FDA Panel Votes in Favor of Fixed-Dose Combination Therapy for ALS

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AMX0035 is an oral, fixed-dose coformulation of sodium phenylbutyrate and taurursodiol, also known as ursodoxicoltaurine.

The Food and Drug Administration (FDA)’s Peripheral and Central Nervous System Drugs Advisory Committee voted 7 “yes” and 2 “no” on the question of whether the available evidence supports the approval of AMX0035 (sodium phenylbutyrate and taurursodiol) for the treatment of amyotrophic lateral sclerosis (ALS). In a prior committee meeting held in March 2022, the vote had not been as favorable.

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.

Despite limitations to newly submitted data, the panel’s most recent recommendation was based on a review of all available evidence, including new analyses intended to contribute to the confirmatory evidence to accompany the primary results of the phase 2 CENTAUR trial (ClinicalTrials.gov Identifier: NCT03127514). 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 (P =.0340).

In the open-label extension study (ClinicalTrials.gov Identifier: NCT03488524), the long-term safety of AMX0035 was evaluated 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 in the AMX0035 arm compared with the placebo arm (difference, 4.8 months; hazard ratio, 0.62; P =.0196).

The new analyses included an individual responder analysis that used patients as their own controls and compared the response rate in the AMX0035 group with the response rate in the placebo group. While the proportion of responders was greater in the AMX0035 arm vs the placebo arm, the FDA noted that the data could not be considered independent confirmatory evidence as it was based on previously analyzed CENTAUR trial data. 

Additionally, survival sensitivity analyses were submitted for review, the first of which predicted overall survival (OS) time from baseline prognostic factors. The analysis used data from more than 10,000 people with ALS from 14 specialized ALS centers across Europe. While the AMX0035 treatment arm demonstrated a prolongation of median OS, the FDA noted a “variety of concerns about the reliability of this analysis.” Specifically, the “nonrandomized comparison to an external control that is subject to potential confounding due to differences between the AMX0035-treated patients and the external controls.”

To estimate survival benefit, Amylyx utilized the rank-preserving structural failure time model approach to estimate the OS time of patients in the placebo group had they never switched to AMX0035. The FDA stated that the analysis was “heavily dependent on untestable assumptions” and was just another method of analyzing the same survival data; it was not considered independent data.

The Company also provided biomarker data from an Alzheimer disease study to show the effects of AMX0035 on markers of neurodegeneration in another neurodegenerative disease. However, the submitted data did not provide clear evidence of a potential benefit for ALS patients.

Acknowledging that there is an unmet medical need in ALS, the panel took into consideration that the investigational therapy did succeed on its primary endpoint, though only in a single trial, and that post hoc survival analyses were nominally positive.

Although not bound by the committee’s recommendations, the FDA does take them into consideration when making decisions on approval. A Prescription Drug User Fee Act (PDUFA) target date of September 29, 2022 has been set for the application.

A double-blind, placebo-controlled phase 3 trial (PHOENIX; ClinicalTrials.gov Identifier: NCT05021536) is further evaluating the safety and efficacy of AMX0035 for treatment of ALS and is expected to be completed in 2024.


  1. Amylyx Pharmaceuticals announces FDA Advisory Committee supports approval of AMX0035 for the treatment of ALS. News release. Amylyx Pharmaceuticals, Inc. Accessed September 7, 2022. https://www.businesswire.com/news/home/20220907006313/en/Amylyx-Pharmaceuticals-Announces-FDA-Advisory-Committee-Supports-Approval-of-AMX0035-for-the-Treatment-of-ALS
  2. FDA Briefing Document: NDA# 216660. Drug Name: AMX0035/sodium phenylbutyrate (PB) and taurursodiol (TURSO). Applicant: Amylyx Pharmaceuticals, Inc. Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) Meeting September 7, 2022. https://www.fda.gov/media/161378/download