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Starting treatment earlier with an investigational, proprietary combination of sodium phenylbutyrate and taurursodiol -- dubbed drug AMX0035 -- led to longer survival in patients with amyotrophic lateral sclerosis (ALS) in an of the phase II trial.

In CENTAUR, ALS patients were randomized 2:1 to sodium phenylbutyrate 3 g and taurursodiol 1 g or to placebo by mouth or feeding tube. When the trial ended, participants in both groups had the option to take the sodium phenylbutyrate-taurursodiol combination for up to 30 months in an open-label extension study.

Survival analysis of extension study patients showed that those randomized to sodium phenylbutyrate-taurursodiol at baseline had 6.5-month longer median survival than those who started with placebo, reported Sabrina Paganoni, MD, PhD, of Massachusetts General Hospital in Boston, and co-authors in .

"The newly released data suggests that treatment with AMX0035 is associated not only with functional benefits, as previously reported, but also with a long-term survival benefit, providing substantial evidence supporting the role of AMX0035 for the treatment of ALS," Paganoni told 番茄社区app.

But National Institute of Neurological Disorders and Stroke Director Walter Koroshetz, MD, was more cautious about the results.

"The longer-term data confirm the original study findings that the early treatment group had a slower progression, but unfortunately, the disease continued on its tragic course even despite the treatment," Koroshetz told 番茄社区app. "Hopefully, persistent science efforts will lead to a treatment with greater effect size in the future."

Unlike other treatments under investigation, 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 disease.

The phase II evaluated 135 ALS patients, including those using two FDA-approved ALS medications, riluzole (Rilutek) or edaravone (Radicava). At trial entry, 77% of patients used at least one of these drugs and 28% used both.

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.

The trial showed that over 6 months, 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, though effects were modest. Secondary outcomes were not significantly different between the two groups, and adverse events with sodium phenylbutyrate-taurursodiol were mostly gastrointestinal.

A total of 90 CENTAUR participants continued into the open-label extension: 34 had been randomized originally to placebo and 56 originally to sodium phenylbutyrate-taurursodiol. Participants and investigators remained blinded to original treatment assignment.

Patients who originally started in the placebo group started the study drug about 7 months later than those who started in the sodium phenylbutyrate-taurursodiol group. The longest follow-up was 35 months after randomization in CENTAUR, with 18 participants who were originally randomized to active treatment and nine participants originally randomized to placebo remaining.

Among all participants randomized in CENTAUR, risk of death was 44% lower among those originally randomized to sodium phenylbutyrate-taurursodiol compared with those originally randomized to placebo (HR 0.56, 95% CI 0.34-0.92, P=0.023) over the duration of follow-up.

Median survival was 25.0 months (95% CI 19.0-33.6 months) in the group originally assigned to sodium phenylbutyrate-taurursodiol and 18.5 months (95% CI 13.5-23.2 months) in the group originally randomized to placebo. Sensitivity analysis showed survival benefits were independent of background medications.

The study is limited by its sample size. No survival comparisons were made between patients who received only the study drug versus those who received only placebo. Next steps for the drug are being discussed and "will depend on ongoing conversations with regulatory authorities," Paganoni said.

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