Journal Article

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

Methven Jeknić, Stevan, Ji, Sun‐Gou, Ji, Alan X., Ju, Jin Hyun, Sinha, Uma, Ahn‐Horst, Travis A., Paull, Morgan

2026

Overview

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. Study Highlights What is the current knowledge on the topic? ○Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a progressive cardiomyopathy driven by dissociation of circulating transthyretin tetramers into monomers that can misfold and form amyloid fibrils. Approved therapies improve outcomes via two paradigms: small molecule tetramer stabilization and hepatic transthyretin knockdown. What question did this study address? ○We built a quantitative model that can assess how different therapeutic approaches translate to reductions in amyloid formation and explain how physiological factors can play a role in disease state and biomarkers such as circulating transthyretin. What does this study add to our knowledge? ○We utilized a quantitative systems pharmacology approach, integrating in vitro, ex vivo, and clinical data across multiple genotypes and pharmaceutical interventions to develop a unified mathematical model. The model quantifies “monomer efflux” as a proxy for amyloidogenic potential. We showed that monomer efflux predictions are correlated with rates of change in clinical outcomes such as 6‐minute walk distance, Kansas City Cardiomyopathy Questionnaire Overall Summary score, and N‐terminal pro‐B‐type natriuretic peptide levels. We utilized the model and monomer efflux predictions to quantify the effect of renal monomer loss rate in modulating disease severity and treatment responses. Additionally, the model provides a comparison of treatment modalities under a common mechanistic framework. How might this change drug discovery, development, and/or therapeutics? ○The framework offers a mechanistic basis for evaluating therapeutic strategies in ATTR‐CM by quantifying the effect of distinct interventions on model‐predicted monomer efflux and serum transthyretin. This can support candidate evaluation and therapeutic choice, for example, by contextualizing changes in serum transthyretin concentration with changes in potential disease severity.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Amyloid - metabolism / Amyloid Neuropathies, Familial - drug therapy / Amyloid Neuropathies, Familial - metabolism / Binding sites / biomarkers / cardiology / Cardiomyopathies - drug therapy / Cardiomyopathies - metabolism / Cardiomyopathy / Clinical trials / Humans / mathematical modeling / mechanism‐based pharmacokinetics‐pharmacodynamics / Models, Biological / Models, Theoretical / Optimization / Ordinary differential equations / pharmacometrics / Physiology / Prealbumin - genetics / Prealbumin - metabolism / Proteins / Sensitivity analysis / systems pharmacology