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An investigational drug known as AMX0035, a proprietary combination of sodium phenylbutyrate and taurursodiol, appeared to slow functional decline in amyotrophic lateral sclerosis (ALS) patients with rapidly advancing disease compared with placebo, the phase II trial showed.

Over 24 weeks, ALS patients treated with sodium phenylbutyrate-taurursodiol declined in functional abilities more slowly than patients in the placebo group as measured by ALS Functional Rating Scale-Revised () scores, reported Sabrina Paganoni, MD, PhD, of Massachusetts General Hospital in Boston, and coauthors in the .

The mean rate of change in the ALSFRS-R score was −1.24 points per month with sodium phenylbutyrate-taurursodiol and −1.66 points per month with placebo (difference 0.42 points per month, 95% CI 0.03 to 0.81; P=0.03), in a modified intention-to-treat analysis. Scores on the ALSFRS-R range from 0 to 48, with higher scores indicating better function.

Secondary outcomes were not significantly different between the two groups, and adverse events with sodium phenylbutyrate-taurursodiol mostly were gastrointestinal.

"This is a milestone in our fight against ALS because the study drug demonstrated statistically significant and clinically meaningful benefit in people with ALS," Paganoni said.

"Participants treated with AMX0035 retained physical function longer than those who received placebo. This is very hopeful news for people affected by ALS and their families," she told MedPage Today.

The treatment uses a novel approach by combining two molecules that each target a different cell component. "The combination provided clinical benefit to study participants who were already taking the two FDA-approved ALS medications, riluzole [Rilutek] and edaravone [Radicava]," she pointed out. "This tells us that we might need a combination of different treatments to fight ALS most effectively."

Unlike other treatments being studied, AMX0035 does not target the root cause of ALS, but aims to preserve motor neurons. Sodium phenylbutyrate and taurursodiol may reduce neuronal death by blocking stress signals within the endoplasmic reticulum and mitochondria, respectively. The combination also is being investigated in .

The phase II trial evaluated 135 ALS patients enrolled between June 2017 and September 2019, including patients using riluzole (at a stable dose for 30 days or longer) or edaravone. At trial entry, 77% of patients used at least one of these drugs and 28% used both.

Participants were randomized 2:1 to sodium phenylbutyrate–taurursodiol (sodium phenylbutyrate 3g and taurursodiol 1g, given orally or through a feeding tube daily for 3 weeks then twice a day) or placebo. Follow-up was every 3 weeks for 24 weeks and participants could join an for up to 132 weeks.

The overall study group was 69% male, 95% white, with mean age of 57.5. Baseline ALSFRS-R total scores averaged 36.0. In the modified intention-to-treat population, 69% of the participants in the sodium phenylbutyrate–taurursodiol group and 77% of those in the placebo group completed the study regimen.

Nearly all participants -- 97% in the sodium phenylbutyrate–taurursodiol group and 96% in the placebo group -- had one or more adverse events during the trial. Events with 2% or greater frequency in the treatment group were primarily gastrointestinal and included diarrhea, nausea, salivary hypersecretion, and abdominal discomfort, most of which are known adverse events associated with taurursodiol. Gastrointestinal adverse events were reported more frequently in the treatment group than in placebo during the first 3 weeks only. Mean changes in weight were similar between the groups.

Serious adverse events were more frequent with placebo (19%) than with treatment (12%). Incidence of respiratory serious adverse events was 8% with placebo and 3% with treatment.

About 19% of the sodium phenylbutyrate–taurursodiol group and 8% of placebo participants discontinued the trial due to adverse events, which were reported most commonly as diarrhea (6% in the treatment group, 0% in placebo) and respiratory failure (6% in placebo, 0% in the treatment group).

"A key question is how patients with ALS and their treating physicians should interpret these data," noted Michael Benatar, MD, PhD, of the University of Miami in Florida, and Michael McDermott, PhD, of the University of Rochester in New York, in an .

"The observed therapeutic effect is modest, and although formal comparisons with previous studies of taurursodiol and sodium phenylbutyrate alone are difficult, it is unclear whether either taurursodiol alone or sodium phenylbutyrate alone might yield similar benefits or whether the doses were the most effective," they wrote.

"In light of the residual questions about efficacy and the ability of patients to continue taking the drug, we agree with the authors' conclusion that '[l]onger and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS,'" the editorialists said.

Limitations of the trial include using ALSFRS-R as an endpoint. While it is the principal functional endpoint in the latest FDA guidance for ALS clinical trials and has been shown to correlate with survival and quality of life, literature about what constitutes clinically meaningful change in ALSFRS-R total scores is limited.

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