A treatment for ataxia-telangiectasia has shown clinically meaningful improvements in functional ability in a phase 3 trial for the first time, raising hopes for the first disease-modifying therapy for the disorder.
In the trial, patients with the condition who received levacetylleucine experienced significant improvements in motor and daily functioning, while the treatment also had a favourable safety and tolerability profile.
“Levacetylleucine showed improvements in neurological manifestations, functioning, and quality of life versus placebo after 12 weeks,” the authors said, in a paper published in The Lancet Neurology [link here].
“High internal consistency between the primary and secondary endpoints reinforced a clinically meaningful improvement with levacetylleucine,” they added.
The phase 3 randomised controlled trial was conducted at 10 research hospitals in the UK, Germany, Slovakia, Spain, Switzerland, and the USA.
Patients aged four years or older with genetically confirmed ataxia-telangiectasia were randomly assigned to receive two or three times daily, orally administered levacetylleucine (n=36) or a matching placebo (n=37).
Findings showed significant improvements in ataxia severity in the levacetylleucine group, as shown by change in the Scale for the Assessment and Rating of Ataxia (SARA) score.
According to the data, the SARA score decreased by 1.92 points with levacetylleucine compared with a 0.14-point decrease with placebo (p<0.0001), indicating a measurable improvement in motor function and coordination.
In addition, the treatment’s effect seemed consistent. “Subgroup analysis showed consistent benefit across all demographics of patients, irrespective of age (paediatric vs adult), age at disease onset, or gender,” said the international authors, who included Dr Clare Bolton, consultant neurologist at Cambridge University Hospitals.
On the safety side, 54 adverse events were reported in 29 patients receiving levacetylleucine, compared with 75 events in 25 patients receiving placebo, with no treatment-related serious adverse events or deaths.
The authors also highlighted that findings were consistent with a previous RCT study of levacetylleucine for Niemann-Pick disease type C and its proposed pharmacological mechanism, “reinforcing its potential applicability as a treatment for rare and common neurological disorders”.
In a linked editorial [click here], consultant neurologist Professor Bart van de Warrenburga and consultant paediatric neurologist Prof Michèl Willemsenb, both at Radboudumc, the Netherlands, said the findings were “encouraging” but urged caution in their interpretation.
“This clinical trial provides evidence of a clinically meaningful effect on a key neurological manifestation of ataxia-telangiectasia and therefore represents an important step forward for the ataxia-telangiectasia community. However, there are also unresolved issues and open questions,” they wrote.
For example, the precise mechanism of action of the therapy in ataxia-telangiectasia remains uncertain, raising questions about the biology behind its observed clinical effects.
In addition, the durability of the effects, and their relevance beyond ataxia, as well as long-term safety, are yet to be established. Also, the trial’s sample size was small, they added.
“Nevertheless, this study strengthens the growing sense that meaningful therapeutic progress in ataxia-telangiectasia is becoming achievable, marking what could represent a turning point in the evolving therapeutic landscape,” they concluded.