ALS Community Invited to Join Petition Calling on FDA to Approve AMX0035

The ALS Association and I AM ALS have opened a petition calling for the earliest possible approval of Amylyx’s experimental oral treatment AMX0035, after a Phase 2/3 trial found the therapy to be safe and to slow functional decline in amyotrophic lateral sclerosis (ALS) patients with rapidly progressing disease.

Addressing the U.S. Food and Drug Administration (FDA) and Amylyx Pharmaceuticals, the petition requests that the FDA forgo a Phase 3 trial, an expected next step before an approval application is filed with the agency.

Given the large number of patients with severe progression in the CENTAUR trial (NCT03127514) and the clinical benefits observed with AMX0035, the groups ask that rigorous studies be made of the therapy’s safety and efficacy while it is being used by ALS patients in lieu of a new and larger trial.

“People with ALS cannot wait for a phase 3 trial to conclude given the promising results show[n] in phase 2,” the ALS Association states in its petition announcement. “Since the FDA has emphasized the appropriateness of exercising flexibility when dealing with serious diseases and unmet medical needs, there is no reason to withhold this promising drug from the ALS community.”

The petition, available here for those considering joining in this request, has five goals:

• The FDA, Amylyx and key representatives of the ALS community, including patients, meet immediately to discuss how to bring AMX0035 to patients
• Amylyx prepares and submits an application to the FDA requesting AMX0035’s approval as an ALS treatment
• The FDA swiftly reviews the application and grants approval
• The agency requires post-approval safety and efficacy studies of the treatment’s real-world use
• Amylyx makes AMX0035 available to patients through expanded access until it is approved and marketed

“With a typical survival time of between 2 to 5 years, people with ALS cannot wait for the full experimental process for AMX0035 to continue,” the petition reads. “We are asking the FDA and Amylyx to work together to bring AMX0035 to people with ALS as soon as possible.”

AMX0035 is made of two small molecules, tauroursodeoxycholic acid and sodium phenylbutyrate, that work to prevent nerve cell death by targeting mitochondria (a cell’s powerhouse) and the endoplasmic reticulum (a cellular structure involved in protein production). Both compounds have been used in the clinic, with evidence supporting them being safe and well tolerated.

The Phase 2/3 CENTAUR study (NCT03127514) evaluated AMX0035’s safety and effectiveness in 137 adults recently diagnosed with sporadic or familial ALS and with evidence of rapidly progressing disease, a criterium added to provide the most powerful results. Its findings were recently published in the New England Journal of Medicine.

Participants were randomized to either AMX0035 (89 patients) or a placebo (48 patients), both given as an oral liquid, twice daily for 24 weeks (about six months).

The trial’s main goal was to assess the therapy’s efficacy, as measured by changes in the ALS functional rating scale-revised (ALSFRS-R, a scale that measures abilities in daily functions that include speech, swallowing, walking, dressing, and hygiene), as well as the therapy’s tolerability and safety profile. The higher the ALSFRS-R score the more function is retained, and a one- or two-point loss can represent a significant drop in a patient’s ability to live independently.

Trial results showed that AMX0035 significantly slowed patient’s functional decline compared to those given a placebo — a mean monthly loss of 1.24 points in the AMX0035 arm compared with 1.66 points in the placebo group.

After 24 weeks, those given AMX0035 also had significantly higher ALSFRS-R scores — a difference of 2.92 points — than those in the placebo group. This score difference with treatment, the petition announcement stated, “could mean the difference between a person with ALS being able to feed themselves versus being fed, or the difference between needing a wheelchair versus not needing one.”

AMX0035’s ability to slow disability progression was found to be independent of the use and duration of other disease therapies. A majority of trial participants, 77%, were using established ALS treatments — riluzole (marketed as Rilutek and Tiglutik), Radicava (edaravone), or both — before or during the trial.

Almost all patients in both groups reported at least one adverse event, but the majority were not considered serious and thought unrelated to the study. AMX0035-treated patients had fewer serious adverse events (19%) than did those on a placebo (12%), but they were more likely to have gastrointestinal side effects (28.1% vs. 12.5%) and to discontinue treatment due to adverse events (19% vs. 8%).

The clinical development of AMX0035 was supported by a $2.2 million grant given by the ALS Association in 2016, one of the first such efforts supported by donations from the ALS Ice Bucket Challenge.