FDA Panel Reconvenes in September to Discuss AMX0035 Approval

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by Lindsey Shapiro, PhD |

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A U.S. Food and Drug Administration (FDA) advisory committee will meet  Sept. 7 to discuss the approval of AMX0035 for the treatment of amyotrophic lateral sclerosis (ALS), Amylyx Pharmaceuticals announced.

While the application was granted priority review earlier this year, with a final decision expected by June 29, the FDA delayed the decision last month, after Amylyx, the investigational therapy’s developer, submitted additional analyses of trial data. The agency considered the data to be major amendments requiring further review.

Informed by the discussion from the advisory committee, the FDA now is expected to make a final decision by Sept. 29.

“We remain engaged with the FDA to advance AMX0035 through the review process as efficiently as possible,” Tammy Sarnelli, global head of regulatory affairs, said in a press release.

“We are pleased that the members of the advisory panel will review additional analyses from our clinical studies, including recently published analyses, supporting the previously reported functional and overall survival benefit for AMX0035,” Sarnelli added.

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Delivered twice daily by mouth or feeding tube, AMX0035 is a fixed-dose combination of tauroursodeoxycholic acid and sodium phenylbutyrate, two compounds thought to protect nerve cells from the cellular stress that contributes to the progression of ALS.

The CENTAUR Phase 2 clinical trial (NCT03127514), which formed the basis of Amylyx’s application to the FDA, tested the experimental therapy against a placebo for six months in 137 adults with recently-diagnosed and rapidly progressing ALS.

Then, 90 participants enrolled in its extension study (NCT03488524), in which all participants received AMX0035 for about 2.5 years.

Top-line data showed that AMX0035 outperformed a placebo in its ability to slow functional decline, as measured with the ALS Functional Rating Scale Revised (ALSFRS-R), meeting the trial’s primary goal.

Additional analyses from the trial and its extension demonstrated that survival was extended in patients who had been on AMX0035 from the study’s start compared with those who started on placebo.

In March, the FDA advisory committee narrowly voted against approval of the therapy, with six of 10 members believing that data from CENTAUR and its extension study did not provide sufficient evidence of AMX0035’s efficacy.

Concerns surrounding the trial included its small sample size, missing data, and questionable statistical analyses. However, the nonbinding vote of the advisory committee serves as a recommendation to the FDA, which may or may not follow the recommendation in its final decision.

New data to be reviewed by the advisory committee in September include results from a study published last month, which estimated what the survival difference would have been if participants initially given a placebo had stayed on placebo throughout the study, instead of switching to active treatment during the open-label extension. Results showed that AMX0035 extended the median survival time by more than 10 months, which reflected a 61% lower risk of death.

The risk of serious outcomes, including tracheostomy, permanent assisted ventilation, or hospitalization, also was reduced by 47%, with patients originally given AMX0035 spending a median of 7.3 months longer without a tracheostomy or ventilation compared with those initially assigned to a placebo.

Shortly after the FDA pushed its timeline, AMX0035 was approved in Canada, where it will be marketed as Albrioza. This Canadian approval is among the reasons a delayed decision in the U.S. has been met with criticism in the ALS community.

On June 29 — the original expected decision date — the ALS Association and other ALS organizations signed a joint letter urging the FDA to act sooner than the new September deadline, citing its safety and efficacy in clinical trials, as well as the urgent need for effective ALS treatments, as additional reasons for accelerating AMX0035’s approval.

“The case for approval in the United States – especially given the recent approval of AMX0035 by Health Canada – is clear, and the time is now,” the letter states. “We urge the FDA to act swiftly to complete its review in advance of a recently extended decision deadline and approve AMX0035.”

According to the ALS Association, many U.S. patients are considering traveling to Canada to access the therapy — a process called medical tourism.

Originally, the FDA said it would need data from the the larger Phase 3 PHOENIX  trial (NCT05021536) before considering AMX0035 for approval. A petition signed by more than 50,000 people and a call-to-action meeting with the agency were thought to have influenced its change of decision.

The PHOENIX trial is expected to confirm AMX0035’s efficacy in up to 600 adults with ALS, whose symptoms started in the past two years, over an 11-month period. It is enrolling participants at several European sites.

“As we have heard from the ALS community, there is a crucial need for new and effective treatments in ALS, and our team will continue to work around the clock to advance treatments for ALS in the U.S.,” Sarnelli said.