Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis

Sabrina Paganoni, Suzanne Hendrix, Samuel P. Dickson, Newman Knowlton, Eric A. Macklin, James D. Berry, Michael A. Elliott, Samuel Maiser, Chafic Karam, James B. Caress, Margaret Ayo Owegi, Adam Quick, James Wymer, Stephen A. Goutman, Daragh Heitzman, Terry D. Heiman-Patterson, Carlayne E. Jackson, Colin Quinn, Jeffrey D. Rothstein, Edward J. KasarskisJonathan 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, Meghan Hall, Gale Kittle, Matthew Eydinov, Michelle McGovern, Joseph Ostrow, Lindsay Pothier, Rebecca Randall, Jeremy M. Shefner, Alexander V. Sherman, Maria E. St Pierre, Eric Tustison, Prasha Vigneswaran, Jason Walker, Hong Yu, James Chan, Janet Wittes, Zi Fan Yu, Joshua Cohen, Justin Klee, Kent Leslie, Rudolph E. Tanzi, Walter Gilbert, Patrick D. Yeramian, David Schoenfeld, Merit E. Cudkowicz

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P =.023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.

Original languageEnglish
Pages (from-to)31-39
Number of pages9
JournalMuscle and Nerve
Volume63
Issue number1
DOIs
StatePublished - Jan 2021

Bibliographical note

Funding Information:
The authors thank the individuals who participated in the CENTAUR and open-label extension trials as well as their caregivers and families. We also thank Steve Kolb and the late Stephen Winthrop, who brought the voices of caregivers for persons with ALS and persons with ALS, respectively, to this trial as members of the Steering Committee; the Partners Human Research Committee, for serving as the single institutional review board of record for the study; the medical monitor, Dr Anne-Marie Wills; data and safety monitoring board members, Dr Lorne Zinman and Dr Myles Keroack; and the CENTAUR coordination center and trial site staff (see Appendix online). This analysis was funded by Amylyx Pharmaceuticals, Inc, the ALS Finding A Cure Foundation, and The ALS Association. Lara Primak, MD, and Dipanwita Ghose, MS, PhD, of PRECISIONScientia provided medical writing assistance with the development and revision of the manuscript under the direction of the authors, with financial support from Amylyx and in compliance with international Good Publication Practice guidelines.

