The Food and Drug Administration’s (FDA) Peripheral and Central Nervous System Drugs Advisory Committee voted 4 “yes” and 6 “no” on the question of whether the available evidence supports the conclusion that sodium phenylbutyrate/taurursodiol (AMX0035) is effective in the treatment of patients with amyotrophic lateral sclerosis (ALS).
AMX0035 is an oral, fixed-dose coformulation of sodium phenylbutyrate and taurursodiol, also known as ursodoxicoltaurine. By targeting the endoplasmic reticulum and mitochondrial-dependent neuronal degeneration pathways in ALS, AMX0035 is expected to reduce neuronal death and dysfunction.
The investigational agent was evaluated in the randomized, double-blind, placebo-controlled phase 2 CENTAUR trial (ClinicalTrials.gov Identifier: NCT03127514), along with the open-label extension study (ClinicalTrials.gov Identifier: NCT03488524).
Results from CENTAUR showed that ALS patients receiving AMX0035 demonstrated statistically significant reductions in clinical decline at the end of the 6-month randomized phase, as measured by the Revised ALS Functional Rating Scale (ALSFRS-R; P =.0340).
In meeting documents, the FDA panel noted that while the study met its primary endpoint, the trial “only had 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 questionable linearity assumption of the ALSFRS-R over time.” Missing data and a randomization implementation problem were also cited as issues.
The open-label extension study evaluated the long-term safety of AMX0035 in 90 patients with ALS who completed the CENTAUR study. Survival analyses up to 132 weeks showed a statistically significant increase in the composite time to survival events (including death, tracheostomy, permanent assisted ventilation and hospitalization) in the AMX0035 arm compared with the placebo arm (difference, 4.8 months; hazard ratio, 0.62; P =.0196).
Due to the small number of patients that continued in the extension phase, as well as the large number of dropouts, the committee did not find the results of the open-label study to be persuasive. The survival analysis was further limited by baseline disease imbalances in the treatment groups. “It is unclear how much of the survival benefit is by chance alone or disease heterogeneity, rather than by an ostensible effect of the drug,” the panel stated. Death alone was also not included in the list of endpoints.
Commenting on the vote, Jamie Timmons, MD, Head of Scientific Communications of 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.”
A double-blind, placebo-controlled phase 3 trial (PHOENIX; ClinicalTrials.gov Identifier: NCT05021536) evaluating the safety and efficacy of AMX0035 for treatment of ALS is also currently enrolling patients worldwide and is expected to be completed in 2024.
Acknowledging that there is an ongoing unmet need for ALS treatments, the FDA had granted Priority Review to AMX0035. The Agency is expected to make a decision on the application by June 29, 2022. Although not bound by the committee’s recommendations, the FDA does take them into consideration when making decisions on approval.
- Amylyx Pharmaceuticals announces outcome of FDA advisory committee meeting on AMX0035 for the treatment of ALS. News release. March 30, 2022. https://www.businesswire.com/news/home/20220330005921/en/Amylyx-Pharmaceuticals-Announces-Outcome-of-FDA-Advisory-Committee-Meeting-on-AMX0035-for-the-Treatment-of-ALS
- Combined FDA and Amylyx Briefing Document for the March 30, 2022 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. https://www.fda.gov/media/157186/download