An ongoing Phase 3 clinical trial in Europe is testing whether tauroursodeoxycholic acidadded to standard therapy, can slow disease progression and extend survival among people with amyotrophic lateral sclerosis (ALS).
The oral compound, also known as TUDCA, is one of the two ingredients in Relyvrio (sodium phenylbutyrate and taurursodiol), a therapy developed by Amylyx Pharmaceuticals and authorized to treat ALS in the US and Canada. Relyvrio is currently under consideration in Europe.
The study is expected to conclude in about a year. Its protocol, meaning its design and objectives, was detailed in the paper, “Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol,” published in the journal Frontiers in Neurology.
TUDCA, a bile acid, has a generally good safety profile
TUDCA is a bile acid that is naturally produced in the liver. It has been used to treat liver disease and generally has a good safety profile, with the most common side effects being soft stools and diarrhea.
It is also able to enter the brain, and studies suggest it may help to protect nerve cells from damage. Proof-of-concept Phase 2 trials (NCT00877604 and NCT03127514) have shown TUDCA to be generally well-tolerated, and their results hinted that adding TUDCA to standard therapy may help to slow ALS progression.
Prompted by these findings, the European Commission supported a Phase 3 trial in recently diagnosed patients — those with a disease duration of 18 or fewer months — called TUDCA-ALS (NCT03800524) to further evaluate its potential.
“The TUDCA-ALS study is the largest clinical trial ever conducted to evaluate the efficacy of TUDCA as add-on treatment in people with ALS,” the researchers wrote.
“Considering the encouraging results” of the Phase 2 studies of TUDCA given alone or in combination, “the TUDCA-ALS project promises to provide innovative answers on the clinical management of ALS patients,” they added.
During their first three months in the study, participants are treated with riluzole (sold as Rilutek, Exservanand Tiglutik), currently the only approved ALS therapy in Europe. Over this run-in period, they undergo disease severity assessments using the ALS Functional Rating Scale–Revised (ALSFRS-R) every six weeks to establish a rate of disease progression.
Patients are then randomly assigned to oral TUDCA, given at 1 g twice daily, or to matching placebo capsules for 18 months, with assessments every three months. All are continuing to take riluzole throughout the study.
The rate of disease progression during the run-in and the treatment period will be compared. TUDCA-ALS’s main goal is to assess whether TUDCA increases the number of people who experience at least a 20% slowing in disease progression.
“The primary outcome is the proportion of responding patients in each treatment arm. Responding patients are defined as those showing a reduction in the ALSFRS-R slope decline by at least 20% when comparing the 18-month trial to the run-in period,” the researchers wrote.
Other measures being assessed include survival outcomes, changes in lung function, treatment safety and tolerability, patient views of benefit using a disease-specific questionnaire, and tests of biomarkers relevant to ALS.
Statistical models indicated that the TUDCA-ALS study needed to enroll 320 patients in order to detect a significant 11% treatment effect. The trial, underway at sites in Belgium, France, Germany, Ireland, Italy, the Netherlands, and the UK, finished enrolling 337 adults in late 2021.
Patient treatment is expected to conclude in October 2023, the researchers noted, and trial results are likely to be available by the end of the year.