The oral drug AMX0035 is associated with a significantly longer survival benefit for patients with amyotrophic lateral sclerosis (ALS) than was originally concluded in a 2020 paper, according to a new statistical analysis of the data.
Compared with the 6.9-month survival benefit in the original prespecified intent-to-treat analysis, the new analysis concludes that, when adjusted for the effects of placebo crossover, the survival benefit ranges from 10.6 to 18.8 months.
Published on May 4 in Muscle & Nerve, the new analysis was conducted by many of the authors of the original CENTAUR trial published on September 3, 2020, in the New England Journal of Medicine (NEJM). CENTAUR was a phase 2, six-month trial with an open-label extension.
Crossover designs, in which patients originally assigned to placebo are offered the chance to switch to active drug, can result in an under-estimation of a drug's true effect, according to the new study. For instance, the group originally assigned in CENTAUR to the active arm ended up receiving the drug six months longer than those in the placebo arm who then switched to the drug in the open-label extension. Moreover, not everyone in the original placebo arm chose to switch to the active drug when offered the chance.
To account for these and other effects, the researchers used a statistical method drawn from cancer studies, called the rank-preserving structural failure time model. Using that method, they found that the median survival duration was 33.6 moths in the group originally assigned to receive AMX0035 and who stayed on it in the open-label extension. By comparison, those originally assigned to placebo, and who did not cross over to active treatment in the open-label extension, had a median survival duration of 14.8 months, or 18.8 months shorter than those who were on the active drug throughout (P<0.0001).
AMX0035 is a combination of sodium phenylbutyrate and taurursodiol developed by Amylyx Pharmaceuticals.
On March 30, the US Food and Drug Administration's Peripheral and Central Nervous System Drugs Advisory Committee voted six to four against approval of the drug. It concluded that CENTAUR did not prove that the drug was effective.
The new paper noted that the post-hoc subgroup analysis has limitations. “The subgroups are small, and potential confounding differences among the groups were not controlled for, although covariates of age at randomization, pre-baseline ALSFRS-R slope, and baseline ALSFRS-R R [Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised] total score attempted to control for some of this bias."
The paper also acknowledged that the rank-preserving structural failure time model method assumes that the response to treatment is the same for all patients. “This assumption may be unreliable in degenerative conditions such as ALS, though the time between randomization and crossover in CENTAUR was relatively short (only six months)," wrote lead study author Sabrina Pagnoni, MD, PhD, an assistant professor at Harvard Medical School, and colleagues.
A phase 3 randomized trial of the drug, PHOENIX (NCT05021536), began last October. Approximately 600 participants at 70 sites across the United States and Europe will be randomized and treated for over 48 weeks. The estimated primary completion date is November 1, 2023, with the full study expected to be completed by March of 2024.
Dr, Paganoni reports research grants from Amylyx Pharmaceuticals, Revalesio Corporation, Alector Therapeutics, UCB, Biohaven Pharmaceuticals, Clene Nanomedicine, Prilenia Therapeutics, Seelos Therapeutics, The ALS Association, the American Academy of Neurology, the Centers for Disease Control, ALS Finding a Cure®, the Salah Foundation, the Spastic Paraplegia Foundation, the Muscular Dystrophy Association, I AM ALS, Tambourine, Target
ALS, Columbia University, and the Cullen Education and Research Fund, and is a site principal investigator for studies funded by Alector Therapeutics, Cytokinetics, and Novus (formerly Anelixis) Therapeutics. Dr Paganoni also reports institutional consulting agreements with Amylyx Therapeutics, Frequency Therapeutics, SOLA Biosciences; and personal consulting
agreements with Cytokinetics, Arrowhead Pharmaceuticals, Orthogonal Neuroscience; and honoraria from Medscape. Remaining disclosures are listed in the study.
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Paganoni S, Watkins C, Cawson M, et al. Survival analyses from the CENTAUR trial in amyotrophic lateral sclerosis: Evaluating the impact of treatment crossover on outcomes. Muscle Nerve 2022; Epub 2022 May 4.
Paganoni S, Macklin EA, Hendrix S. Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis. N Engl J Med 2020;383(10):919-930