A March 30 vote by the US Food and Drug Administration's (FDA) Peripheral and Central Nervous System Drugs Advisory Committee against the approval of AMX0035, an oral drug for treating amyotrophic lateral sclerosis (ALS), has drawn mixed response from ALS researchers and advocates.
The committee, comprised of independent advisors, acknowledged that the drug appears to be safe and well-tolerated. But it said that the data from the CENTAUR clinical trial, sponsored by Amylyx Pharmaceuticals, did not prove that the experimental drug was an effective treatment for ALS. The vote was narrow, however, with four “yes" votes and six “no" votes.
In a briefing document released by the committee before the meeting, the members acknowledged the ongoing unmet needs of patients living with ALS. But the document also outlined concerns with some of the primary analysis methods applied in the trial.
For example, it said “the study demonstrated only a modest p-value using non-preferred analysis methods that ignore the loss of data due to patient deaths during the study and relied on a questionable linearity assumption of the ALSFRS-R [Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised] over time.
They also pointed out that the CENTAUR trial was powered for the primary outcome but “was not designed to be powered to detect changes on secondary outcomes."
AMX0035 is an oral fixed-dose combination of two small molecules: sodium phenylbutyrate, which is a small molecular chaperone designed to reduce the unfolded protein response that causes cell death, and taurursodiol, which is a Bax inhibitor designed to reduce cell death through apoptosis. It was designed to target the endoplasmic reticulum and mitochondrial-dependent neuronal degeneration pathways in ALS and other neurodegenerative diseases.
The CENTAUR study, which tested the effectiveness of AMX0035, was a multicenter phase 2 clinical trial with a six-month randomized placebo-controlled phase and an open-label, long-term follow-up phase. The primary endpoint of the study, which included 137 participants with ALS, was the rate of decline in the ALSFR-T total score.
The findings, which were first published in the New England Journal of Medicine on September 3, 2020, showed that sodium phenylbutyrate–taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over the trial period. However, it had no survival benefit and the study authors noted that the secondary outcomes were not significantly different between the two groups. Longer and larger trials would be necessary to evaluate the efficacy of the drug, the investigators said.
As reported in Neurology Today in 2020, neuromuscular experts viewed the findings as promising but not yet strong enough to merit approval. “While I don't think this trial is a home run, it is a strong single," Robert G. Miller, MD, FAAN, a neuromuscular specialist at California Pacific Medical Center in San Francisco, who was not involved in the trial, said of the 2020 study.
“A home run would have shown more than a modest benefit on the primary outcome measure," along with secondary outcomes that were also statistically significant, he said, “and would have had a biomarker that went along with the clinical response. For all those reasons, there is more work to do. To approve a drug at phase 2 would be very unusual," given the degree of benefit demonstrated here, he added.
In a statement released by Amylyx, Jamie Timmons, MD, head of scientific communications for Amylyx said: “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…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."
ALS patients, physicians, and advocates who spoke at the open meeting cited the need for treatment as early as possible to stop the degenerative effects of ALS.
“By the time I diagnose someone in my clinic, the ALS clock has been ticking for months and their life expectancy is only about two years," said Sabrina Paganoni , MD, PhD, the lead investigator for the CENTAUR trial and the co-director of the Neurological Clinical Research Institute and Healy & AMG Center for ALS at Massachusetts General Hospital, at the open meeting. “Patients tell us that they want to retain independence but once the function is lost it cannot be regained. This is why it is important to start treatment as early as possible to try to preserve the remaining neurons and in turn prolong functional independence and survival for as long as possible."
Larry Falivena, a person living with ALS, urged the committee to vote yes for the drug. “Don't let perfect get in the way of good," he said. “You must consider that this treatment is the opportunity to give ALS patients the one thing we desperately need: more time."
In a statement released by The ALS Association after the panel's decision, Calaneet Balas, president and CEO of The ALS Association said the “FDA has a choice to make–whether it will approve a drug that has been proven safe that will help people living with ALS today, or whether it will delay approval and require more evidence while more people with ALS die…The FDA's own ALS Guidance acknowledges that people with ALS are willing to accept greater risk for the possibility of some benefit."
The FDA's final decision on the drug is expected by June 29. The agency typically follows the panel's recommendations, but it is not required to do so.
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Paganoni S, Macklin E, Hendrix S, et al. Trial of sodium phenylbutyrate–taurursodiol for amyotrophic lateral sclerosis. NEJM 2020; Epub 2020 Sept 3.