Abstract 18049: Mathematical Modeling Predicts Treatment Efficacy in Transthyretin Cardiac Amyloidosis

Abstract

Introduction: Increased recognition of transthyretin cardiac amyloidosis (ATTR-CA) led to the development of treatments with different therapeutic targets. Optimal patient selection, treatment choice, timing and duration remain unclear. We evaluated the efficacy and timing of common and emerging ATTR-CA treatments with a mathematical model based on therapeutic mechanisms. Methods: We developed a system of ordinary differential equations describing transthyretin amyloid (ATTR) deposition and myocardial clearance by clusterin (Figure 1A,B). Published data and equilibrium analyses determined parameters for initial maximal ATTR density. Mechanisms of four therapies were modeled and simulated at varying levels of efficacy. Complete success of the mechanism defines 100% efficacy, i.e. full stabilization of tetramer. Expected clinical efficacy (ECE) is based on studies of clinical doses. Minimum effective clearance (MEC) is the theoretical efficacy required to reduce ATTR fibrils below the threshold for complete clearance. Results: All treatments reduced ATTR fibril density, correlating with efficacy (Fig 1C). At ECE, only NI006 demonstrated complete clearance of ATTR fibrils. With other current treatment strategies, amyloid density will be lowered but never cleared. The secondary mechanism of diflusinil did not change equilibrium behavior compared to tafamidis. MEC values and time to clearance at MEC were lowest for NI006 (14.7%; 65 days) and doxycycline (16.1%; 36 months). Tetramer stabilization required almost complete efficacy (99.3%) and about a decade (119 months) for tetramer clearance. Conclusion: This mathematical model predicts ATTR clearance by four distinct mechanisms of action. The novel anti-ATTR antibody NI006 is a promising treatment with predicted faster onset and higher effectiveness for clearance of ATTR fibrils from the myocardium. This model can evaluate future treatment strategies and therapeutic targets.