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Sodium Phenylbutyrate and Tauroursodeoxycholic Acid: A Story of Hope Turned to Disappointment in Amyotrophic Lateral Sclerosis Treatment

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Abstract

The absence of a definitive cure for amyotrophic lateral sclerosis (ALS) emphasizes the crucial need to explore new and improved treatment approaches for this fatal, progressive, and disabling neurodegenerative disorder. As at the end of 2023, five treatments – riluzole, edaravone, dextromethorphan hydrobromide + quinidine sulfate (DHQ), tofersen, and sodium phenylbutyrate-tauroursodeoxycholic acid (PB-TUDCA) – were FDA approved for the treatment of patients with ALS. Among them PB-TUDCA has been shown to impact DNA processing impairments, mitochondria dysfunction, endoplasmic reticulum stress, oxidative stress, and pathologic folded protein agglomeration defects, which have been associated with ALS pathophysiology. The Phase 2 CENTAUR trial demonstrated significant impact of PB-TUDCA on the ALS Functional Rating Scale-Revised (ALSFRS-R) risk of death, hospitalization, and the need for tracheostomy or permanent assisted ventilation in patients with ALS based on post hoc analyses. More recently, contrasting with the CENTAUR trial results, results from the Phase 3 PHOENIX trial (NCT05021536) showed no change in ALSFRS-R total score at 48 weeks. Consequently, the sponsor company initiated the process with the US FDA and Health Canada to voluntarily withdraw the marketing authorizations for PB-TUDCA. In the present article, we review ALS pathophysiology, with a focus on PB-TUDCA’s proposed mechanisms of action and recent clinical trial results and discuss the implications of conflicting trial data for ALS and other neurological disorders.

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Authors and Affiliations

  1. NextGen Precision Health, University of Missouri, 1030 Hitt St., Columbia, MO, 65211, USA

    Arsh Ketabforoush & W. David Arnold

  2. Department of Physical Medicine and Rehabilitation, University of Missouri, Columbia, MO, USA

    Arsh Ketabforoush & W. David Arnold

  3. Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran

    Faezeh Faghihi, Fereshteh Azedi & Mohammad Taghi Joghataei

  4. Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran

    Fereshteh Azedi & Mohammad Taghi Joghataei

  5. School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Armin Ariaei & Maryam Khalili

  6. Clinical Research Development Center, Shahid Beheshti Hospital, Qom University of Medical Sciences, Qom, Iran

    Mohamad Amin Habibi

  7. Department of Neurology, Firouzgar Hospital, Iran University of Medical Sciences, Tehran, Iran

    Bahram Haghi Ashtiani

  8. Department of Neurology, University of Missouri, Columbia, MO, USA

    W. David Arnold

  9. Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA

    W. David Arnold

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  1. Arsh Ketabforoush
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WDA: Research Funding from NMD Pharma and Avidity Biosciences, Consulting for NMD Pharma, Avidity Biosciences, Dyne Therapeutics, Novartis, Design Therapeutics, Catalyst Pharmaceuticals, Novartis. Other authors claim that there are no conflicts of interest.

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AK: Research funding from the Missouri Spinal Cord Injury Disease Research Program.

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Ketabforoush, A., Faghihi, F., Azedi, F. et al. Sodium Phenylbutyrate and Tauroursodeoxycholic Acid: A Story of Hope Turned to Disappointment in Amyotrophic Lateral Sclerosis Treatment. Clin Drug Investig (2024). https://doi.org/10.1007/s40261-024-01371-1

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