Funding Information:
S. Paganoni reports grants from Amylyx Pharmaceuticals, Inc, The ALS Association, and ALS Finding A Cure during the conduct of the study, and grants from Revalesio, Ra Pharma, Biohaven, Clene Nanomedicine, and Prilenia, outside the submitted work. S. Hendrix reports other personal fees from Pentara Corporation, outside the submitted work. S.P. Dickson reports other personal fees from Pentara outside the submitted work. E.A. Macklin reports grants from Amylyx, The ALS Association, and ALS Finding A Cure Foundation during the conduct of the study. He is also a data and safety monitoring board member (DSMB) and reports grants from Acorda Therapeutics; steering committee membership for Biogen; consultant work for Cerevance; grants from GlaxoSmithKline; consultant work for Inventram, Lavin Consulting, and Myolex; grants from Mitsubishi Tanabe Pharmaceuticals; and DSMB membership for Novartis Pharmaceuticals and Shire Human Genetic Therapies, outside the submitted work. J.D. Berry reports grants from ALS Finding A Cure, The ALS Association, and Amylyx during the conduct of the study; personal fees from Biogen and Clene Nanomedicine; and grants from Alexion, Biogen, MT Pharma of America, Anelixis Therapeutics, Brainstorm Cell Therapeutics, Genentech, nQ Medical, National Institute of Neurological Disorders and Stroke, and the Muscular Dystrophy Association, outside the submitted work. M.A. Elliott has received personal fees from Amylyx and personal fees from Biogen. C. Karam reports grants and personal fees from Akcea, Alnylam, and Genzyme, and personal fees from Acceleron, Biogen, Alexion, Argenx, Cytokinetics, and CSL Behring, outside the submitted work. J.B. Caress reports grants from Amylyx during the conduct of the study, and grants from Orion Pharmaceuticals, MTB Pharma, and Cytokinetics, outside the submitted work. J. Wymer reports grants from Amylyx during the conduct of the study. S.A. Goutman reports grants from The ALS Association during the conduct of the study; grants from the National Institutes of Health/National Institutes of Environmental Health Sciences, The ALS Association, and Target ALS, outside the submitted work; consultant work for Biogen and ITF Pharma, outside the submitted work; and personal fees from Biogen, ITF Pharma, Watermark Research Partners, and for expert testimony, outside the submitted work. T.D. Heiman‐Patterson reports grants from Mitsubishi Tanabe Pharma America, Amylyx Pharmaceuticals, The ALS Association, and Orion Pharma, and personal fees from Cytokinetics, ITF, and Biohaven, outside the submitted work. C.E. Jackson reports grants from Amylyx during the conduct of the study; grants and personal fees from Cytokinetics, personal fees from CSL Behring, grants and personal fees from Mitsubishi Tanabe Pharma America, DSMB membership, and personal fees from Brainstorm and Mallinckrodt during the conduct of this study; and personal fees from ITF Pharma, outside the submitted work. C. Quinn received personal fees for serving on an advisory board of Amylyx, outside the submitted work. J.D. Rothstein reports licensing agreement and nonfinancial support from Ionis Pharmaceuticals; nonfinancial support from Calico, Biogen, and IBM Watson; research grant support from the National Institute of Neurological Disorders and Stroke, National Institute on Aging, Department of Defense, the Chan Zuckerberg Initiative, Microsoft, The ALS Association, the Muscular Dystrophy Association, Target ALS, F Prime, ALS Finding A Cure, Answer ALS, Robert Packard Center for ALS Research, GlaxoSmithKline, Travelers Insurance, American Airlines, Caterpillar, and the National Football League; and personal consulting fees from Expansion Therapeutics and Team Gleason. He also reports that his institution was a trial site and thus had a contract with Amylyx to participate in the study. J. Katz reports personal fees from MT Pharma America, Denali Pharmaceuticals, Genentech, and Calico, outside the submitted work. S. Ladha reports grants from Amylyx, Biogen, and MT Pharma, and personal fees from Amylyx and Biogen. T.M. Miller reports licensing agreement and nonfinancial support from Ionis Pharmaceuticals, a licensing agreement with C2N, grants and personal fees from Biogen, and personal fees from Cytokinetics and Disarm Therapeutics, outside the submitted work. S.N. Scelsa reports grants from Amylyx during the conduct of the study, and grants from Orion Pharma, outside the submitted work. T.H. Vu reports personal fees from the speakers bureau of Mitsubishi Tanabe Pharmaceuticals, and has participated in clinical trials sponsored by Amylyx, Orion, Biogen, Mallinckrodt, and Cytokinetics during the conduct of the study. J.D. Glass reports that his institution was a trial site and thus had a contract from Amylyx to participate in the study. A. Swenson reports research support from Amylyx, The ALS Association, Massachusetts General Hospital, the National Institutes of Health/National Institute of Neurological Disorders and Stroke, and serving on an independent data monitoring committee for Alexion. P.L. Andres reports personal fees from Amylyx for consulting during the conduct of the study and has an isometric strength testing apparatus (US Patent 7493812B2) held by the Hospital Corporation. S. Babu reports research support from the American Academy of Neurology, the AANEM Foundation, The ALS Association, the Muscular Dystrophy Association, Biogen, Orion, Voyager Therapeutics, and Novartis. M. Chase reports grants to the Massachusetts General Hospital (MGH) from The ALS Association, grants to the MGH from ALS Finding A Cure, and fee for service from Amylyx during the conduct of the study. M. Hall reports grants for funding for clinical trial monitoring and outcomes training support from The ALS Association and Amylyx during the conduct of the study. G. Kittle reports grants from The ALS Association and Amylyx during the conduct of the study. J.M. Shefner reports grants and personal fees from Amylyx during the conduct of the study; personal fees for consulting work from Cytokinetics and Brainstorm; grants and personal fees for outcomes training and study design from Mitsubishi Pharma America, outside the submitted work; personal fees for consulting from Neurosense and Otsuka, outside the submitted work; and grants for outcomes training from Alexion, Medicinova, and Biogen, outside the submitted work. He is also Neuromuscular section editor for UpToDate. J. Wittes and Z.‐F. Yu report payments from Amylyx to their employer during the conduct of the study. J. Cohen and J. Klee report a relationship with Amylyx during the conduct of the study, and they serve as co‐CEOs of Amylyx, outside the submitted work, with multiple patents issued to Amylyx. K. Leslie reports being full‐time employee of Amylyx during the conduct of the study, and personal fees from Amylyx, outside the submitted work. R.E. Tanzi reports personal fees from Amylyx outside the submitted work; has helped with inception and design of the clinical trial but was not involved with running the trial and had no contact with the trial subjects; and owns founding equity in Amylyx and serves as head of the company's scientific advisory board. W. Gilbert was director of Amylyx during the conduct of the study and a company shareholder. P.D. Yeramian reports full‐time employment at Amylyx during the conduct of the study. D. Schoenfeld reports grants from The ALS Association, during the conduct of the study, and personal fees from Immunitypharma and Alexion, outside the submitted work. M.E. Cudkowicz reports grants from Massachusetts General Hospital during the conduct of the study; grants from Clene Nanomedicine, Ra Pharma, Biohaven, and Prilenia, outside the submitted work; and personal fees from Takeda, Biogen, Sunovian, Cytokinetics, and Immunity Pharma, outside the submitted work. The remaining authors declare no potential conflicts of interest.

Funding Information:
The authors thank the individuals who participated in the CENTAUR and open‐label extension trials as well as their caregivers and families. We also thank Steve Kolb and the late Stephen Winthrop, who brought the voices of caregivers for persons with ALS and persons with ALS, respectively, to this trial as members of the Steering Committee; the Partners Human Research Committee, for serving as the single institutional review board of record for the study; the medical monitor, Dr Anne‐Marie Wills; data and safety monitoring board members, Dr Lorne Zinman and Dr Myles Keroack; and the CENTAUR coordination center and trial site staff (see Appendix online). This analysis was funded by Amylyx Pharmaceuticals, Inc, the ALS Finding A Cure Foundation, and The ALS Association. Lara Primak, MD, and Dipanwita Ghose, MS, PhD, of PRECISIONScientia provided medical writing assistance with the development and revision of the manuscript under the direction of the authors, with financial support from Amylyx and in compliance with international Good Publication Practice guidelines.

Publisher Copyright:
© 2020 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.

Keywords

  • CENTAUR
  • amyotrophic lateral sclerosis
  • motor neuron disease
  • sodium phenylbutyrate-taurursodiol
  • survival analysis

ASJC Scopus subject areas

  • Physiology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Physiology (medical)

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