In a meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, six members voted not to approve the NDA for Amylyx’s ALS candidate, AMX0035, while four voted in favor.
From left: Amylyx Co-founders and Co-CEOs Justin Klee and Josh Cohen/Courtesy Amylyx
In a razor-thin vote of the U.S. Food and Drug Administration‘s Peripheral and Central Nervous System Drugs Advisory Committee, six members voted that the Phase II trial of Amylyx Pharmaceuticals’ amyotrophic lateral sclerosis (ALS) candidate, AMX0035, was not sufficient to prove efficacy in the disease.
Ultimately, the panel determined that the data was just not as strong or clear-cut as they had hoped it would be.
After a lengthy presentation by Amylyx and a question and answer period, committee members were asked to vote on the question: “Do the data from the single randomized, controlled trial and the open-label extension study establish a conclusion that sodium phenylbutyrate/taurursodiol is effective in the treatment of patients with amyotrophic lateral sclerosis (ALS)?”
Members voting ‘no’ did so primarily on the basis of the design of the Phase II CENTAUR trial, including the relatively small treated and placebo populations, while also putting a lot of emphasis and expectation on the Phase III PHEONIX trial, which is already underway. Committee members also questioned the modest survival benefit, and expressed concerns that the difference in decline measured on the ALSFRS-R scale between the placebo and treatment groups was not great enough.
In the study, which was comprised of 137 participants, AMX0035 showed a 6 ½ month survival benefit for the treatment group. After 24 weeks, patients on placebo were moved to active therapy with the drug. The median survival duration through the open-label, long-term follow-up phase was 25 months in the group that started on AMX0035 compared to 18.5 months in the group that began on the placebo.
“On balance, I thought the data presented did not meet the threshold of being a single, very persuasive study. I look forward to a rapid and successful conclusion of the PHOENIX study,” said Advisory Committee Chairperson Dr. Thomas J. Montine, M.D., Ph.D., chair of the department of pathology at Stanford Medicine and an Endowed Professor at Stanford University School of Medicine, when explaining his position.
Among those voting yes, the point was raised that patients are already self-medicating with the two components that comprise AMX0035. Sodium phenylbutyrate was approved by the FDA in 1996 to treat urea disorder in infants, and taurursodiol is available from Amazon at what patients have described as a “steep price.”
“Supplements are all over the place when it comes to quality. Comparing the two components to AMX0035 being approved as a combination product, [it] would have to meet USP (United States Pharmacopeia) standards, so the quality is assured,” Layne Oliff, a New Jersey pharmacist living with ALS, told BioSpace in a previous interview.
Both Amylyx and the FDA concluded that AMX0035 did not pose a safety risk to patients. While some pointed out that it was a reasonable risk proposition for patients to take on if they chose, the overall consensus of those in the majority reflected the preference to stick to known regulatory standards, as opposed to exercising regulatory flexibility for a disease that has very few approved treatments.
During the question and answer period, concerns arose around an absence of correlation between exposure and survival. There were also queries about potentially accelerating the results of the PHOENIX study.
The Phase III trial will be significantly larger, as Amylyx aims to enroll 600 participants across 70 sites in the U.S. and Europe with definite or clinically probable ALS within 24 months of symptom onset. The company states that this study will have broader inclusion criteria than the CENTAUR study.
Dr. Jamie Timmons, M.D., head of scientific communications at Amylyx, said the “PHOENIX study is currently powered at 95% for the primary endpoint”, regardless of patients who may or may not be able to finish the trial.
The FDA tends to follow the recommendation of its advisory committees. There are exceptions, however, as in the case of Biogen’s Aduhelm. The same Central Nervous System Drugs Advisory Committee voted overwhelmingly against this drug, which the FDA went ahead and approved anyway in June 2021.
Amylyx issued a statement following the vote.
“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,” Timmons said. “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. 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.”
