FDA panelists expressed concern over the drug's efficacy and data analysis, indicating the need for a confirmatory clinical trial.
The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee has voted that current data on AMX0035, Amylyx’s orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol for the treatment of amyotrophic lateral sclerosis (ALS), is not sufficient in demonstrating efficacy.1
The committee voted 6–4 (6 no; 4 yes; 0 abstain) that the data from the phase 2/3 CENTAUR trial (NCT03127514) and open-label extension study did not adequately establish AMX0035 as an effective treatment for ALS. AMX0035 has a PDUFA date of June 29, 2022.
Several of the AdComm members who voted against the drug had concerns over the trial's conduct and robustness of the data. Additionally, some felt as though the ALS Functional Rating Scale-Revised (ALSFRS-R) scores for patients in the placebo arm were high, which may have altered the perception of the data.
"It’s clear that there’s a very compelling degree of unmet need and it’s also clear that many with ALS are willing to accept the product as is and are willing to assume the risks associated with it," G. Caleb Alexander, MD, MS, member of the committee, said in his reasoning for voting no. "Despite this, law and statute and regulatory guidance are clear. There are many features of CENTAUR that limit its persuasiveness as a standalone trial in a regulatory sense."
Do you agree with the FDA AdComm's assessment of AMX0035 for treatment of ALS?
Notably, the FDA altered the wording of the key question it posed to the committee in the day before the meeting, changing the phrasing from asking whether the data from the trial "support" a conclusion to "establish" a conclusion, effectively removing a degree of uncertainty from the scenario.
Participants in the CENTAUR clinical trial were randomly assigned 2:1 to AMX0035 or matching placebo, administered twice daily by mouth or feeding tube for a planned duration of 24 weeks. Patients eligible for the open-label extension were given the option to enroll and receive the active drug for up to 132 weeks.
In November, Amylyx submitted its new drug application to the FDA for AMX0035, with data from CENTAUR showing that the trial met its primary end point.2 The company reported an average ALSFRS-R score of 2.32 points higher among AMX0035-treated patients (n = 87) than placebo (n = 48) after 24 weeks of treatment. Additional data showed that from baseline, there was a 2.92-point higher mean ALSFRS-R score for the AMX0035 group (P = .01) and a –1.24 points per month change in total ALSFRS-R score compared to –1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03-0.81; P = .03).3
A survival analysis from CENTAUR published in 2020 showed that the therapy was associated with a 6.5-month longer median survival compared with placebo. In total, those treated with AMX0035 has a median overall survival of 25 months (95% CI, 19.0-33.6) compared with survival of 18.5 months in the placebo group (95% CI, 13.5-23.2) for a hazard ratio of 0.56 (95% CI, 0.34-0.92; P = .023), equating to a 44% lower risk of death.4
The estimated probability of survival at 1 year for those in the treatment group was 80.9% (95% CI, 71.1–87.7) and for placebo was 72.9% (95% CI, 58.0–83.3%). For 2 years, the estimates were 51.6% (95% CI, 38.9–62.9) and 33.9% (95% CI, 19.4–49.1), respectively. The median time to censoring was 21.3 months.
Some of the committee members who voted “no” claimed the ongoing phase 3 PHOENIX study may help answer lingering questions regarding the medication. PHEONIX is a 48-week, randomized, placebo-controlled trial whose efficacy outcomes are ALSFRS-R over 48 weeks and survival. It will also assess secondary efficacy outcomes such as change in slow vital capacity measured both at home with a self-administered spirometer to support virtual data collection and at clinic sites, serial assessments of patient-reported outcomes, ventilation-free survival rates, and others.5
"The PHOENIX trial builds on the success of the CENTAUR trial, which was designed and conducted at US sites of Northeast ALS Consortium (NEALS), a network of 140 trial-ready research centers primarily based in North America,” principal investigator of the CENTAUR study, Sabrina Paganoni, MD, PhD, investigator, Healey & AMG Center for ALS, Mass General and member, Executive Committee of NEALS, said in a statement at the time of its announcement.5 "I strongly believe in global collaboration and PHOENIX will be the first trial to include a global partnership between TRICALS and NEALS. The study design of PHOENIX is a true testament to this collaboration, and we look forward to advancing this research and what it might mean for those living with ALS."