The pathogenesis of amyotrophic lateral sclerosis (ALS) is not fully understood. Currently, only the drug riluzole is available to slow down the progression of the disease, to an extent. Otherwise, the only option left to the therapists is to provide the best possible support for the affected patients through multimodal supportive therapy. The CENTAUR Phase-II trial1 has shown that oral administration of a combination of sodium phenylbutyrate and taurursodiol could delay progression.
In experimental studies on neurodegenerative diseases, the combination of sodium phenylbutyrate and taurursodiol has been shown to prevent neuron death, presumably by protecting certain cellular components (more specifically, the endoplasmic reticulum) and cellular energy supply. Sodium phenylbutyrate is the sodium salt of a fatty acid (phenylbutyric acid), and has been used successfully to treat pediatric metabolic defects. Taurursodiol is a bile acid with known cytoprotective or antiapoptotic properties. In clinical pilot studies, the tolerability of sodium phenylbutyrate taurursodiol in ALS patients has been demonstrated.
In a multicentre, double-blind, randomized phase II study1 in the USA, 137 ALS patients were now receiving an oral drug combination of 3g sodium phenylbutyrate and 1g taurursodiol daily (verum group, n=89; once daily for three weeks, then twice) - or a placebo (placebo group, n=48) with the same appearance and taste (dissolved as a powder in water).
The patients treated were in the early or middle course of the disease (diagnosis within the last 18 months). 77% of patients had already taken riluzole and/or the antioxidant edaravone. The primary endpoint of the study was the ALS-FRS-R-Score ("Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised"), which measures the motor function of people with ALS over a period of 24 weeks (values from 0 to 48; 0 corresponds to a loss of motor function).
After 24 weeks of therapy, there was a significant slowdown in ALS-FRS-R score deterioration; the absolute difference was 2.32 scale points. The difference in the monthly decrease in score was also significant (-1.24 points in the verum group versus -1.66 points in the placebo group; p=0.03). The effect was most pronounced in terms of fine motor skills, as the authors point out.
Even when taking riluzole (or edaravone, not authorized in the EU) at the same time, the study results showed a slowdown in ALS in the verum group. With regard to secondary study endpoints (e.g. isometric muscle strength, the ALS biomarker pNF-H in the blood, lung function, hospital stays), the therapy did not show any benefit. Serious adverse events occurred in 19% of patients in the placebo group and 12% in the verum group (pulmonary complications 8% and 3%). A total of 25% of the patients stopped taking the drug prematurely - most of them due to gastrointestinal problems, but this also applied to 21% of the patients in the placebo group.
"The efficacy of sodium phenylbutyrate and taurursodiol cannot yet be proven with this phase 2 trial, but the results give hope that the course of ALS can be delayed in the future", comments Prof. Dr. Thomas Meyer, ALS outpatient clinic of the Charité University Hospital (Berlin, Germany). "The preservation of everyday motor functions for as long as possible is an important goal of new drugs and is of the utmost relevance for the quality of life of those affected", Dr. Meyer added.
1. Paganoni S, Macklin EA, Hendrix S et al Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med 2020 Sep 3; 383 (10): 919-930 doi: 10.1056/NEJMoa1916945.