FDA Advisory Panel Rejects Novel ALS Drug

Pauline Anderson

March 31, 2022

A US Food and Drug Association (FDA) advisory panel has concluded there's not enough evidence to support approval of a new drug to treat amyotrophic lateral sclerosis (ALS).

Members of the FDA Peripheral and Central Nervous System Drugs Advisory Committee met to discuss a new drug application for AMX0035 (Amylyx Pharmaceuticals Inc), a combination of sodium phenylbutyrate (PB) and taurursodiol (TURSO).

Six of 10 members voted that the efficacy evidence from a single randomized controlled trial (CENTAUR) and an open-label extension is insufficient.

Panel members acknowledged the compelling need for new treatments for this devastating disease and were moved by passionate testimony from patients, caregivers, and others. However, they believe the evidence doesn't meet the required standard for FDA approval, based on a single trial.

"We were asked to look for substantial evidence of persuasiveness and robustness, and I think this one trial doesn't quite meet that bar and was problematic," said Kenneth Fischbeck, MD, Distinguished Investigator, National Institute of Neurological Disorders and Stroke, National Institutes of Health.

"It would be a disservice to patients and their families to move ahead and approve a treatment that is of uncertain benefit," said Fischbeck.

Functional Decline Slowed

AMX0035 is designed to reduce neuronal death by mitigating endoplasmic reticulum stress and mitochondrial dysfunction. The drug is formulated as a powder and packaged in sachets, each containing 3 g PB and 1 g TURSO, and can be administered orally or via feeding tube.

The CENTAUR trial was conducted in 25 US centers in two phases ― a 24-week randomized controlled phase and an open-label phase.

The study randomly assigned 137 patients (mean age, 58 years) the drug (n = 89) or placebo (n = 48). On average, participants were enrolled in the trial 6 months after being diagnosed with ALS and about 13.5 months after initial symptom onset. Most patients were taking one or both of the currently approved ALS drugs ― riluzole or edaravone.

AMX0035 has a bitter taste, but the placebo was taste-matched and included a bittering agent.

The primary outcome was the score on the ALS Functional Rating Scale–Revised (ALSFRS-R), which measures independence in performing daily function, including swallowing. The score is calculated by adding answers to 12 questions, each rated on a scale of 0 to 4, for a total range of 0–48. At baseline, the average ALSFRS-R total score for the two groups was about 36.0.

Jamie Timmons, MD, head of scientific communications, Amylyx Pharmaceuticals, reported that the drug slowed functional decline. The mean rate of change in the ALSFRS-R score was −1.24 points per month with the active drug and −1.66 points per month with placebo, for a difference of 0.42 points per month (95% CI, 0.03 – 0.81; P = .034).

This represents a 25% slower decline in function for the AMX0035 group compared to the patients taking placebo, said Timmons. A change of 20% or more is considered clinically meaningful.

At the end of the randomization phase, this slowing of functional decline in the treated group resulted in a 2.32-point benefit on the ALSFRS-R scale, and results were consistent across a number of sensitivity analyses, said Timmons.

Secondary outcomes, including Accurate Rest for Limb Isometric Strength (ATLIS), did not differ significantly between the two groups.

Adverse events (AEs) were mainly gastrointestinal, and the overall difference in AE incidence was small – about 66% in the active and 63% in placebo groups. Events were generally mild or moderate and were manageable.

Compared to patients who received placebo, patients in the treatment arm had fewer serious AEs, most of which related to ALS progression. There were few deaths during the randomization phase ― five in the treatment and two in the placebo arms.

Phase 3 Study in the Works

In the open-label phase, participants originally assigned to receive AMX0035 showed sustained benefit of treatment on the ALSFRS-R at 48 weeks, and there was some evidence for a benefit when the placebo group crossed over to AMX0035.

The company reported a statistically significant median difference of 4.8 months in time to death, first hospitalization, or tracheostomy/permanent assisted ventilation in the group originally assigned to receive AMX0035 compared to the group originally assigned to receive placebo (hazard ratio, 0.62; P = .023).

This is the first time a treatment has shown a benefit on both function and survival in ALS, the two key measures in a relentlessly progressive, fatal disease, noted Joshua Cohen, co-CEO and co-founder of Amylyx Pharmaceuticals.

During the meeting, ALS patients expressed their willingness to accept greater risk for the possibility of having even a little more time with their loved ones and argued the drug contains two compounds that are already available. They pleaded for the FDA to exercise its regulatory flexibility in approving this experimental drug.

However, the FDA panel raised a number of issues with the trial. These concerns included the study's small sample size, imbalances in baseline disease characteristics, a modest effect in the primary endpoint, and no survival benefit at 24 weeks.

FDA officials also noted a possible risk of unblinding due to AEs and the taste of the drug, and a risk for confounding due to an imbalance in the number of participants in each arm for whom edaravone or riluzole was initiated after baseline. In addition, there was a problem concerning randomization. For example, the first 18 consecutive patients were assigned to the active drug.

Much of the meeting was spent discussing which statistical approach is most appropriate to account for deaths and missing data.

Many panel members agreed with the FDA. In addition to the small sample size and baseline imbalances, "features that limit the persuasiveness" of the trial include the modest impact on the primary outcome and the absence of any statistically significant effect on secondary outcomes, said Caleb Alexander, MD, professor of epidemiology and medicine, Johns Hopkins Bloomberg School of Public Health.

"The open-label study has even more serious limitations for it to be used as a supplemental and confirmatory evidence," including the absence of a control group and the high dropout rate, said Alexander.

Many panel members said they hope an ongoing phase 3 multicenter trial ― PHOENIX ― will be more definitive because it's larger and the inclusion criteria are broader. The primary outcome of that trial is a joint analysis of survival and function; results are anticipated by early 2024.

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