Relyvrio Falls Short of Primary Endpoint in Phase III PHOENIX Trial in Patients with ALS

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Amylyx Pharmaceuticals’ Relyvrio (AMX0035) did not meet the primary endpoint of a statistically significant reduction in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score at week 48 compared with placebo, according to findings from the global Phase III PHOENIX trial. In light of the disappointing results, Amylyx intends to continue discussing the future of Relyvrio with regulatory authorities and the amyotrophic lateral sclerosis (ALS) community, mentioning that a complete market withdrawal was not off the table.

“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,” said Justin Klee and Joshua Cohen, co-CEOs, Amylyx, in a press release.

“Over the next eight weeks, our team will continue to engage with regulatory authorities and the ALS community to discuss the results from PHOENIX. 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.”

The study, which included 664 adults currently living with ALS, had the following results:

• No major difference was observed between participants treated with Relyvrio compared with placebo in ALSFRS-R total score change from baseline at week 48 (p=0.667). Additionally, there were no reported differences among participants who were part of Amylyx’s previous CENTAUR trial.
• Despite the setback, Relyvrio was well tolerated in this study, with no new inidications of safety risks.
• European patients were given the option of joining a two-year open label extension, which is currently in progress.

Reportedly, the treatment has shown potential when it comes to reducing markers associated with neurodegenerative diseases in clinical trials, such as tau—a major protein collection in several neurodegenerative diseases—and YKL-40, an indicator for neuroinflammation. Additionally, AMX0035 has been found to be effective in targeting two different destructive neurodegenerative disease pathways by alleviating endoplasmic reticulum stress and the associated unfolded protein response and mitochondrial dysfunction.¹

Another Phase III study focusing on progressive supranuclear palsy, ORION, is still ongoing, having started back in December. It is expected to continue into 2025 or 2026 before receiving topline results.¹

Relyvrio was initially approved by the FDA for the treatment of ALS in late 2022. According to a previous trial, the treatment significantly slowed the loss of physical function in people living with ALS.²

“Today’s FDA approval of Relyvrio is an exciting milestone for the ALS community and is a major step toward achieving our mission to one day end the suffering caused by neurodegenerative diseases,” said Cohen and Klee, in a press release regarding the previous FDA approval.²

According to ALS News Today, the ALS Association estimates that around 5,000 people in the United States are diagnosed with the disease on an annual basis. Other statistics include:

1. An average of 15 new cases a day.
2. A life expectancy of two to five years.
3. An average of 20,000 Americans suffering from the disease at a given time.
4. It is most common for ALS to appear between the ages of 40-70 years, averaging at 55 years of age.
5. 10% of patients are under the age of 45 years.3

“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. With data collected from 664 participants in PHOENIX, we are certain there will be important learnings that will help inform future ALS research,” Cohen and Klee said in the release. “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.”1

References

1. Amylyx Pharmaceuticals Announces Topline Results From Global Phase 3 PHOENIX Trial of AMX0035 in ALS. Amylyx, 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. Amylyx. September 29, 2022. Accessed March 8, 2024. https://www.amylyx.com/news/amylyx-pharmaceuticals-announces-fda-approval-of-relyvriotm-for-the-treatment-of-als

3. ALS Facts and Statistics. ALS News Today. Accessed March 8, 2024. https://alsnewstoday.com/als-facts-statistics/#:~:text=According%20to%20the%20ALS%20Association,disease%20at%20any%20given%20time.