Oral tauroursodeoxycholic acid (TUDCA) is a dietary supplement and medication for the treatment of primary biliary cirrhosis. It is currently being tested in patients with amyotrophic lateral sclerosis (ALS), alone or in combination with sodium phenylbutyrate (Relyvrio/AMX0035). It is also used in traditional Chinese medicine.
Current evidence indicates a protective effect of TUDCA in ALS, alone or in combination with phenylbutyrate (PB) at doses of 2000 mg/day.
Phenylbutyrate alone was tested in a phase II clinical study in 2009 for ALS, but the results appear to have been negative. On the contrary, TUDCA has been evaluated in clinical trials in the United States (2010) and South Korea (2012) and is approved in South Korea for the treatment of patients with amyotrophic lateral sclerosis. However, gastrointestinal adverse events are common.
Italian scientists became interested and carried out their own clinical trial in 2015. The results were very encouraging. It appears that Italian patients subsequently often took TUDCA in a controlled manner. As ALS is an incurable disease, the Emilia-Romagna Regional Health System (ERR) supports the off-label use of treatments that have shown promising evidence in early clinical studies. In this context, since 2015, TUDCA has been prescribed by specialized ALS centers operating in ERR, which participate in the ERR ALS register.
This recent Italian study aimed to determine, in a real-world setting, whether TUDCA had an impact on the overall survival of ALS patients treated with this drug compared to patients who received only standard care.
This propensity score-matched study was conducted in the Emilia-Romagna region. A propensity score-matched cohort study aims to reduce the impact of confounding variables (factors that could skew results) by matching subjects into two groups based on their propensity scores. Propensity scores are calculated to mimic the randomization of subjects, characteristic of double-blind clinical studies. However, propensity scores are defined by researchers, biases may exist. In a double-blind clinical study, researchers and participants do not know who is receiving the treatment and who is in the control (placebo) group. This blinding aims to eliminate bias and ensure that the results are objective.
In practice, clinical trials are often outsourced and are not as rigorous as they seem in theory. Additionally, companies and sponsors typically attempt to distort unsuccessful results by performing unscientific post-hoc analyzes and shifting the focus to obscure biomarkers. In addition, patients lie, how can we know that we have a 1 in 2 chance of being in the placebo arm without also taking supplements just in case? Thus, a propensity score matched study should certainly not be dismissed on the grounds that it is not a double-blind clinical study.
Of 627 ALS patients diagnosed between January 1, 2015 and June 30, 2021 and recorded in the registry with available death/tracheostomy information, 86 patients took TUDCA and were matched in a 1:2 ratio with 172 patients who received only usual care.
This matching (propensity scores) was performed based on age at onset, sex, phenotype, latency to diagnosis, ALS Functional Rating Scale-Revised (ALSFRS-R) at first visit, rate of disease progression at first visit, and BMI at diagnosis. The primary endpoint was the difference in survival (time from symptom onset to tracheostomy/death) between patients exposed to TUDCA and those not exposed.
TUDCA-exposed patients were then stratified based on dosage (less than or equal to 1000 mg/day or more) and duration (less than or equal to 12 months or more) of treatment. Median overall survival was 49 months in those treated with TUDCA and 36 months in the control group. This increase in survival is double that provided by Relyvrio/AMX0035. There was a reduced risk of death observed in patients exposed to a higher dosage (defined as ≥ 1000 mg/day) of TUDCA compared to both the control group and those with lower TUDCA dosages.
TUDCA was generally well-tolerated, except for a minority of patients (n = 7, 8.1%) who discontinued treatment due to side effects, primarily gastrointestinal and mild in severity; only 2 adverse events required hospital access so beware of strong doses of TUDCA on the long term.
There is an ongoing phase III clinical trial of TUDCA in Europe (NCT03800524), its results will probably be available in early 2024.