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

doi:10.1056/NEJMoa1916945

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 JenkinsShafeeq 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

Research output: Contribution to journal › Article › peer-review

310 Scopus citations

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.).

Original language	English
Pages (from-to)	919-930
Number of pages	12
Journal	New England Journal of Medicine
Volume	383
Issue number	10
DOIs	https://doi.org/10.1056/NEJMoa1916945
State	Published - Sep 3 2020

Bibliographical note

Publisher Copyright:
Copyright © 2020 Massachusetts Medical Society.

Funding

Supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. A data sharing statement provided by the authors is available with the full text of this article at NEJM.org. Supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association.

Funders	Funder number
ALS Finding a Cure Foundation
Amylyx Pharmaceuticals, Inc.
NIH Office of the Director	S10OD020007
NIH Office of the Director
Hennepin Faculty Associates Amyotrophic Lateral Sclerosis Association Certified ALS Center
Amylin Pharmaceuticals Incorporated

ASJC Scopus subject areas

General Medicine

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10.1056/NEJMoa1916945

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Paganoni, S., Macklin, E. A., Hendrix, S., Berry, J. D., Elliott, M. A., Maiser, S., Karam, C., Caress, J. B., Owegi, M. A., Quick, A., Wymer, J., Goutman, S. A., Heitzman, D., Heiman-Patterson, T., Jackson, C. E., Quinn, C., Rothstein, J. D., Kasarskis, E. J., Katz, J., ... Cudkowicz, M. E. (2020). Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis. New England Journal of Medicine, 383(10), 919-930. https://doi.org/10.1056/NEJMoa1916945

@article{2a22e33bb9e6497599c29d6a7c0c11d1,

title = "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.).",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2020 Massachusetts Medical Society.",

year = "2020",

month = sep,

day = "3",

doi = "10.1056/NEJMoa1916945",

language = "English",

volume = "383",

pages = "919--930",

number = "10",

}

Paganoni, S, Macklin, EA, Hendrix, S, Berry, JD, Elliott, MA, Maiser, S, Karam, C, Caress, JB, Owegi, MA, Quick, A, Wymer, J, Goutman, SA, Heitzman, D, Heiman-Patterson, T, Jackson, CE, Quinn, C, Rothstein, JD, Kasarskis, EJ, Katz, J, Jenkins, L, Ladha, S, Miller, TM, Scelsa, SN, Vu, TH, Fournier, CN, Glass, JD, Johnson, KM, Swenson, A, Goyal, NA, Pattee, GL, Andres, PL, Babu, S, Chase, M, Dagostino, D, Dickson, SP, Ellison, N, Hall, M, Hendrix, K, Kittle, G, McGovern, M, Ostrow, J, Pothier, L, Randall, R, Shefner, JM, Sherman, AV, Tustison, E, Vigneswaran, P, Walker, J, Yu, H, Chan, J, Wittes, J, Cohen, J, Klee, J, Leslie, K, Tanzi, RE, Gilbert, W, Yeramian, PD, Schoenfeld, D & Cudkowicz, ME 2020, 'Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis', New England Journal of Medicine, vol. 383, no. 10, pp. 919-930. https://doi.org/10.1056/NEJMoa1916945

TY - JOUR

T1 - Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis

AU - Paganoni, Sabrina

AU - Macklin, Eric A.

AU - Hendrix, Suzanne

AU - Berry, James D.

AU - Elliott, Michael A.

AU - Maiser, Samuel

AU - Karam, Chafic

AU - Caress, James B.

AU - Owegi, Margaret A.

AU - Quick, Adam

AU - Wymer, James

AU - Goutman, Stephen A.

AU - Heitzman, Daragh

AU - Heiman-Patterson, Terry

AU - Jackson, Carlayne E.

AU - Quinn, Colin

AU - Rothstein, Jeffrey D.

AU - Kasarskis, Edward J.

AU - Katz, Jonathan

AU - Jenkins, Liberty

AU - Ladha, Shafeeq

AU - Miller, Timothy M.

AU - Scelsa, Stephen N.

AU - Vu, Tuan H.

AU - Fournier, Christina N.

AU - Glass, Jonathan D.

AU - Johnson, Kristin M.

AU - Swenson, Andrea

AU - Goyal, Namita A.

AU - Pattee, Gary L.

AU - Andres, Patricia L.

AU - Babu, Suma

AU - Chase, Marianne

AU - Dagostino, Derek

AU - Dickson, Samuel P.

AU - Ellison, Noel

AU - Hall, Meghan

AU - Hendrix, Kent

AU - Kittle, Gale

AU - McGovern, Michelle

AU - Ostrow, Joseph

AU - Pothier, Lindsay

AU - Randall, Rebecca

AU - Shefner, Jeremy M.

AU - Sherman, Alexander V.

AU - Tustison, Eric

AU - Vigneswaran, Prasha

AU - Walker, Jason

AU - Yu, Hong

AU - Chan, James

AU - Wittes, Janet

AU - Cohen, Joshua

AU - Klee, Justin

AU - Leslie, Kent

AU - Tanzi, Rudolph E.

AU - Gilbert, Walter

AU - Yeramian, Patrick D.

AU - Schoenfeld, David

AU - Cudkowicz, Merit E.

PY - 2020/9/3

Y1 - 2020/9/3

N2 - 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.).

AB - 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.).

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SN - 0028-4793

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EP - 930

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 10

ER -

Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis

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