A Review of Oral Fixed-Dose Sodium Phenylbutyrate and Ursodoxicoltaurine in People with Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is estimated to affect approximately 300,000 individuals worldwide. From symptom onset, the disease has rapid progression, and typically leads to death in approximately 3 years, though there is wide phenotypic variability. ALS pathophysiology is probably driven by several cellular and molecular mechanisms, including endoplasmic reticulum (ER) dysfunction, apoptosis, oxidative stress, impaired intracellular transport, neuroinflammation, and defective RNA metabolism and protein homeostasis. Several agents that target these pathways are in development, and a few are approved in certain regions. A fixed-dose combination of sodium phenylbutyrate and ursodoxicoltaurine (PB and TURSO, also known as AMX0035) was developed to target ER stress and mitochondrial dysfunction. This combination was approved for the treatment of ALS in the USA and Canada in 2022, following findings from the CENTAUR trial. CENTAUR was a Phase II trial comprising a 24-week randomised placebo-controlled phase and an open-label extension (OLE) phase. Treatment with PB and TURSO significantly slowed the rate of functional decline over 24 weeks compared with placebo, meeting the primary endpoint of the study. Over long-term follow-up, median survival duration was about 4.8 months longer in the group originally randomised to PB and TURSO, compared with the group originally randomised to placebo. PHOENIX, a Phase III trial of PB and TURSO planned to be completed in 2024, includes a 48-week randomised controlled phase, followed by an OLE. The PHOENIX trial is expected to provide additional insights regarding the effects of PB and TURSO in ALS.