TUDCA-ALS Late-Stage Trial in ALS Patients Fails

Rare Daily Staff

The TUDCA-ALS consortium said top-line results from the European phase 3 clinical trial of TUDCA in patients with amyotrophic lateral sclerosis did not meet the primary endpoint.

Amyotrophic lateral sclerosis (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 within 2 to 5 years after initial diagnosis. More than 90 percent of people with ALS have sporadic disease, showing no clear family history.

The TUDCA-ALS consortium was organized by several European research hospitals and funded by the European Union’s Horizon 2020 research and innovation program to study the effects of tauroursodeoxycholic acid (TUDCA) in people living with ALS. The phase 3 study ran over 18 months, with 25 European sites participating in the study across seven European countries.

The study failed to meet its primary endpoint, defined as a difference in responding and non-responding patients in month 18 as measured by Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores. Furthermore, no statistically significant difference was found between TUDCA and placebo in secondary outcomes including time of survival and changes in biomarkers such as neurofilament light protein. Treatment with TUDCA was well tolerated and generally safe, with predominantly mild gastrointestinal adverse effects occurring both in the placebo and treatment arms.

“We are very disappointed to see there was no overall benefit demonstrated. Given the heterogeneity of ALS, it is important to explore whether the lack of effect was uniform across the whole trial population,” said Alberto Albanese, professor, study leader, and Neurology Unit director at Humanitas Research Hospital, Italy.

The trial took place during the COVID-19 pandemic and faced numerous challenges posed by repeated pandemic waves. This included a drop from the projected 440 to 336 participants, equally distributed between treatment arms at the start of the trial. Markedly more placebo participants dropped out of the trial during the first 9 months than from the TUDCA arm, with about half of patients reaching the 18-month mark in each treatment arm.

The consortium is undertaking additional tasks, including further statistical analysis of data and biomarkers at various timepoints, to gain a clearer understanding of the effects of TUDCA in slow progressing patients compared to fast progressors. These analyses will be presented at the meeting of the European Network for the Cure of ALS in Stockholm, June 2024.

Studies have previously shown that TUDCA has neuroprotective properties, preventing motor neurons from dying. A phase 2b clinical trial showed that patients who received TUDCA in addition to riluzole for 54 weeks had a prolonged median survival of 4-5 months. The TUDCA-ALS trial was developed to determine the clinical efficacy of TUDCA in ALS.

Aspects of the data are being pursued further to explore additional differences between placebo and treatment arms, including different time points and analysis in slow versus fast progressing groups. Full results will be presented at a later stage.

Photo: Alberto Albanese, professor, study leader, and Neurology Unit director at Humanitas Research Hospital, Italy.