2.10 Relyvrio’s setback in ALS is a clinical and a regulatory failure

The failure of Relyvrio in a post-approval phase 3 study in amyotrophic lateral sclerosis (ALS) means its days as a commercial drug are probably numbered. It initially gained approval in Canada in June 2022 (where it is, confusingly, known as Albrioza) and secured FDA approval the following September.

Both approvals rested on the 24-week phase 2 ‘Centaur’ trial, in which the drug showed modest effects as compared with placebo in slowing patients’ decline in physical functions. Those data were published in the New England Journal of Medicine (Paganoni et al., 3 Sep. 2020). A follow-up analysis, published in the Annals of Clinical and Translational Neurology (Paganoni et al., 9 Oct. 2023) even suggested it could have a survival benefit. But the Phoenix trial recruited almost five times as many patients (664 vs. 137) and was twice as long, which means it is a far more rigorous test of the drug’s effects. The setback has raised questions about the FDA’s apparent leniency in approving a drug that its own expert advisory panel initially rejected.

Its approval followed a second such hearing, which, in the absence of new data, is highly irregular. If nothing else, the episode highlights the difficulty of developing effective therapies for highly varied and complex conditions whose disease biology is still not fully understood. Relyvrio’s mechanism was not a settled matter either. The drug, a fixed-dose combination of sodium phenylbutyrate and taurursodiol, ameliorates endoplasmic reticulum stress and mitochondrial dysfunction, according to its developer.

According to the FDA product label, its mechanism in ALS patients is unknown. There is an urgent need for effective therapies in ALS. Insights from genetic forms of the condition (which account for about 10% of cases) are helping scientists to unpick some of its molecular underpinnings. In time, these may help to form the basis of therapies that could help patients with either form of the condition. But for patients living with the condition at present, therapeutic options are still tragically limited.

Companies mentioned in this episode:
Amylyx Pharmaceuticals, Biogen, Ionis Pharmaceuticals, QurAlis, Sarepta Therapeutics 

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