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DENVER -- Topline data presented here showed why Amylyx Pharmaceuticals decided to remove its amyotrophic lateral sclerosis (ALS) drug sodium phenylbutyrate and taurursodiol (Relyvrio), also known as AMX0035, from the market.

On April 4, the company said it was working with the FDA and Health Canada to voluntarily discontinue marketing authorizations for the drug based on results from the phase III PHOENIX trial, which did not meet its prespecified efficacy endpoints.

In a plenary session at the American Academy of Neurology annual meeting, Leonard van den Berg, MD, PhD, of University Medical Center Utrecht in the Netherlands, gave a preliminary look at details from the study.

"PHOENIX was a well-powered and well-executed trial," van den Berg said. "Despite the positive results in the phase II study, there were no differences between groups on the primary endpoints and the secondary endpoints in the phase III study."

In 2022, the FDA approved AMX0035 based on results from the phase II CENTAUR trial. In CENTAUR, AMX0035 appeared to slow functional decline compared with placebo in people with rapidly advancing ALS, most of whom were already taking two FDA-approved ALS medications, riluzole (Rilutek) and edaravone (Radicava). Data from an open-label extension of CENTAUR suggested a survival benefit with AMX0035.

evaluated AMX0035 in a larger population of ALS patients over a longer placebo-controlled duration than CENTAUR -- 48 weeks instead of 24 weeks. A total of 664 participants were enrolled, 552 from Europe and 112 from the U.S. Mean age was 59.5 years. Most participants were male (62%) and white (83%).

About one in five participants (22%) had bulbar-onset disease. Mean time since ALS symptom onset was 14.4 months. At screening, 92% of participants were taking riluzole and 3% were taking edaravone.

Participants were randomized 3:2 to AMX0035 or placebo. Of all people in the intention-to-treat population, 42% in the AMX0035 group and 43% in the placebo group discontinued the trial.

The primary endpoint was the change from baseline in ALS Functional Rating Scale-Revised () total score at week 48. The ALSFRS-R assesses independence in performing daily activities like walking, talking, dressing, and eating. At 48 weeks, the mean change was -14.98 points in the AMX0035 group and -15.32 points in the placebo group (difference 0.343, 95% CI -1.22 to 1.91, P=0.667).

No differences were seen in secondary endpoints, including ALS-specific quality of life and breathing capacity. Safety outcomes were in line with those seen in CENTAUR.

Subgroup analyses and biomarker studies are underway, van den Berg said. Of particular interest will be further investigation of ALS patients in PHOENIX who were similar to CENTAUR participants, he added.

The lessons learned from PHOENIX and CENTAUR could help ALS researchers design future studies, observed Merit Cudkowicz, MD, MSc, of Massachusetts General Hospital in Boston.

"When you go from a study in one country with a very homogenous population like CENTAUR to a broader group and global study like PHOENIX, you introduce a lot of noise," she said. "One issue might be that the variability went up, and if you have a drug with a small effect, you can lose that small effect," Cudkowicz told 番茄社区app.

"Another possibility is that the CENTAUR study was just wrong; small studies can have false positives," she continued. "The other thing is that maybe different populations react differently; we just don't know. Another drug, edaravone, was very positive in a Japanese population, but it didn't repeat in Europe."

The PHOENIX researchers also will continue to collect survival data. "Longer follow-up past week 48 is needed for the overall survival analysis to reach maturity," van den Berg noted. Complete survival outcomes will not be available until 2025 or 2026, he said.

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