Utreloxastat fails to slow ALS disease progression in Phase 2 trial
PTC Therapeutics to halt plans for oral candidate's development in ALS
Twice-daily treatment with PTC Therapeutics’ oral candidate utreloxastat failed to significantly slow disease progression in adults with amyotrophic lateral sclerosis (ALS) in a global, placebo-controlled Phase 2 clinical trial.
The results of CardinALS (NCT05349721) showed that, while the therapy was generally safe, it failed to meet its main and secondary goals, which included a number of disease-related efficacy measures. The findings have led PTC to drop plans to proceed with utreloxastat’s development for ALS.
“We are of course disappointed that we were not able to demonstrate treatment efficacy and provide a potential therapy that could address the significant unmet medical need of ALS patients,” Matthew B. Klein, MD, PTC’s CEO, said in a company press release. “We wish to thank all of the patients, their families and physicians who participated in the CardinALS trial.”
ALS causes progressive damage to motor neurons, the nerve cells that control voluntary movement, leading to symptoms that include muscle weakness and difficulty walking, keeping balance, breathing, swallowing, and speaking.
A type of cellular damage called oxidative stress that occurs when harmful oxygen molecules outnumber protective antioxidants within cells is thought to promote an iron-dependent oxidative mode of cell death called ferroptosis that contributes to ALS neurodegeneration.
Harmful oxygen molecules are known to boost the production of an enzyme called 15-lipoxygenase (15-LO), which increases oxidative stress, activates pro-inflammatory cells in the brain, accumulates iron, and ultimately causes ferroptosis.
Testing utreloxastat in ALS
Utreloxastat, formerly known as PTC857, is an orally available molecule that works by suppressing 15-LO, which was expected to protect motor neurons from damage. In a first-in-human Phase 1 clinical trial in healthy adults, an oral solution of utreloxastat was found to be safe and well tolerated when given as either a single dose of up to 1,000 mg or multiple doses of up to 500 mg a day for about two weeks.
CardinALS, which included 307 adults with a diagnosis of definite or probable ALS for no longer than two years, was designed to evaluate utreloxastat’s safety and efficacy against a placebo. The participants were randomly assigned to take an oral solution of either 250 mg of utreloxastat or a placebo, twice daily for 24 weeks, nearly six months.
Its main goal was to assess whether the therapy was superior to a placebo at slowing disease progression, based on a combined measure of ALS Functional Rating Scale-Revised (ALSFRS-R) and survival. Secondary goals included changes in other efficacy measures, including lung function, muscle strength, cognitive function, rate and time to death, and quality of life, along with safety measures. Changes in blood levels of neurofilament light chain (NfL), a marker of nerve cell damage, were also measured.
While PTC didn’t provide detailed results, the company said utreloxastat was associated with a “modest numerical benefit” over a placebo on the main goal that didn’t reach statistical significance. This despite the fact that there seemed to be an association between clinical benefits and reductions in blood NfL levels, the company noted. Differences between utreloxastat and the placebo groups also failed to reach statistical significance regarding secondary goals.
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