Transthyretin Kinetic Stabilizers for ATTR Amyloidosis: A Narrative Review of Mechanisms and Therapeutic Benefits.

Transthyretin amyloidosis (ATTR amyloidosis) is a systemic disease affecting multiple organ systems, particularly the heart and peripheral nervous system. Decades of research suggest the disease is caused by the dissociation, misfolding, and aggregation of transthyretin (TTR), resulting in extracellular deposition of amyloid fibrils in tissue and organs. If untreated, ATTR amyloidosis leads to substantial functional impairment, quality-of-life burden, and mortality. Because dissociation of the TTR tetramer is rate-limiting for aggregation and amyloid fibril formation, small molecules that bind to and stabilize the natively folded tetramer of TTR have been developed. Subunit exchange experiments demonstrated that tafamidis and acoramidis effectively slow TTR tetramer dissociation and aggregation in plasma at concentrations achieved with approved oral doses in patients with ATTR amyloidosis. In randomized controlled clinical trials, these TTR kinetic stabilizers have significantly reduced cardiomyopathy progression and improved quality of life in patients with variant or wild-type disease (tafamidis is also approved to slow polyneuropathy progression). Current availability of two kinetic stabilizers has increased interest in their pharmacological properties and clinical effects, including potential similarities and disparities. In this review, the mechanisms involved in TTR kinetic stabilization are summarized with preclinical and clinical study findings on the use of the kinetic stabilizers tafamidis and acoramidis.