Trial Data Not Enough for AMX0035 Approval, FDA Committee Votes
There is no substantial evidence supporting the efficacy of Amylyx Pharmaceuticals’ AMX0035 for the treatment of amyotrophic lateral sclerosis (ALS), according to a 6–4 vote by a U.S. Food and Drug Administration (FDA) advisory committee.
The close vote against the therapy came at the end of a virtual meeting, held March 30, in which both the FDA and Amylyx presented their cases. In the public comment session that following those presentations, ALS patients, caregivers, and physicians had the opportunity to share their AMX0035 opinions and experiences — with patients and family members continuing to advocate strongly for the therapy’s approval.
The committee’s appraisal of the experimental therapy was in line with briefing documents released ahead of the meeting, in which the FDA raised concerns over Amylyx’s CENTAUR Phase 2/3 clinical trial (NCT03127514) due to its small size, missing data, and questionable statistical analysis.
Still, the nonbinding vote serves only as a recommendation to the FDA, which is expected to make its decision by June 29 on whether or not to approve AMX0035. The regulatory application had been granted priority review late last year, which shortened the standard 10-month review period to six months.
The acceptance to review the regulatory application, based on CENTAUR data alone, had reflected a change of heart by the FDA, which initially had requested data from the larger PHOENIX Phase 3 trial (NCT05021536) before considering AMX0035 for approval.
Now, the FDA’s committee voted six “No” to four “Yes” on the question before it: “Do the data from the single randomized, controlled trial [CENTAUR] and the open-label extension study establish a conclusion that [AMX0035] is effective in the treatment of patients with amyotrophic lateral sclerosis (ALS)?”
“We remain confident in the data from the Phase 2 CENTAUR trial and the potential benefits of AMX0035 as a treatment option for people living with ALS,” Jamie Timmons, MD, Amylyx’s head of scientific communications, said in a press release.
“We are motivated by the hundreds of people impacted by this devastating disease who shared their personal testimonies, both written and spoken, in conjunction with today’s meeting. We are also encouraged by the expert ALS physicians who shared their clinical perspectives,” Timmons added.
“Our application is under review by the FDA, and we remain committed to pursuing its approval given the pressing need for new treatments for ALS,” Timmons said.
Similar applications also are being reviewed by health authorities in Canada and in Europe.
AMX0035 received orphan drug designation in both the U.S. and the EU for the treatment of ALS. That status is meant to speed the therapy’s development and review by providing regulatory support and financial benefits, as well as a marketing exclusivity period — for seven years in the U.S. and 10 in Europe — should it be approved.
Given twice a day by mouth or via feeding tube, AMX0035 is a fixed-dose combination of two orally available small molecules in clinical use: tauroursodeoxycholic acid and sodium phenylbutyrate.
Individually, these medications are known to be safe and well-tolerated, and to protect nerve cells from cellular stress-induced damage — which has been implicated in ALS.
The regulatory applications were based on data from the CENTAUR trial, which evaluated AMX0035’s six-month safety and effectiveness against a placebo in 137 adults who had recently diagnosed with ALS and whose disease was progressing rapidly.
Top-line data showed that AMX0035 significantly slowed patients’ functional decline compared with a placebo, meeting the trial’s main goal. Treatment also was associated with a trend toward a slower decline in muscle strength and lung function, as well as fewer hospitalizations.
Nearly three years of follow-up data spanning both CENTAUR and its extension study (NCT03488524) then demonstrated that patients consistently on AMX0035 had a 44% lower risk of death, living a mean of 6.5 months longer relative to those initially assigned to a placebo. A similar 44% reduction also was observed in a combined assessment of death, tracheostomy or permanent assisted ventilation, or first hospitalization.
The therapy’s benefits are now being assessed in the larger PHOENIX Phase 3 trial, which is expected to include up to 600 adults with ALS whose symptoms started in the past two years — a less-stringent criteria than that required for CENTAUR.
Participants — currently being enrolled at some U.S. study locations with further sites expected in the country and in Europe — will be randomly assigned to receive either AMX0035 or a placebo for 48 weeks (about 11 months). The trial’s main goal is to assess changes in a composite measure of functional decline and survival, while secondary goals include changes in lung function, the need for ventilation, and quality of life.
Should the FDA decide to wait for PHOENIX results — expected in 2024 — the company can resubmit the application and potentially win approval then.
But this would not be the first time the agency goes against its committee’s recommendation. The most recent — and controversial — example is the conditional approval granted Aduhelm (aducanumab) in 2021 for the treatment of Alzheimer’s disease.
Meanwhile, Amylyx has launched an expanded access program (NCT05286372) for AMX0035 in the U.S that provides availability to patients ineligible for PHOENIX. These include adults who experienced their first ALS symptoms in the three years or more prior to entering the program and have received consistent care from an experienced physician.
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