (Aqneursa) improved neurologic symptoms and functioning in adults and children with ataxia-telangiectasia in a phase III, randomized, crossover trial.

The 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 (no ataxia) to 40 (severe ataxia).

At 12 weeks, treatment with oral levacetylleucine led to an improvement in SARA scores of -1.88 points compared with placebo (-1.92 points vs -0.14 points, P<0.001), reported Kyriakos Martakis, MD, of the University of Cologne in Germany, and co-authors in Lancet Neurology. A 1-point change is considered clinically meaningful.

Levacetylleucine also showed improvements in quality of life compared with placebo. Overall, 54 adverse events occurred in 29 patients on levacetylleucine, and 75 adverse events occurred in 25 patients on placebo. Two patients had three treatment-emergent adverse events related to levacetylleucine (diarrhea, eczema, and insomnia); all were transient. There were no treatment-related discontinuations, serious adverse events, or deaths.

“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,” Martakis and colleagues stated. “An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective, and disease-modifying effects.”

Levacetylleucine (N-acetyl-L-leucine) is a modified amino acid that has been shown to improve certain neurologic symptoms. The drug was approved to treat neurologic manifestations of Niemann-Pick disease type C in 2024.

Ataxia-telangiectasia is a rare inherited disorder caused by variants in the ATM gene that encodes the ATM protein, which regulates DNA damage response. Mutations in the ATM gene cause progressive degeneration to the cerebellum, central nervous system, and immune system, leading to cognitive and physical decline and premature death.

“The disease is characterized by progressive cerebellar ataxia and other neurological features, typically beginning in early childhood, accompanied by immunodeficiency, cancer predisposition, and other systemic complications that lead to substantial morbidity and a reduced lifespan,” wrote Bart van de Warrenburg, MD, PhD, and Michèl Willemsen, MD, both of the Radboud University Medical Center in Nijmegen, the Netherlands, in an accompanying editorial.

“Despite major advances in understanding the pathophysiology of ataxia-telangiectasia, therapeutic options remain largely supportive,” van de Warrenburg and Willemsen pointed out.

This trial provides “original evidence that a pharmacological, downstream intervention indeed can produce clinically meaningful symptomatic improvement in this disorder,” the editorialists noted. “At the same time, important questions remain regarding the long-term safety and efficacy, mode of action, and broader effects on multisystem disease progression of levacetylleucine in people with ataxia-telangiectasia.”

The phase III trial was conducted at 11 sites across six countries: the U.S., U.K., Germany, Slovakia, Spain, and Switzerland. Eligible patients had genetically confirmed ataxia-telangiectasia, were at least 4 years old, and had a SARA score of 7 to 34 points.

The study enrolled 73 patients; most (64%) were under age 18 and just over half were female. Most participants (70%) were diagnosed with ataxia-telangiectasia before age 2, and most were white and of North American or European descent.

Participants were randomly assigned to receive either weight-based doses of oral levacetylleucine or placebo two to three times a day. Patients spent 12 weeks on their first assigned treatment before switching to the opposite treatment for another 12 weeks. Each 12-week block included two scheduled visits.

“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 and co-authors said.

Subgroup analyses showed that neurologic symptoms improved with levacetylleucine in all demographics. Quality of life assessments in adults indicated a decrease in patient-reported rates of moderate to severe mobility problems, a decrease in pain and discomfort, and an increase in the ability to perform usual activities with levacetylleucine. Pediatric patients showed improvements in mobility and self-care.

The safety profile was consistent with the phase III trial results of levacetylleucine in Niemann-Pick disease type C, the researchers noted.

The study had several limitations, they acknowledged. It was designed to investigate symptomatic effects and excluded patients younger than age 4, asymptomatic patients, and patients with advanced disease who would not reliably be able to complete functional assessments.

In March, drugmaker IntraBio submitted an application to the FDA to expand the levacetylleucine label to include ataxia-telangiectasia. The agency is expected to decide by Sept. 19.