TUDCA study failure extends trail of ALS disappointments

2024-03-27

临床2期临床3期上市批准临床结果

Patients with amyotrophic lateral sclerosis (ALS) were already reeling from the disheartening setback of Amylyx Pharmaceuticals' Relyvrio (sodium phenylbutyrate/taurursodiol) failing its confirmatory PHOENIX trial earlier this month. Now a group of European researchers testing one of the constituent components of Relyvrio has some more bad news; that trial failed, too.

The TUDCA-ALS consortium was running a Phase III study evaluating tauroursodeoxycholic acid (TUDCA), also known as taurursodiol, as a single agent over a period of 18 months across seven European countries. Top-line results were initially expected toward the end of last year.

However, on Wednesday, researchers reported that the TUDCA-ALS trial failed on the primary endpoint of ALS Functional Rating Scale - Revised (ALSFRS-R) scores, nor were there any significant differences between TUDCA and placebo on secondary outcomes including time of survival and changes in biomarkers such as neurofilament light protein.

COVID disruptions

The study began in 2018 and continued throughout the COVID-19 pandemic. Investigators suggested that disruptions from waves of the pandemic resulted in a decrease in the expected number of participants from 440 to 336, and had a detrimental effect on the statistical analysis due to a low number of participants at later stages of the study.

They noted that an earlier Phase IIb trial indicated that TUDCA has neuroprotective properties, with patients who received TUDCA in addition to riluzole for 54 weeks achieving prolonged median survival of four to five months.

"Given the heterogeneity of ALS, it is important to explore whether the lack of effect was uniform across the whole [TUDCA-ALS] trial population. Therefore, thorough analysis of subgroups based at intermediate time points is ongoing," commented study lead Alberto Albanese. Detailed results will be presented at the upcoming European Network for the Cure of ALS (ENCALS) in June.

Bleaker prospects for Relyvrio

The study outcome likely adds another nail in the coffin of Relyvrio, whose future was already in limbo following the PHOENIX failure. The drug had been granted a controversial full FDA approval in 2022 based on Phase II data from the CENTAUR trial, with Amylyx co-CEO Justin Klee pledging during an FDA advisory hearing that the company was prepared to pull the $158,000-a-year treatment from the market if it didn't pass its confirmatory trial.

Amylyx is in the process of deciding what the future holds for Relyvrio, although Evercore ISI analyst Umer Raffat recently suggested that if the TUDCA-ALS trial succeeded in showing that "one of the two components in Relyvrio is active, the odds of any risk of market withdrawal should now be near zero."

For more, see KOL Views Q&A: Leading neurologist outlines where ALS field goes next after Amylyx’s Relyvrio failure.

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