Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy.
BACKGROUND Transthyretin (TTR) amyloidosis (ATTR) is an under diagnosed disease caused by destabilization of TTR due to pathogenic mutations or aging. Both pathogenic and protective mutations illuminate mechanisms of disease and potential interventions. AG10 is a selective, oral TTR stabilizer under development for ATTR cardiomyopathy (ATTR CM) that mimics a protective TTR mutation. OBJECTIVES This randomized, double blind, placebo controlled study evaluated safety, tolerability, pharmacokinetics and pharmacodynamics of AG10 in ATTR CM patients with symptomatic, chronic heart failure. METHODS ATTR CM, NYHA Class II III subjects (n 49, mutant or wild type) were randomized 1:1:1 to AG10 400mg, 800mg or placebo bid for 28 days. Safety and tolerability were assessed by clinical and laboratory criteria. AG10 plasma levels were measured. TTR stability was assessed by changes in serum TTR and two established ex vivo assays (Fluorescent Probe Exclusion [FPE] and Western blot) RESULTS AG10 treatment was well tolerated, achieved target plasma concentrations and demonstrated near complete stabilization of TTR. TTR stabilization was more complete and less variable at the higher dose with stabilization by FPE of 92 10% (mean+ SD) at trough and 96 9% at peak (both p<10 12 vs placebo) Average serum TTR increased by 36 21% and 51 38% at 400 mg and 800 mg respectively (both p<0.0001 vs placebo) Baseline serum TTR in treated subjects was below normal in 80% of mutant and 33% of wild type subjects. AG10 treatment restored serum TTR to the normal range in all subjects. CONCLUSIONS AG10 has the potential to be a safe and effective treatment for patients with ATTR CM. A Phase 3 trial is planned.
Journal of the American College of Cardiology