FDA Pushes Decision on AMX0035 to September for Further Review

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Note: This story was updated June 7, 2022, to note that CENTAUR is a Phase 2, not Phase 2/3, trial and that AMX0035 reduced the risk of death by 43%, instead of 44%. There also has been no indication that U.S. sites will open soon for the PHOENIX trial.

The U.S. Food and Drug Administration (FDA) is extending by three months its review of AMX0035, Amylyx Pharmaceuticals’ experimental oral therapy for amyotrophic lateral sclerosis (ALS).

A decision — originally expected by June 29 after the FDA granted priority review to the application — is now expected by Sept. 29.

The extension is the result of Amylyx‘s submission of additional analyses of trial data. This was considered a major amendment to the application by the agency, which now needs more time to complete its review.

“We are confident in the potential of AMX0035 to help people living with ALS and other neurodegenerative diseases, and we continue to work closely with the FDA as they complete their review,” Justin Klee and Joshua Cohen, Amylyx’s co-CEOs and co-founders, said in a press release.

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This extension comes on the heels of a close vote against the therapy by an FDA advisory committee, with six of its 10 members considering that the CENTAUR Phase 2 clinical trial (NCT03127514) and its extension study (NCT03488524) do not provide enough evidence to prove AMX0035’s efficacy.

Still, the nonbinding vote serves only as a recommendation to the FDA, which may or may not follow the committee’s advice.

The committee’s appraisal was in line with the agency’s concerns over CENTAUR due to its small size, missing data, and questionable statistical analysis. The FDA had initially requested data from the larger PHOENIX Phase 3 trial (NCT05021536) before considering AMX0035 for approval. However, a petition signed by more than 50,000 people and a call-to-action meeting with the agency asking for a quick approval likely weighed on its change of heart.

Similar applications based on CENTAUR and its open-label extension also are being reviewed by health authorities in Canada and in the European Union (EU).

AMX0035, given twice a day by mouth or via feeding tube, received orphan drug designation in both the U.S. and the EU for the treatment of ALS. The designation is meant to expedite the therapy’s clinical development and regulatory review.

The therapy is a fixed-dose combination of tauroursodeoxycholic acid and sodium phenylbutyrate, two small molecules with a well-established safety profile that are thought to protect nerve cells from cellular stress-induced damage — which has been implicated in ALS.

The CENTAUR trial tested AMX0035 against a placebo for six months in 137 adults who had been recently diagnosed with ALS and whose disease was progressing rapidly. Then, 90 of 98 eligible participants chose to enter the extension study, in which all received the therapy for about 2.5 years.

CENTAUR’s top-line data showed AMX0035 was superior to a placebo at slowing patients’ functional decline, meeting the trial’s main goal.

Also, initial analyses of nearly three years of follow-up data spanning both CENTAUR and its extension study demonstrated patients consistently on AMX0035 lived a mean of 6.9 months longer compared with those initially assigned to a placebo — reflecting a 43% lower risk of death.

Additional analyses, published last month, suggested AMX0035 extended the median survival time by more than 10 months, compared with an estimated survival if patients had remained on a placebo for the full trial. This represented a reduced risk of death by 61%.

The risk of tracheostomy, permanent assisted ventilation, or hospitalization also was reduced by 47%. Specifically, median time spent without tracheostomy or ventilation was 7.3 months longer among patients originally given AMX0035, compared with those initially assigned to a placebo (25.8 vs. 18.5 months).

The larger PHOENIX Phase 3 trial is expected to confirm the therapy’s benefits over a placebo in up to 600 adults with ALS whose symptoms started in the past two years — a less stringent criteria than that required for CENTAUR.

The 11-month study is enrolling participants at several European sites. Results are anticipated by 2024.