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

Abstract

An orally administered, fixed-dose coformulation of sodium phenylbutyratetaurursodiol (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 followup 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 CEN-TAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.

The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS

“…Therefore, compounds acting against neuroinflammation can also show efficacy. Some interesting options are: a) masitinib, a tyrosine kinase inhibitor, which is predicted to work by decreasing microglia-induced inflammation of MNs in the brain and spinal cord [146] (NCT02588677); b) a combination of sodium phenylbutyrate and tauroursodeoxycholic acid (AMX0035), which may limit cell death and neuroinflammation (NCT03127514, NCT03488524, NCT04516096) [147], and c) cyclic nucleotide phosphodiesterase (PDE) inhibitors to prevent glial cell activation (e.g., ibudilast, NCT02238626 IBU-ALS-1201, NCT04057898 COMBAT-ALS). Interestingly, ibudilast also enhances the autophagy-mediated clearance of ALS-associated TAR DNA-binding SOD1 and TDP-43 aggregates [148].…”

Role of the HSP70 Co-Chaperone SIL1 in Health and Disease

“…4-Phenylbutyrate (PBA) and tauroursodeoxycholic acid (TUDCA) are hydrophobic chemical chaperones whose proposed mechanisms of action involve their ability to interact with exposed hydrophobic regions in misfolded or unfolded proteins. Both of these chemical entities are orally bioavailable, have reasonable blood-brain barrier permeability with a no-to-low toxicity profile [112,113], have been used successfully in preclinical models for protein folding diseases [114,115], and are currently being evaluated in clinical trials for ALS [112,113,116,117]. Although plasma cell differentiation and antibody production are not dependent on SIL1 [75], MSS-derived LBLs that are deficient for SIL1 were more prone to cell death than normal controls when treated with tunicamycin, an ER stressor [118].…”

The Role of PERK in Understanding Development of Neurodegenerative Diseases

“…In addition, recent reporting from a phase II double-blind placebo-controlled trial, the CENTAUR trial, shows the potential of targeting the ER stress pathway for the treatment of neurodegenerative diseases [ 115 , 116 ]. The CENTAUR trial tested the combination of sodium phenylbutyrate and taurursodiol in ALS patients.…”

“…Taurursodiol, also known as tauroursodeoxycholic acid helps to prevents apoptosis due to its role in the BAX pathway by preventing translocation of the BAX protein into the mitochondria [ 119 ]. The trial showed slowing of functional decline and increased survival in ALS patients, but longer and larger trials are necessary to further verify the efficacy of this combination [ 115 , 116 ]. These results are very encouraging and support drug development for neurodegeneration by manipulating the ER stress pathway.…”