Evaluation of the Current ATTR-CM Treatment Landscape via a Mathematical Model of TTR Dissociation and Amyloid...

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, often fatal disease arising from the dissociation of circulating transthyretin (TTR) tetramers into monomers that misfold and form amyloid fibrils that deposit in the myocardium and other tissues. Approved treatment paradigms involve tetramer stabilization with small molecules or TTR knockdown via RNA interference. Despite the clinical success of these drugs across several metrics (including all-cause mortality and cardiovascular hospitalization), gaps remain in understanding how measurable biological changes, such as differences in serum TTR concentration, translate into reductions in amyloid deposition. To address this, we built a mechanistic mathematical model of the TTR system that integrates heterogeneous data sources, including in vitro assays and clinical data, and recapitulates key features of ATTR-CM disease biology. The model predicts "monomer efflux," the rate at which unfolded monomers could potentially form amyloid, as a proxy for the pathogenic mechanism, which is difficult to measure. Model-predicted monomer efflux linearly correlated with reported rates of change in clinical measures, supporting its validity as a comparative metric. The model showed that monomer efflux is nearly twice as high in hereditary ATTR-CM (ATTRv) as in wild-type ATTR-CM (ATTRwt). Comparison of treatment modalities showed that acoramidis yields the greatest reduction in monomer efflux (96% in ATTRwt, 95% in ATTRv) due to rapid, near-complete stabilization of TTR. This framework enables quantitative interrogation of the disease system and principled comparisons across modalities that may help inform treatment selection.