Amylyx Mulls Over Pulling AMX0035 Following Disappointing Phase 3 PHOENIX Findings

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Over the coming weeks, Amylyx will undergo heavy discussions with regulators and community members to decide the next best steps for AMX0035 after the agent failed to meet its primary end point in its latest study.

Justin Klee

Justin Klee

Amylyx Pharmaceuticals has announced negative topline data from its large-scale, pivotal phase 3 PHOENIX trial (NCT05021536), with results showing that AMX0035 (Relyvrio) did not meet its primary end point of change in ALS Functional Rating Scale-Revised (ALSFRS-R). The company will engage with regulatory authorities and the broader ALS community to assess the next steps, which may include voluntarily withdrawing the agent from market.1

In its release, Amylyx noted that it will discuss the results of PHOENIX over the next 8 weeks and make an informed decision based on those conversations. At this time, the therapy and its related patient support program will continue to be available for patients with amyotrophic lateral sclerosis (ALS). Additionally, the company has also voluntarily paused the promotion of the therapy during this time.

In PHOENIX, results showed no significance difference on ALSFRS-R between AMX0035-treated and placebo-treated patients over a 48-week treatment period (P = .667). In addition, investigators observed no significant differences in a subset of participants who met the CENTAUR trial (NCT03127514) criteria, the previous phase 3 study that led to the therapy’s 2022 approval. AMX0035, a coformulation of sodium phenylbutyrate and taurursodiol, maintained its safe profile, with no new safety signals observed.

Josh Cohen

Josh Cohen

Justin Klee and Josh Cohen, co-chief executive officers of Amylyx, said in a statement that, “We are surprised and deeply disappointed by the PHOENIX results following the positive data from the CENTAUR trial. Our main priority at the moment is sharing the information with people living with ALS and their treating physicians; this is part of our continued commitment to them and our mission. Over the next eight weeks, our team will continue to engage with regulatory authorities and the ALS community to discuss the results from PHOENIX."1

The duo added, "We will be led in our decisions by two key principles: doing what is right for people living with ALS, informed by regulatory authorities and the ALS community, and by what the science tells us. On behalf of the entire Amylyx team, we are grateful to the ALS community and for the dedication of trial participants, investigators, and study site teams."

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PHOENIX, a randomized, placebo-controlled trial spanning approximately 65 sites in the US and Europe, was a follow-up to CENTAUR. In the trial, 664 patients were randomly assigned 3:2 to either AMX0035 or placebo for a 48-week treatment period, followed by an optional open-label extension, which remains ongoing. In addition to ALSFRS-R, the trial looked at other outcomes such as decline in slow vital capacity, participant quality of life, decline in King’s and Milano-Torino staging, ventilation free survival, and long-term survival. Despite the disappointing results, Amylyx is still planning to present the data at an upcoming medical meeting and will publish the results in a medical journal later this year.1

Approved by the FDA in 2022, AMX0035’s pathway to market was unique.2 Less than a month before it was approved, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee did an about-face, voting 7-2 (7 Yes; 2 No) in favor of recommending the therapy for FDA approval after previously voting against it in March 2022, citing doubts in the drug’s efficacy.3

CENTAUR met its primary end point, with treated patients on AMX0035 reporting an ALSFRS-R score of 2.32 points higher than those on placebo (P = .03) after 24 weeks. Additional data showed that from baseline, there was a 2.92-point higher mean ALSFRS-R score for the AMX0035 group (P = .01) and a –1.24 point change in total ALSFRS-R score compared with –1.66 points per month with placebo (difference, 0.42; 95% CI, 0.03-0.81; P = .03).4 The NDA was also supported by survival data released in October 2020, which demonstrated a median survival of 25 months (95% CI, 19.0-33.6) for those on study drug 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.5

"We are steadfast in our commitment to the ALS community and our mission, including with AMX0035 where it has shown potential in neurodegenerative diseases such as Wolfram syndrome and progressive supranuclear palsy, and with AMX0114, our investigational antisense oligonucleotide targeting calpain-2, in ALS,” Klee and Cohen added.1

The ORION study, a phase 3 trial of AMX0035 in patients with progressive supranuclear palsy (PSP), remains ongoing. Announced in May 2023, the trial is expected to enroll 600 adults with PSP who will be assessed over a 52-week double-blind period, followed by an optional 52-week open-label extension. AMX0035 is thought to mitigate tau pathology in PSP through multiple pathways, with preclinical evidence and data from the PEGASUS trial, a study of AMX0035 in Alzheimer disease (AD), to support this theory.6

REFERENCES
1. Amylyx Pharmaceuticals announces topline results from global phase 3 PHOENIX trial of AMX0035 in ALS. News release. March 8, 2024. Accessed March 8, 2024. https://www.amylyx.com/news/amylyx-pharmaceuticals-announces-topline-results-from-global-phase-3-phoenix-trial-of-amx0035-in-als
2. Amylyx Pharmaceuticals announces FDA approval of Relyvrio for the treatment of ALS. News release. Amylyx Pharmaceuticals. September 29, 2022. Accessed March 8, 2024. https://www.amylyx.com/media/amylyx-pharmaceuticals-announces-fda-approval-of-relyvriotm-for-the-treatment-of-als
3. FDA. Peripheral and Central Nervous System Drugs Advisory Committee Meeting. September 7, 2022. Accessed March 8, 2024. https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-7-2022-meeting-peripheral-and-central-nervous-system-drugs-advisory-committee-meeting
4. 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
5. 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
6. Progressive supranuclear palsy (PSP) investor and analyst conference call. News release. Amylyx Pharmaceuticals. July 26, 2023. Accessed March 8, 2024. https://investors.amylyx.com/static-files/4a2e66ce-8516-488c-9745-29164875869f
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