AMX0035 Safe, Effective in Slowing ALS Functional Decline, Trial Data Shows

Amylyx’s experimental oral treatment AMX0035 safely and effectively slows functional decline in amyotrophic lateral sclerosis (ALS) patients with rapidly progressing disease, according to full data from the CENTAUR Phase 2/3 trial.

Only changes in upper limb strength were significantly different from those seen in placebo-treated patients, the data show. Meanwhile, AMX0035 was associated with a trend toward slower rates of decline in muscle strength and lung function, as well as fewer hospitalizations.

“CENTAUR met its prespecified primary outcome, showing a clinically meaningful and statistically significant treatment benefit on the Revised ALS Functional Rating Scale (ALSFRS-R), the most commonly used scale in clinics worldwide to measure function in ALS,” Sabrina Paganoni, MD, PhD, the trial’s principal investigator, of the Sean M. Healey & AMG Center for ALS at Mass General, in Boston, and an assistant professor at Harvard Medical School, said in a press release.

“This development is a breakthrough for the ALS community and we are working collaboratively and expeditiously with agencies worldwide to bring this potential new treatment option forward,” said Josh Cohen, co-founder, co-CEO, and chairman of Amylyx.

The trial’s full data, “Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis,” were recently published in the New England Journal of Medicine.

AMX0035 combines two small molecules, tauroursodeoxycholic acid and sodium phenylbutyrate, that prevent nerve cell death. They work to block stress signals within mitochondria — the powerhouses of cells — and the endoplasmic reticulum, a cellular organelle involved in protein production, modification, and transport. Both compounds have been used in the clinic, with proof of being safe and well tolerated.

The therapy received orphan drug designation from the U.S. Food and Drug Administration for ALS in 2017, and may soon get a similar designation from the European Commission, after a branch of the European Medicines Agency issued a positive recommendation for the same indication.

The multicenter Phase 2/3 CENTAUR study (NCT03127514) evaluated AMX0035’s safety and effectiveness in 137 adults recently diagnosed with sporadic or familial ALS. All showed rapidly progressing disease — a stringent enrollment criteria meant to provide the most powerful results possible.

The participants were randomly assigned to receive either AMX0035 (89 patients) or a placebo (48 patients) twice daily for 24 weeks (about six months).

The trial’s main goals were to assess changes in ALSFRS-R — which measures patients’ abilities in several daily functions, including speech, swallowing, walking, dressing, and hygiene — and the therapy’s tolerability and safety profile. Of note, the higher the ALSFRS-R score the more function is retained, and a 1–2 point loss can represent a significant reduction in a patient’s ability to function independently.

The secondary goals included changes in muscle strength, lung function, and ALS biomarkers, as well as in survival, need for permanent ventilation, and hospitalizations.

The results showed AMX0035-treated patients had a significantly slower functional decline than those given a placebo (mean monthly loss of 1.24 points vs. 1.66 points with a placebo). In addition, individuals given AMX0035 showed significantly higher ALSFRS-R scores (by 2.92 points) than those in the placebo group at the end of 24 weeks of follow-up.

Most (77%) participants were receiving an approved ALS therapy — riluzole (marketed as Rilutek and Tiglutik), Radicava (edaravone), or both — before and/or during the trial. Additional analyses highlighted that AMX0035’s impact on disability progression was independent of the use and duration of other therapies.

The AMX0035 group also showed a trend toward slower muscle strength and lung function decline and fewer hospitalizations than the placebo group. However, these differences were not statistically significant, with the exception of upper limb strength.

More than 95% of participants in both groups reported at least one adverse event, with most being considered non-serious and unrelated to the study. None led to treatment modification or interruption.

AMX0035 was generally well tolerated, showing similar rates of adverse events to those reported in the placebo group. However, individuals receiving AMX0035 had fewer serious adverse events (12%) than those in the placebo group (19%). The AMX0035-treated patients were more likely to have early, generally mild, gastrointestinal side effects (28.1% vs. 12.5%) and to discontinue treatment due to adverse events (19% vs. 8%).

“The data published today makes a clear and compelling case that AMX0035 should be made available to people with ALS as soon as possible,” said Calaneet Balas, president and CEO of The ALS Association.

“We look forward to working with Amylyx, the FDA, and the entire community to help make that happen. We are grateful to all the Ice Bucket Challenge donors whose contributions helped make this trial possible,” Balas added.

CENTAUR was a collaboration between Amylyx, The ALS Association, the ALS Finding a Cure Foundation, the Northeast ALS Consortium, and the Massachusetts General Hospital Neurology Clinical Research Institute.

Merit Cudkowicz, MD, chief medical officer of ALS Finding a Cure, said that the trial “is a phenomenal example of what can happen when a community works closely together to accelerate ALS progress.”

Most (92%) eligible participants who completed CENTAUR chose to enter its open-label extension study (NCT03488524), in which all patients will receive AMX0035 for up to 30 months (about two and a half years).

Interim long-term safety, effectiveness, and survival data from this extension study will be published in a peer-reviewed scientific journal in the near future.

“We also look forward in the coming months to sharing results from the CENTAUR open-label extension study and the long-term survival analysis, and we will continue to keep the community closely informed on next steps,” said Justin Klee, Amylyx’s co-founder and co-CEO.