Tauroursodeoxycholic Acid Falls Short in Phase 3 Study of Amyotrophic Lateral Sclerosis
TUDCA, a hydrophilic bile acid that is normally produced endogenously in humans in the liver, failed to slow ALS disease progression in comaprison with placebo.
Alberto Albanese, MD
Recently announced topline data from a large-scale, phase 3 study (NCT03800524) showed that tauroursodeoxycholic acid, or TUDCA, failed to distinguish itself from placebo in slowing disease progression among patients with amyotrophic lateral sclerosis (ALS). Aspects of the data re being pursued further to explore additional differences between placebo and treatment arms, including various time points and analysis in slow vs fast progressing groups.1
After 18 months of treatment, the therapy fell short of reaching its primary end point, as measured by ALS Functional Rating Scale-Revised scores. In addition, investigators observed no between-group differences on other secondary end points, including time of survival, and changes in biomarkers such as neurofilament light protein. The TUDCA-ALS consortium, organized by Humanitas Research Hospital in Italy, will have additional analyses presented at the meeting of the European Network for the Cure of ALS in Stockholm, June 2024.
"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. Therefore, thorough analysis of subgroups based at intermediate time points is ongoing," study lead Alberto Albanese, neurology unit director at Humanitas Research Hospital, said in a statement. "We would like to express our deep gratitude to the people with ALS who so generously participated in the trial."
The randomized, placebo-controlled, parallel-group study was also impacted by the COVID-19 pandemic, which forced some participants to drop, lowering the enrollment from 440 to 336. In addition, markedly more participants on placebo dropped out of the trial in the first 9 months than those in the TUDCA arm, with about half of the patient cohort reaching the 18-month mark in each treatment arm. The trial, which spanned 25 centers across 7 countries in Europe, also showed that TUDCA was well tolerated and generally safe, with predominantly mild gastrointestinal adverse events occurring in both arms.
TUDCA is a hydrophilic bile acid that is normally produced endogenously in humans in the liver, by conjugation of taurine to ursodeoxycholic acid (UDCA). It is commonly used for the treatment of chronic cholestatic liver diseases and for gallstone. Previous data has shown that TUDCA has neuroprotective effects in motor neuron-neuroblastoma hybrid cells expressing mutant superoxide dismutase 1 mutations A4V and G93A. Preclinical data also has reported an anti-apoptotic and neuroprotective role of TUDCA in models of other neurodegenerative diseases.
The phase 3 study followed a successful proof-of-concept phase 2b study, where treatment with TUDCA resulted in about a 7-point less per-year decline in ALSFRS-R compared with riluzole (Rilutek), the first FDA-approved therapy for ALS, alone. This corresponded to a prolongation of median survival by 4-5 months. In addition, there were no between-group differences for adverse events, and a higher proportion of patients on TUDCA were responders on ALSFRS-R (87% vs 43%; P = .021).2
The combination of TUDCA and UDCA have been reported to be effective in animal models of spinal cord injury, head trauma, glaucoma, acute renal failure, pancreatitis, metabolic syndrome, psoriasis, myocardial infarction, neuropathic pain, ischemia reperfusion syndromes, gastrointestinal disorders, and diabetic retinopathy in addition to liver-related disorders. Obese patients have also been show to benefit from T/UDCA via the inhibition of endoplasmic reticulum stress and UPR dysfunction.3
