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.
View details for PubMedID 30885685