Relationship of tafamidis binding site occupancy, transthyretin stabilization, and disease modification in tafamidis treated transthyretin amyloid cardiomyopathy patients

Abstract Introduction Tafamidis inhibits progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) by binding TTR tetramer and inhibiting its dissociation to monomers which can denature and result in amyloid fibril formation and deposition in cardiac tissue. Purpose While the phase 3 ATTR-ACT clinical data clearly demonstrated efficacy, quantification of TTR stabilization in patients and the degree to which the approved dose captures the full potential of the mechanism has yet to be assessed. Methods Isothermal titration calorimetry and subunit fraction exchange were used to determine affinities to the two binding sites on TTR. These values were used to develop a model of tafamidis binding to TTR in plasma that was applied to individual patient data to calculate TTR binding site occupancy and the change in total TTR levels induced by TTR stabilization. Population pharmacodynamic (PD) models were developed for three measures of disease progression, plasma NT-proBNP levels, Kansas City Cardiomyopathy Questionnaire – Overall Score (KCCQ-OS), and six-minute walk test (6MWT) distance, to evaluate patient response with the degree of TTR occupancy. Results In vitro binding data of wild-type TTR confirmed tafamidis binds two sites of TTR with negative cooperativity and provided precise estimates of the binding affinity to TTR and albumin. Modeling individual patient data of tafamidis exposure and increased TTR plasma levels using the in vitro derived binding affinity values confirms single site binding is consistent with complete tetramer stabilization. Patients given 80 mg tafamidis meglumine, the clinically approved dose for ATTR-CM, had a 92% reduction in unbound, unstabilized TTR, which correlated with a 53% decrease in NT-proBNP elevation, a 56% decrease in KCCQ-OS worsening and a 49% reduced decline in the 6MWT. For 100% receptor occupancy and stabilization, the expected effects on these measures are 58%, 61%, and 54% for NT-proBNP, KCCQ-OS, and 6MWT, respectively. Conclusions These results demonstrate a quantitative relationship between TTR stabilization, the mechanism of action of tafamidis, and accepted laboratory and patient-based outcomes in ATTR-CM. These results also support the value of TTR stabilization as a clinically beneficial treatment option which maintains the protein in its physiologically active form within the body. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Pfizer.