TUDCA (tauroursodeoxycholic acid) is a small molecule that is being explored for its potential as a treatment for amyotrophic lateral sclerosis (ALS).

Research has shown that TUDCA can decrease nerve cell death, a hallmark of ALS, through its ability to act as an antioxidant that prevents toxic reactive oxygen species from accumulating inside cells. The molecule also has the ability to control immune function.

How TUDCA works

ALS is a progressive neurological disorder characterized by the death of motor neurons — the nerve cells that control voluntary muscles. Patients with ALS experience severe difficulties in movement, breathing, eating, and speaking.

The energy that is needed by all cells, including nerve cells, is produced by tiny cellular structures called mitochondria. Sometimes the mitochondria become dysfunctional, meaning they don’t work properly, and start producing excessive cytotoxic molecules called reactive oxygen species. These can trigger cell death mechanisms by activating cell death-regulating proteins belonging to the Bcl-2 and caspase family.

Studies have shown that TUDCA incorporates itself into the mitochondrial membranes and prevents association with critical pro-death proteins such as Bax (a Bcl2 family protein that promotes cell death). Through this mechanism, TUDCA can delay or prevent neuronal cell death. It therefore was predicted that TUDCA could prevent or significantly delay the death of motor neurons in ALS patients.

TUDCA in clinical trials

TUDCA is undergoing clinical trials alone, and in combination with sodium phenylbutyrate, as a treatment called AMX0035. These trials are aimed at determining AMX0035’s safety, tolerability, and efficacy in patients with ALS.

A randomized, double-blind, multicenter, placebo-controlled study (NCT00877604) evaluated the efficacy and tolerability of TUDCA in 34 people with ALS. Researchers gave patients TUDCA tablets daily as an add-on therapy for 54 weeks. (The patients were already being treated with riluzole). The study’s results were published in the European Journal of Neurology. They showed that TUDCA was well-tolerated and safe, and significantly slowed the progression of ALS compared with placebo, as measured by the ALS Functional Rating Scale-Revised (ALSFRS‐R).

A Phase 3, multi-center, randomized, double-blind, placebo-controlled, parallel-group study (NCT03800524) is currently recruiting an estimated 440 ALS patients in Italy to evaluate the safety and efficacy of TUDCA as an add-on therapy. That study will monitor the percentage of responders in the treatment and placebo groups for a period of 18 months. It also will measure secondary outcomes, including survival time and biomarkers of ALS pathology. Researchers will assess improvements in participants’ physical mobility, activities of daily living and independence, eating and drinking abilities, communication, pain, and emotional functioning.  The trial is expected to be completed in January 2021.

TUDCA also is being tested in clinical trials as part of AMX0035. A Phase 2, randomized, double-blind, placebo-controlled trial (NCT03127514) called CENTAUR has recently completed enrollment of 132 participants and is evaluating the safety, tolerability, efficacy, and activity of AMX0035. That study will assess whether AMX0035 can delay the progression of ALS as measured by ALSFRS-R. It also will evaluate the effects of AMX0035 on muscle strength, vital capacity, and other ALS biomarkers. Completion of that study is expected in December 2019.

Participants will then have the opportunity to take part in an open-label extension study  (NCT03488524) called CENTAUR-OLE that aims to assess the long-term safety and efficacy of AMX0035.

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