N Engl J Med 2020 Sep 3
Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.
Abstract
Background
Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known.
Methods
In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization.
Results
A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal.
Conclusions
Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).
Related Questions
Would the concerns about respiratory side effects from sodium phenylbutyrate and taurusodiol change your management of patients with predominantly bulbar ALS?
Side effects seen in the trial should be discussed. However, most people would agree that there is a favorable benefit/risk ratio in the context of ALS.
How do you counsel patients on the side effects of sodium phenylbutyrate and taurursodiol?
The most common side effects were gastrointestinal (nausea, diarrhea, abdominal pain) and, when they occurred, they generally did so during the first 3 weeks of treatment. For most patients, these were mild and manageable.
Do you typically assess plasma levels of the phosphorylated axonal neurofilament H subunit (pNF-H) in patients with ALS?
I do not. While I am a fan of using neurofilament levels in trials, I am not yet convinced that these help me care for patients. Several more studies are ongoing which may eventually change my mind.
How clinically meaningful are the differences in the primary outcome between treatment and placebo groups in the CENTAUR trial?
Defining the term "clinically meaningful" proves challenging. Patients involved in the three positive and approved drug trials are unable to detect a slowdown in the progression rate. Attempts were made to gauge ALS providers' opinions regarding a meaningful change in the ALSFRS-R scale, suggesting ...
Based on its mechanism of action, do you think sodium phenylbutyrate and taurursodiol could have benefit in other neurodegenerative disorders?
Yes. Mitochondrial dysfunction (Kim et al., PMID 35682574) are present and believed to be important in driving the progression of several neurodegenerative diseases. Amylyx is currently investigating this drug in patients with Alzheimer's disease (Amylyx Pharmaceuticals announces oral presentation o...