Initial data on survival benefits for ALS drug shows

Early treatment with a unique combination of sodium phenylbutyrate and taurulusodiol (called AMX0035) increased the survival of patients with amyotrophic lateral sclerosis (ALS). Blind expansion Phase II Centaur trial.

In CENTAUR, ALS patients were randomized 2: 1 to 3 g sodium phenylbutyrate and 1 g taurulusodiol, or to placebo by mouth or feeding tube. At the end of the study, participants in both groups had the option of taking a combination of sodium phenylbutyrate and taurulusodiol for up to 30 months in an open-label, extended study.

Survival analysis of patients in extended trials showed that patients randomized to sodium phenylbutyrate-taurulusodiol at baseline had a median survival of 6.5 months longer than patients starting with placebo, Massachusetts, Boston. Co-authored with Sabrina Paganoni, MD, General Hospital Muscles and nerves..

“Newly published data suggest that treatment with AMX0035 is relevant as well as functional benefit. As previously reported, But also with the benefit of long-term survival, provides substantial evidence supporting the role of AMX0035 in the treatment of ALS, “Paganoni said. Today’s MedPage.

However, the National Center of Neurology and Neurology and Stroke Director Walter Colossets, MD, were more cautious about the results.

“Long-term data support the initial findings that the initial treatment group progressed slowly, but unfortunately, despite treatment, the disease continued to follow a tragic course,” said Colossets. It was. Today’s MedPage. “Hopefully, sustainable scientific efforts will lead to greater effect sizes of treatment in the future.”

Unlike other therapies under investigation, AMX0035 does not target the root cause of ALS, but it does aim to protect motor neurons. Sodium phenylbutyrate and taurulusodiol may reduce neuronal cell death by blocking stress signals in the endoplasmic reticulum and mitochondria, respectively.It is also combined Investigated in Alzheimer’s disease disease.

Phase II CENTAUR research We evaluated 135 ALS patients, including those taking two FDA-approved ALS drugs, riluzole (Rilutek) or edaravone (Radicava). At the start of the study, 77% of patients used at least one of these drugs and 28% used both.

In the modified ITT population, 69% of participants in the sodium phenylbutyrate-taurulusodiol group and 77% of participants in the placebo group completed the study regimen.

In this study, ALS patients treated with sodium phenylbutyrate-taurulusodiol for more than 6 months had lower functional capacity than patients in the placebo group when measured with the revised ALS Function Assessment Scale (revised edition). Was shown to be slow.ALSFRS-R) Score, but the effect was moderate. Secondary outcomes were not significantly different between the two groups, and the adverse event with sodium phenylbutyrate-taurulsodiol was predominantly gastrointestinal.

A total of 90 CENTAUR participants continued the blind extension. 34 were originally randomized to placebo and 56 were originally randomized to sodium phenylbutyrate-taurulsodiol. Participants and researchers were unaware of the original treatment assignments.

Patients who originally started in the placebo group started the study drug about 7 months later than those who started in the sodium phenylbutyrate-taurulusodiol group. The longest follow-up was 35 months after randomization at CENTAUR, with 18 participants originally randomized to aggressive treatment and 9 participants originally randomized to placebo.

Of all CENTAUR-randomized participants, the risk of death was that of the first randomized participants to sodium phenylbutyrate-taurulusodiol compared to those originally randomized to placebo. Was 44% lower between (HR 0.56, 95% CI 0.34-0.92, P= 0.023) During the follow-up period.

Median survival was 25.0 months (95% CI 19.0-33.6 months) in the group initially assigned to sodium phenylbutyrate-taurulusodiol and 18.5 months (18.5 months) in the group initially randomized to placebo. It was 95% CI 13.5-23.2 months). Sensitivity analysis showed that the benefit of survival was independent of background medication.

The study is limited by its sample size. No survival comparison was made between patients receiving study drug alone and patients receiving placebo alone. The next step in the drug is being discussed and “will depend on ongoing conversations with regulators,” Paganoni said.

Last updated: October 16, 2020