Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis
Sabrina Paganoni, Eric A Macklin, Suzanne Hendrix, James D Berry, Michael A Elliott, Samuel Maiser, Chafic Karam, James B Caress, Margaret A Owegi, Adam Quick, James Wymer, Stephen A Goutman, Daragh Heitzman, Terry Heiman-Patterson, Carlayne E Jackson, Colin Quinn, Jeffrey D Rothstein, Edward J Kasarskis, Jonathan Katz, Liberty Jenkins, Shafeeq Ladha, Timothy M Miller, Stephen N Scelsa, Tuan H Vu, Christina N Fournier, Jonathan D Glass, Kristin M Johnson, Andrea Swenson, Namita A Goyal, Gary L Pattee, Patricia L Andres, Suma Babu, Marianne Chase, Derek Dagostino, Samuel P Dickson, Noel Ellison, Meghan Hall, Kent Hendrix, Gale Kittle, Michelle McGovern, Joseph Ostrow, Lindsay Pothier, Rebecca Randall, Jeremy M Shefner, Alexander V Sherman, Eric Tustison, Prasha Vigneswaran, Jason Walker, Hong Yu, James Chan, Janet Wittes, Joshua Cohen, Justin Klee, Kent Leslie, Rudolph E Tanzi, Walter Gilbert, Patrick D Yeramian, David Schoenfeld, Merit E Cudkowicz, Sabrina Paganoni, Eric A Macklin, Suzanne Hendrix, James D Berry, Michael A Elliott, Samuel Maiser, Chafic Karam, James B Caress, Margaret A Owegi, Adam Quick, James Wymer, Stephen A Goutman, Daragh Heitzman, Terry Heiman-Patterson, Carlayne E Jackson, Colin Quinn, Jeffrey D Rothstein, Edward J Kasarskis, Jonathan Katz, Liberty Jenkins, Shafeeq Ladha, Timothy M Miller, Stephen N Scelsa, Tuan H Vu, Christina N Fournier, Jonathan D Glass, Kristin M Johnson, Andrea Swenson, Namita A Goyal, Gary L Pattee, Patricia L Andres, Suma Babu, Marianne Chase, Derek Dagostino, Samuel P Dickson, Noel Ellison, Meghan Hall, Kent Hendrix, Gale Kittle, Michelle McGovern, Joseph Ostrow, Lindsay Pothier, Rebecca Randall, Jeremy M Shefner, Alexander V Sherman, Eric Tustison, Prasha Vigneswaran, Jason Walker, Hong Yu, James Chan, Janet Wittes, Joshua Cohen, Justin Klee, Kent Leslie, Rudolph E Tanzi, Walter Gilbert, Patrick D Yeramian, David Schoenfeld, Merit E Cudkowicz
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.).
Copyright © 2020 Massachusetts Medical Society.
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Source: PubMed