EVALUATION OF TRANSTHYRETIN TETRAMER STABILIZATION AND TTR PLASMA CONCENTRATIONS IN THE TAFAMIDIS IN TRANSTHYRETIN CARDIOMYOPATHY CLINICAL TRIAL (ATTR-ACT)

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a fatal disease caused by destabilization of the transthyretin (TTR) tetramer resulting in formation of amyloid fibrils that deposit in the heart, leading to heart failure and ultimately death. Tafamidis, a specific stabilizer of TTR, binds to the thyroxine binding sites and inhibits TTR dissociation, the rate limiting step in the amyloidogenic process. In ATTR-ACT, tafamidis significantly reduced all-cause mortality and cardiovascular-related hospitalizations in participants with ATTR-CM. Here, we evaluated the effects of tafamidis 80 mg on TTR stabilization and TTR serum concentrations compared to placebo treated patients. Methods Patient blood samples were collected at baseline and Months 1, 6, 12, 18, 24 and 30. TTR tetramer stability was measured using an immunoturbidimetric assay with urea denaturation. The TTR tetramer plasma level was measured prior to and after urea denaturation. The pre-denaturation TTR level provided the TTR plasma concentration at each time point. Results A significantly greater proportion of participants in the tafamidis 80 mg group (144/164 [87.8%]) demonstrated TTR stabilization at Month 1 than was observed for participants in the placebo group (6/170 [3.5%]) (p <0.0001). The difference in stabilization remained through month 30. Mean TTR serum concentrations increased at Month 1 from baseline and remained elevated throughout the study with tafamidis 80 mg. Tafamidis-treated participants had a mean TTR concentration of 29.21 mg/dL (a 34% increase from baseline) compared to placebo-treated participants with a mean of 21.8 mg/dL at 30 months. Conclusion These results suggest more TTR was conserved in its tetrameric structure and less consumed in the amyloidogenic cascade supporting the robustness of tafamidis as a TTR stabilizer. Tafamidis 80 mg resulted in almost 90% of participants demonstrating TTR stabilization and mean TTR serum levels were consistently elevated over the 30 months of ATTR-ACT. Stabilization of the TTR tetramer is an important consideration in treatment of ATTR-CM allowing for the preservation of functional transthyretin in plasma for normal physiologic activity.