Amylyx Pharmaceuticals’s Phase III trial for amyotrophic lateral sclerosis (ALS) Relyvrio has failed to meet any of its endpoints.

Following the Phase III flop, Amylyx said it will now engage with regulatory authorities and the broader ALS community, to discuss the results from the Phoenix trial over the next eight weeks and decide how to move forward. The company added this could include withdrawing Relyvrio from the market.

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The candidate was approved by the US Food and Drug Administration (FDA) in September 2022 based on findings from the multicentre Phase II Centaur trial that enrolled 137 ALS patients. In October 2023, the drug, which was set to be marketed as Albrioza in Europe, was rejected for approval by the European Medicines Agency (EMA).

Once the market opened, the company’s stock crashed by 85.7%.

The global, 48-week, randomised, placebo-controlled Phase III clinical trial of Relyvrio (AMX0035) did not meet its primary endpoint of reaching statistical significance from baseline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score. There was also no statistical significance seen in secondary endpoints.

The trial saw 664 patients randomised into two arms, Relyvrio or placebo, with both treatment groups receiving standard of care (SoC).

In a statement, Amylyx co-CEOs Justin Klee and Joshua Cohen said: “We are surprised and deeply disappointed by the Phoenix results following the positive data from the Centaur trial. 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.”

Despite the disappointing efficacy results, Relyvrio was well-tolerated with no new safety signals.

European participants who completed the 48-week randomised phase had the option to enrol in an open-label extension of the trial of up to two years in duration, which remains ongoing.

Momna Ali, healthcare analyst at GlobalData, said: “When Relyvrio was initially approved, there was a swirl of controversy anyway. It’s a shame that the late-stage trial found no significant difference between ALS patients treated with Relyvrio and those on placebo after 48 weeks.

“There are approximately 4,000 people in the US on Relyvrio and if Amylyx does pull its drug, sadly patients would only be left with three approved therapies. One, from Biogen, which targets a very small portion of the population with certain genetic mutations. The other two, called Radicava and riluzole, have shown modest therapeutic effects on both function and survival.”

GlobalData is the parent company of the Clinical Trials Arena.

Amylyx has two other ongoing studies with Relyvrio, a Phase III study in progressive supranuclear palsy (PSP) and a Phase II study in Wolfram syndrome.

Relyvrio is a combination of sodium phenylbutyrate and taurursodiol, which cause a reduction of damage to nerve cells.

ALS landscape

Also known as classical motor neuron disease, ALS is a progressive and fatal neurodegenerative disorder caused by motor neuron death in the brain and spinal cord. Motor neuron loss in ALS leads to deteriorating muscle function, the inability to move and speak, respiratory paralysis, and eventually, death.

GlobalData has predicted global sales of Relyvrio to hit $1.33bn in 2029.

Developing disease-modifying for ALS has proven challenging, with a high failure rate often attributed to the disease’s unclear aetiology and complex pathophysiology.

Earlier this year, Sanofi and Denali Therapeutics’s SAR443820 failed to meet its primary endpoint in a Phase II trial and Ferrer Internacional’s FAB122 failed to meet its primary endpoint in a Phase III study.