AMX0035 Extends Survival in Amyotrophic Lateral Sclerosis


The combination agent resulted in a 44% lower risk of death for patients with ALS, with a 6.5-month longer median survival compared with placebo.

Sabrina Paganoni, MD, PhD, investigator, Healey & AMG Center for ALS, Massachusetts General Hospital

Sabrina Paganoni, MD, PhD

Data from the overall survival analysis from the phase 2/3 CENTAUR trial (NCT03127514) of AMX0035 (Amylyx Pharmaceuticals), an orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) for the treatment of amyotrophic lateral sclerosis (ALS) suggest that the therapy is associated with a 6.5-month longer median survival compared with placebo.1,2

The analysis included 135 patients randomized in the trial, with median overall survival being 25 months (95% CI, 19.0–33.6) for those treated with AMX0035 compared with a median survival of 18.5 months in the placebo group (95% CI, 13.5–23.2) for a hazard ratio (HR) of 0.56 (95% CI, 0.34–0.92; P =.023), equating to a 44% lower risk of death.

The investigators, led by Sabrina Paganoni, MD, PhD, of the Healey & AMG Center for ALS at Massachusetts General Hospital, noted that these data in combination with the previously reported results of the study suggest that the therapy provides patients both functional and survival benefits.

"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," Paganoni told NeurologyLive. "These results provide substantial evidence supporting the role of AMX0035 for the treatment of ALS. The next steps will depend on ongoing conversations with regulatory authorities."

In the randomized trial, included individuals were randomized in 2:1 fashion to AMX0035 (3-g PB and 1-g TURSO per sachet) or matching placebo, administered twice daily by mouth or feeding tube for a planned duration of 24 weeks. Additionally, patients eligible for the open-label extension (OLE) were given the option to enroll in an OLE (NCT03488524) and receive the active drug for up to 132 weeks. In total, 92% of the study population enrolled.

The estimated probability of survival at 1 year for those in the treatment group was 80.9% (95% CI, 71.1–87.7) and for placebo was 72.9% (95% CI, 58.0–83.3%). For 2 years, the estimates were 51.6% (95% CI, 38.9–62.9) and 33.9% (95% CI, 19.4–49.1), respectively. The median time to censoring was 21.3 months.

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The median exposure duration for all patients who were randomized, including those who did not opt into the OLE, was 8.8 months (range, 0.1–33.0). Those originally randomized to placebo had a median exposure of 1.9 months (range, 0–22.5), all of which were during the OLE. The average AMX0035 exposure duration was 10.6 months in the treatment group and 4.7 months in the placebo group.

The 2 groups also had similar rates of death-equivalent events—defined as tracheostomy or permanent assisted ventilation (PAV) for >22 hours daily for >7 days, with date of PAV onset being the first of the 7 days. All told, 6 (6.7%) participants originally randomized to treatment and 4 (8.3%) originally randomized to placebo experienced death-equivalent events.

“These results support that AMX0035 has both functional and long-term survival benefits,” said Merit Cudkowicz, MD, director, Healey & AMG Center for ALS; chief, Neurology, Mass General; chief medical officer, ALS Finding a Cure; and Julieanne Dorn Professor of Neurology, Harvard Medical School, in a statement. “ALS is a serious disease that progresses rapidly. With these results, we have shown that AMX0035 may provide patients hope and the chance to function better and live longer lives. On behalf of ALS Finding a Cure, our colleagues, and foundations that supported us, I want to thank all participants not only in this study, but also in all previous ALS studies, for their critical role in helping to reach wonderful milestones like this.”

These findings are notable in the context of the landscape of ALS therapy, as there are only 2 available disease-modifying agents for ALS, riluzole and edaravone, and as of yet, only riluzole has been shown to prolong survival in clinical study. Edaravone’s effect on survival is currently unknown. Paganoni et al. noted that the findings of the 3 sensitivity analyses they ran to account for the concomitant use of 1 or both of those agents at baseline—77% of patients were on at least 1—maintained its statistical significance of benefit over placebo. “These results suggest that the benefit of PB-TURSO was independent of baseline concomitant medication use,” they wrote.

Amylyx noted that it is submitting the long-term functional and safety data from the CENTAUR and OLE studies to a peer-reviewed journal and expects those data to be published in the near future. Interim data from the ongoing extension study will be presented later this year.2

“We want to thank all of the CENTAUR participants for their involvement in the study,” said Justin Klee, co-CEO and co-founder, Amylyx, in a statement. “The commitment of so many people with ALS to this research over the course of nearly three years, especially when weighing just how valuable time is for this patient community, has led us to this critical development milestone where we can now reimagine outcomes for ALS. We know there is nothing more valuable than time to these and other patients, so we hope to share updates on our progress with AMX0035 with the ALS community as soon as possible.”

Paganoni recently sat down with NeurologyLive to detail the status of the OLE study of AMX0035 and its analyses and expanded on what she hopes future assessments might reveal about the agent’s impact on survival in ALS. Watch her share her thoughts below.

1. Paganoni S, Hendrix S, Dickson SP, et al. Long‐Term Survival of Participants in the CENTAUR Trial of Sodium Phenylbutyrate‐Taurursodiol in ALS. Muscle Nerve. Published online October 16, 2020. doi: 10.1002/mus.27091.
2. Amylyx Pharmaceuticals Announces Publication of CENTAUR Survival Data Demonstrating Statistically Significant Survival Benefit of AMX0035 for People with ALS. News release. Cambridge, MA. Amylyx Pharmaceuticals. Published October 16, 2020. Accessed October 16, 2020.
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