Oral Therapy for the Treatment of Transthyretin-Related Amyloid Cardiomyopathy

Abstract

The care of systemic amyloidosis has improved dramatically due to improved awareness, accurate diagnostic tools, the development of powerful prognostic and companion biomarkers, and a continuous flow of innovative drugs, which translated into the blooming of phase 2/3 interventional studies for light chain (AL) and transthyretin (ATTR) amyloidosis. The unprecedented availability of effective drugs ignited great interest across various medical specialties, particularly among cardiologists who are now recognizing cardiac amyloidosis at an extraordinary pace. In all amyloidosis referral centers, we are observing a substantial increase in the prevalence of wild-type transthyretin (ATTRwt) cardiomyopathy, which is now becoming the most common form of cardiac amyloidosis. This review focuses on the oral drugs that have been recently introduced for the treatment of ATTR cardiac amyloidosis, for their ease of use in the clinic. They include both old repurposed drugs or fit-for-purpose designed compounds which bind and stabilize the TTR tetramer, thus reducing the formation of new amyloid fibrils, such as tafamidis, diflunisal, and acoramidis, as well as fibril disruptors which have the potential to promote the clearance of amyloid deposits, such as doxycycline. The development of novel therapies is based on the advances in the understanding of the molecular events underlying amyloid cardiomyopathy.

Keywords: ATTR amyloidosis; amyloid cardiomyopathy; amyloidosis; cardiac amyloidosis; emerging therapies; oral therapies; transthyretin.

Figure 1

Current and emerging therapies for the treatment of ATTR amyloidosis. Transthyretin, which is mainly synthesized by liver, the retinal pigment epithelium, and the choroid plexus, circulate in body fluids as a homotetramer (crystallographic structure of PDB 2ROX). The rate-limiting step for TTR amyloid formation is TTR tetramer dissociation (unequal arrows denote that the thermodynamic equilibrium is shifted towards TTR tetramers rather than monomeric units), followed by partial denaturation of TTR monomer, leading to aggregation and amyloid formation. Ligands (including the physiologic ligand T₄) stabilize TTR tetramers. Pathogenic mutations associated with the development of hereditary ATTR amyloidosis (ATTRv) can favor tetramer dissociation, monomer misfolding, or both. Current and emerging therapeutic approaches against ATTR amyloidosis include orthotopic liver transplantation, TTR tetramer stabilizers, TTR gene editing, TTR gene knockdown, and agents aimed at disrupting amyloid fibrils or favoring amyloid clearance. Pharmacologic therapies include drugs administered through the oral (red) or the parenteral route (blue). TUDCA: tauroursodeoxycholic acid.