Early and sustained increase in serum TTR levels by acoramidis independently predicted improved survival in the ATTRibute-CM study- BridgeBio Pharma

BridgeBio Pharma Inc. published data showing that an early, sustained increase in serum transthyretin (TTR) levels predicted improved survival in ATTRibute-CM, its Phase III  trial of acoramidis in transthyretin amyloid cardiomyopathy (ATTR-CM). These findings were published in Journal of the American College of Cardiology (JACC) in the Special Focus Issue: Amyloid. Acoramidis is a selective, small molecule, orally administered, near-complete (≥90%) TTR stabilizer. These findings further support the thesis that ever better increases in serum TTR lead to ever better clinical outcomes and that early elevations in serum TTR are an important prognostic marker to inform treatment selection.

In patients with ATTR-CM, aging or an inherited variant can cause tetrameric TTR to destabilize and misfold, causing buildup of amyloid fibrils in the organs, specifically in the heart. These data demonstrate that by using acoramidis, a selective near-complete TTR stabilizer to bind serum TTR, a rapid and sustained increase in tetrameric TTR was independently associated with an improvement in overall survival, even after adjustment for known predictors like TTR variant status, baseline New York Heart Association (NYHA) functional class, baseline National Amyloidosis Centre (NAC) stage, and baseline serum TTR levels.  Findings from the analysis included:

• Treatment with acoramidis resulted in a sharp, significant early rise in serum TTR levels (mean 9.1 mg/dL) within 28 days which was sustained throughout the 30-month treatment period
• For every 5-mg/dL increase in serum TTR level, the Cox proportional hazards model predicted a relative risk reduction of mortality of 26.6% and the logistic model predicted a relative reduction of 31.6% in odds of death till Month 30
• An early increase in serum TTR levels on Day 28 of dosing was associated with reduced all-cause mortality (ACM) in univariate analysis, an association which persisted in multivariate analysis independent of TTR variant status, baseline NYHA functional class, baseline NAC stage, and baseline serum TTR levels
• Logistic modeling demonstrated that among participants treated with acoramidis, the early increase in serum TTR was associated with reduced ACM, whereas there was no prompt and sustained increase in serum TTR observed in participants treated with placebo
• Causal mediation analysis showed evidence that the acoramidis treatment effect on ACM probability at month 30 was fully mediated by the observed prompt and sustained increase in serum TTR

Data from 42 months sustained treatment in the open-label extension study from ATTRibute-CM showed that rapid and sustained TTR stabilization from acoramidis demonstrated statistically significant reductions in both ACM and cardiovascular-related hospitalizations (CVH, which included urgent outpatient treatment for heart failure exacerbations). The continued curve separation of the composite endpoint of ACM and CVH emphasizes the importance of early and continuous treatment resulting in early and sustained clinical benefits. These data further underscore the hypothesis that ever better levels of stabilization lead to ever better clinical outcomes and emphasizes the importance of a prognostic biomarker, serum TTR, to inform decision making for patient care.

"This landmark analysis adds an incredibly important proof point to acoramidis’s repository of compelling data that higher serum TTR levels are directly correlated with and mediate a reduction in mortality risk.” said Dr. Jonathan Fox, Chief Medical Officer of BridgeBio Cardiorenal. “We believe that this will be an important measure for physicians treating ATTR-CM to consider and will be encouraging information for new and existing patients when reviewing options to treat their condition.”

 “Patients with ATTR-CM have progressive amyloid accumulation in the heart, which when untreated manifests as progressive heart failure, arrhythmias, and eventually can result in death. Increases in serum TTR seen with acoramidis therapy within 28 days of initiation and that were sustained with therapy, were associated with a decrease in all-cause mortality independent of baseline risk among subjects in the ATTRibute-CM trial. The increase in serum TTR is hypothesized to be due to a leftward shift in amyloidogenic TTR to a more stable tetrameric TTR. This is the first concrete evidence that there is a link between this rapid increase in serum TTR and survival. Such data may inform clinical practice, as early and sustained increases in serum TTR could represent a new potential ATTR disease-specific and prognostic biomarker that may further inform clinical decisions in optimizing care for ATTR-CM patients,” said Dr.  Mathew Maurer, of Columbia University Irving Medical Center.

Citation- Maurer M, Judge  D, Gillmore, J. et al. Early Increase in Serum Transthyretin by Acoramidis Independently Predicts Improved Survival in TTR Amyloid Cardiomyopathy. J Am Coll Cardiol. 2025  85 :1911 https://doi.org/10.1016/j.jacc.2025.03.542