Abstract
Objective: Safety and tolerability of an oral, fixed-dose sodium phenylbutyrate/taurursodiol (PB/TURSO) coformulation were assessed in phase 2 trials in amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD). Background: PB/TURSO was designed to reduce neurodegeneration by targeting endoplasmic reticulum and mitochondrial stress, both implicated in the pathophysiology of ALS and AD. Design/Methods: In the AMX-3500 Study (CENTAUR) in ALS, participants (PB/TURSO, n=89; placebo, n=48) completing the 24-week randomized phase (NCT03127514) were eligible to enroll in an open-label extension (OLE) phase (NCT03488524) and receive PB/TURSO (≤132 weeks, week 24 reported). Study AMX-8000 (PEGASUS; NCT03533257) was a 24-week randomized trial in adults with AD or mild cognitive impairment (PB/TURSO, n=51; placebo, n=44). PB/TURSO safety and tolerability was the primary objective of both trials. Results: Mean (SD) ages were 57.7 (9.6) and 70.7 (7.5) years in CENTAUR and PEGASUS, respectively. Treatment-emergent adverse event (TEAE) incidence was similar between groups in the CENTAUR randomized phase (PB/TURSO, 97%; placebo, 96%); 77% reported ≥1 TEAEs in the OLE phase. In PEGASUS, TEAEs occurred in 67% and 59% of the PB/TURSO and placebo groups, respectively. Gastrointestinal TEAEs were more frequent during initial PB/TURSO exposure (week ≤3) in CENTAUR and accounted for the predominance of PB/TURSO-related TEAEs in PEGASUS. Incidence of cardiac events with PB/TURSO was low (CENTAUR, 8%; PEGASUS, 4%), and in both studies, electrocardiographic findings were similar between groups at baseline, with no clinically meaningful changes observed over the course of treatment. Conclusions: These findings support the PB/TURSO safety profile in ALS and AD. TEAE incidence was generally similar between PB/TURSO and placebo in both trials. PB/TURSO-associated TEAEs were mostly gastrointestinal, consistent with the known profiles for PB and TURSO. Findings in AD further elucidate the PB/TURSO safety profile, as TEAEs in CENTAUR appear to have been largely disease driven. An updated safety analysis (pooled and OLE data) will be presented.