Enrollment for Pivotal Phase 3 PHOENIX Study of AMX0035 Completed

Sabrina Paganoni, MD, PhD

Months after AMX0035 (Relyvrio; Amylyx Pharmaceuticals) gained FDA approval as a treatment for patients with amyotrophic lateral sclerosis (ALS), the company has announced it has successfully completed enrollment in its pivotal phase 3 PHOENIX study (NCT05021536), a 48-week trial assessing the agent in 664 individuals with ALS.¹ Topline results are expected in 2024.

"We are pleased to share this milestone from the PHOENIX trial, a collaborative effort to advance our scientific understanding of ALS and build upon the positive data from our Phase 2 CENTAUR trial," Sabrina Paganoni, MD, PhD, principal investigator of the CENTAUR study (NCT03127514), investigator at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, and member of the Executive Committee of the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS), said in a statement.¹

PHOENIX, a randomized, placebo-controlled trial, is expected to span across approximately 65 sites in the US and Europe, assessing the safety and efficacy of AMX0035, a coformulation of sodium phenylbutyrate-taurursodiol. In the study, patients will be randomly assigned 3:2 to AMX0035 or placebo for a 48-week treatment period, and will be assessed on change in the primary outcome of ALS Functional Rating Scale-Revised (ALSFRS-R). Other primary outcome measures include safety, as described by number of adverse events (AEs), and number of participants able to remain on study drug until planned discontinuation.

Most of the participants in PHOENIX are members of the NEALS or Treatment Research Initiative to Cure ALS (TRICALS) consortia. Following the completion of the 48-week trial, patients will be eligible to enter an open-label extension phase, where all participants will be on AMX0035. Aside from the primary outcomes, investigators will also assess individuals on rate of decline in slow vital capacity, participant quality of life, decline in King’s and Milano-Torino staging, ventilation free survival, participant health status, and long-term survival.

"The Phase 3 PHOENIX trial was an excellent collaboration between European and United States Centers for excellence in ALS research and care," Leonard H. van den Berg, MD, PhD, professor of neurology, UMC Utrecht, the Netherlands, and chairman of TRICALS, said in a statement.¹ "We anticipate that PHOENIX will help us generate further data about the safety and efficacy of AMX0035."

The design of PHOENIX was informed by the results of the phase 2 CENTAUR trial, the study that led to AMX0035’s approval. Published in the New England Journal of Medicine, findings from CENTAUR showed that the therapy met its primary end point, with treated patients reporting an ALSFRS-R score of 2.32 points higher than those on placebo (P = .03) after 24 weeks. CENTAUR featured 137 patients with ALS who were randomly assigned 2:1 to 3 g of sodium phenylbutyrate and 1 g of taurursodiol administered once a day for 3 weeks and then twice a day, or placebo.²

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When AMX0035 was approved, it became the third approved therapy to help slow disease progression or mortality in ALS, following riluzole (Rilutek) in 1995 and edaravone (Radicava; MT Pharma) in 2017. It was approved under the accelerated approval pathway following 2 meetings with the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, who voted 7-2 (7 yes; 2 no) in favor of recommending the therapy for approval in the final meeting after previously voting against it back in March 2022.³

In CENTAUR, 77% of the patient cohort were receiving an approved ALS therapy—either riluzole (n = 96), edaravone (n = 46), or both (n = 38)—during and/or before trial entry. When Paganoni and colleagues conducted sensitivity analyses to correct for this, their findings were similar, with an estimated between-group difference in ALSFRS-R total scores of 2.15 points (95% CI, −0.05 to 4.35) for those on edaravone and 2.34 points (95% CI, 0.19 to 4.48) for those on riluzole.

"We are grateful for the people living with ALS and their families who are participating in PHOENIX and the dedication of the study investigators," Joshua Cohen and Justin Klee, co-chief executive officers, Amylyx, said in a statement. "We remain committed to continuing research and exploring the full potential of AMX0035 as part of our mission to one day end the suffering caused by ALS and other neurodegenerative diseases."

REFERENCES
1. Amylyx Pharmaceuticals announces completion of enrollment in global phase 3 PHOENIX trial of AMX0035 in ALS. News release. February 2, 2023. Accessed February 3, 2023. https://www.businesswire.com/news/home/20230202005258/en/Amylyx-Pharmaceuticals-Announces-Completion-of-Enrollment-in-Global-Phase-3-PHOENIX-Trial-of-AMX0035-in-ALS
2. Paganoni S, Macklin EA, Hendrix S, et al. Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. 2020;383:919-930. doi:10.1056/NEJMoa1916945
3. Amylyx Pharmaceuticals announces FDA approval of Relyvrio for the treatment of ALS. News release. Amylyx Pharmaceuticals. September 29, 2022. Accessed February 3, 2023. https://www.amylyx.com/media/amylyx-pharmaceuticals-announces-fda-approval-of-relyvriotm-for-the-treatment-of-als