Amylyx Pharmaceuticals Discontinues AMX0035 After Failing Primary End Point in Phase 3 PHOENIX Trial

According to an announcement, Amylyx Pharmaceuticals will voluntarily discontinue AMX0035 (Relyvrio) and remove it from the market in the United States and Canada based on negative topline data from its phase 3 PHOENIX trial (NCT05021536) that showed AMX0035 did not meet its primary end point of change in ALS Functional Rating Scale-Revised (ALSFRS-R).^1,2 Although AMX0035 will no longer be available for new patients with amyotrophic lateral sclerosis (ALS), those currently on therapy in the US and Canada who wish to stay on treatment and consult with their clinician can be transitioned to a free drug program.

In PHOENIX, results showed no significant 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.

“While this is a difficult moment for the ALS community, we reached this path forward in partnership with the stakeholders who will be impacted and in line with our steadfast commitment to people living with ALS and other neurodegenerative diseases. The decision to remove AMX0035 from the market and provide therapy free of charge for those who wish to continue was informed by the PHOENIX trial results, engagement with regulatory authorities, and discussions with the ALS community. Thank you to each and every person who shared feedback with us and continues to support our commitment to the ALS community,” Joshua Cohen and Justin Klee, coCEOs at Amylyx, said in a statement.¹

The company noted in its release that it will continue to assess and present findings from PHOENIX to help inform future ALS research, collecting available data on survival from ALS specialists. The PHOENIX open label extension is ongoing and topline data from PHOENIX will be presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Dever, Colorado. In addition, the company noted that it continues to advance 2 key programs exploring its lead asset AMX0035 in Wolfram syndrome and progressive supranuclear palsy (PSP), and AMX0114, an antisense oligonucleotide targeting calpain-2, in ALS.

“Our pipeline is supported by compelling clinical and preclinical science demonstrating the potential of AMX0035 and AMX0114 in neurodegenerative diseases. AMX0035 was designed to slow or mitigate neurodegeneration by targeting endoplasmic reticulum stress and mitochondrial dysfunction, 2 connected central pathways that lead to cell death and neurodegeneration. We are investigating AMX0035 in diseases where these 2 pathways are implicated, which includes Wolfram syndrome and progressive supranuclear palsy,” Camille L. Bedrosian, MD, chief medical officer at Amylyx, said in a statement.¹

READ MORE: Tauroursodeoxycholic Acid Falls Short in Phase 3 Study of Amyotrophic Lateral Sclerosis

Bedrosian continued in the statement, “We look forward to presenting interim data from our phase 2 HELIOS study of AMX0035 in Wolfram syndrome, a rare, genetic, fatal neurodegenerative disease with no FDA-approved treatment options, later this month. In addition, our phase 3 ORION study remains ongoing to evaluate AMX0035 for the treatment of progressive supranuclear palsy, a rare neurodegenerative disorder characterized as a tauopathy. We continue to plan for an interim analysis to evaluate the data from ORION that is now expected in mid-2025.”¹

Approved by the FDA in 2022, AMX0035’s pathway to market was unique.³ 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.⁴

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).⁵ 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.⁶

“We are so thankful and grateful to our Amylyx team for their contributions and steadfast dedication,” Cohen and Klee, said in a statement.¹ “Together, the work we have accomplished across the world has helped build a vital foundation to achieve our mission of one day ending the suffering caused by neurodegenerative diseases, which continue to have critical, unaddressed needs.”

"We commend Amylyx for pulling AMX0035 off the market, while still ensuring that patients living with ALS can access the drug if they believe it is helping them. ALS is a fatal and heterogenous disease with few treatment options, and creative solutions are needed. We believe the example of AMX0035 shows how the system can work," the ALS Association said in its official regarding Amylyx Pharmaceuticals' formal intention to remove AMX0035 from the market. "FDA approved AMX0035 based on solid safety data and positive efficacy data from a phase 2 trial on function and survival. Safe and potentially effective treatments can be made accessible rapidly until further research can confirm their efficacy. There are more than 40 more potential treatments in the pipeline and we are focused on trying to advance the safe and effective ones as quickly as possible."

REFERENCES
1. Amylyx Pharmaceuticals Announces Formal Intention to Remove RELYVRIO®/ALBRIOZA™ from the Market; Provides Updates on Access to Therapy, Pipeline, Corporate Restructuring, and Strategy. News Release. Amylyx Pharmaceuticals. Published April 4, 2024. Accessed April 4, 2024. https://www.businesswire.com/news/home/20240404501040/en/Amylyx-Pharmaceuticals-Announces-Formal-Intention-to-Remove-RELYVRIO%C2%AEALBRIOZA%E2%84%A2-from-the-Market-Provides-Updates-on-Access-to-Therapy-Pipeline-Corporate-Restructuring-and-Strategy
2. Amylyx Pharmaceuticals announces topline results from global phase 3 PHOENIX trial of AMX0035 in ALS. News release. March 8, 2024. Accessed April 4, 2024. https://www.amylyx.com/news/amylyx-pharmaceuticals-announces-topline-results-from-global-phase-3-phoenix-trial-of-amx0035-in-als
3. Amylyx Pharmaceuticals announces FDA approval of Relyvrio for the treatment of ALS. News release. Amylyx Pharmaceuticals. September 29, 2022. Accessed April 4, 2024. https://www.amylyx.com/media/amylyx-pharmaceuticals-announces-fda-approval-of-relyvriotm-for-the-treatment-of-als
4. FDA. Peripheral and Central Nervous System Drugs Advisory Committee Meeting. September 7, 2022. Accessed April 4, 2024. https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-7-2022-meeting-peripheral-and-central-nervous-system-drugs-advisory-committee-meeting
5. 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
6. 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