Introduction: The Shifting Paradigm in ATTR-CM Therapy
Transthyretin amyloid cardiomyopathy (ATTR-CM) has transitioned from being considered a rare, terminal condition to a frequently diagnosed cause of heart failure, particularly in the elderly and those with heart failure with preserved ejection fraction (HFpEF). The disease is characterized by the systemic or localized deposition of misfolded transthyretin (TTR) proteins as insoluble amyloid fibrils in the myocardium. This leads to progressive restrictive cardiomyopathy, conduction disturbances, and eventually, death.
Until recently, the therapeutic landscape was dominated by TTR stabilizers, such as tafamidis, which prevent the dissociation of the TTR tetramer into the monomers that form fibrils. While stabilizers and newer TTR silencers (RNA interference or antisense oligonucleotides) have significantly improved survival and reduced hospitalizations, they share a common limitation: they primarily address the production or stability of new TTR proteins without actively removing the amyloid already deposited in the heart. The Coramitug Phase 2 trial represents a critical pivot toward ‘amyloid clearance,’ utilizing a humanized monoclonal antibody to stimulate the body’s own immune system to resolve existing deposits.
