Oral, fixed-dose formulation of two compounds reduces rate of functional decline in ALS

Coformulated, fixed-dose sodium phenylbutyrate–taurursodiol reduced the rate of functional decline compared with placebo in patients with amyotrophic lateral sclerosis, or ALS, according to findings from the CENTAUR study.

The findings were published in The New England Journal of Medicine.

“Oral, fixed-dose coformulation of the compounds sodium phenylbutyrate and taurursodiol (also known as tauroursodeoxycholic acid) was designed to reduce neuronal death in persons with ALS by simultaneously mitigating endoplasmic reticulum stress and mitochondrial dysfunction,” the researchers wrote. “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 ALS are not known.”

Sabrina Paganoni, MD, of the Sean M. Healey and AMG Center for ALS and the Neurological Clinical Research Institute at Massachusetts General Hospital and Spaulding Rehabilitation Hospital at Harvard Medical School, and colleagues conducted a multicenter, randomized, double-blind trial. The researchers enrolled participants with confirmed ALS who had experienced symptom onset within the preceding 18 months.

Paganoni and colleagues randomly assigned participants in a 2:1 ratio to receive sodium phenylbutyrate–taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol) once per 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 week 24. Secondary outcomes included rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels and the slow vital capacity; time to death, tracheostomy or permanent ventilation; and time to death, tracheostomy, permanent ventilation or hospitalization.

Of 177 patients with ALS screened for eligibility, 137 enrolled in the trial. More participants were randomly assigned to receive sodium phenylbutyrate–taurursodiol (n = 89) compared with placebo (n = 48).

Most patients were men in both the sodium phenylbutyrate–taurursodiol (70%) and placebo (67%) groups. Almost all participants in both groups were white (94% and 96%, respectively). Mean age was 57.6 (± 10.4) years in the sodium phenylbutyrate–taurursodiol group and 57.3 (± 7.6) years in the placebo group.

According to Paganoni and colleagues, most participants (77%) received treatment with riluzole or edaravone at the time of, or prior to, trial entry, with 28% of participants receiving both agents. More participants in the placebo group (50%) received treatment with edaravone at the time of, or prior to, trial entry than in the sodium phenylbutyrate taurursodiol group (25%). A greater percentage of patients in the sodium phenylbutyrate taurursodiol group had bulbar-onset ALS (30% vs. 21%).

The researchers observed estimated mean rates of change in the ALSFRS-R total score among the modified intention-to-treat population of 1.24 points per month for patients receiving sodium phenylbutyrate–taurursodiol and 1.66 points per month for patients receiving placebo (difference, 0.42 points per month; 95% CI, 0.03-0.81). The post hoc intention-to-treat analysis, which included all 137 participants who were randomized, generated results like those seen in the modified intention-to-treat analysis.

In a sensitivity analysis, a correction for the use of edaravone produced results in the same direction of the results of the primary analysis, but demonstrated an estimated between-group difference in week 24 ALSFRS-R total scores of 2.15 points (95% CI, 0.05 to 4.35). A sensitivity analysis that corrected for use of riluzole resulted in an estimated between-group difference in week 24 ALSFRS-R total scores of 2.34 points (95% CI, 0.19-4.48). In exploratory analyses, ALSFRS-R subdomain scores did not differ significantly between the groups, except for the fine-motor subscore.

Secondary outcomes did not differ significantly between the groups, according to Paganoni and colleagues.

Almost all participants in both groups (97% in the sodium phenylbutyrate–taurursodiol group and 96% in the placebo group) experienced one or more adverse events during the trial. Events occurring at 2% or greater frequency in the sodium phenylbutyrate–taurursodiol group were mainly gastrointestinal and included diarrhea, nausea, salivary hypersecretion and abdominal discomfort; all of these events, except for salivary hypersecretion, are known to be associated with taurursodiol.

“In our trial, treatment of ALS with sodium phenylbutyrate–taurursodiol resulted in a slower decline in the ALSFRS-R total score over a period of 24 weeks. Between-group differences in secondary outcomes were not significant,” the researchers wrote. “Participants who received sodium phenylbutyrate–taurursodiol were more likely than those who received placebo to discontinue the trial regimen owing to adverse events and to have early gastrointestinal adverse events. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”