Ratio of sTTR and NT-proBNP Change May Predict Treatment Results in ATTR-CM

A combination of measurements of transthyretin stabilization (sTTR) with a later myocardial stress marker like NT-proBNP creates a biomarker ratio that may predict clinical outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM).¹

These data, from an analysis of the ATTRibute-CM trial, were presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2026 in Phoenix, Arizona, by James Januzzi, MD, chief scientific officer and C. Michael Gibson Chair in Medicine at the Baim Institute for Clinical Research and Adolph Hutter Professor of Medicine at Harvard Medical School.¹

“Acoramidis is an oral therapy used to stabilize transthyretin, and it’s known that treatment with acoramidis leads to an early increase in transthyretin, and it’s known that treatment leads to an early increase in transthyretin concentrations that are actually favorable,” Januzzi told HCPLive in an exclusive interview. “We hypothesized that the increase in transthyretin might predict changes in NT-proBNP later after treatment.”

ATTRibute-CM was a phase 3, randomized, double-blind, placebo-controlled study comparing acoramidis to placebo in ATTR-CM. Patients were eligible for inclusion if they had either wild-type or variant ATTR-CM and a history of heart failure, among other criteria. Patients with acute myocardial infarction, hemodynamic instability, or primary light chain amyloidosis, among other criteria, were excluded.^2,3

A total of 632 patients were enrolled in the study and randomly assigned in a 2:1 ratio to either acoramidis hydrochloride at 800 mg twice daily or matching placebo. Over 30 months, investigators evaluated a 4-step hierarchical analysis of death from any cause, cardiovascular-related hospitalization, change in NT-proBNP from baseline, and change in 6-minute walk distance from baseline.²

This primary analysis ultimately favored acoramidis, with a corresponding win ratio of 1.8 (95% CI, 1.4 to 2.2) and 63.7% of pairwise comparisons favoring acoramidis. All-cause mortality and cardiovascular hospitalization contributed >50% of the wins and losses to the win ratio, while NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses.²

For the present post-hoc evaluation, Januzzi and colleagues used observed biomarker data from the intention-to-treat population to conduct time-to-event analyses. Samples were collected from this population at baseline, day (D)28, and every 3 months (M) from then on; sTTR and NT-proBNP were measured centrally. The team constructed an integrated biomarker ratio of log2-transformed D28 sTTR/log2-transformed M12 NT-proBNP from these data.¹

Of the 632 intention-to-treat patients, 587 had baseline and M30 biomarker values. The mean age among these patients was 77 +/- standard deviation (SD) 7 years. 90% of patients had wild-type ATTR-CM, 72% were New York Heart Association functional class 2, and 59% were National Amyloidosis Centre stage 1. Median sTTR and NT-proBNP were 23 mg/dL and 2324 ng/L, respectively.¹

Early changes in sTTR preceded later changes in NT-proBNP, with the former increasing rapidly by D28 and remaining elevated with acoramidis compared to little change with placebo. NT-proBNP increased to a lesser extent with acoramidis versus placebo. These changes correlated weakly when measured at the same time point, but correlations between D28 sTTR change and later NT-proBNP change were stronger.¹

This ratio was also strongly associated with all-cause mortality and cardiovascular hospitalization risks in M12 landmark analyses. Januzzi and colleagues found that each 0.1-unit increase in the ratio was associated with a 63% lower adjusted risk of these endpoints (HR, 0.37; 95% CI, 0.24 to 0.58; P <.001). The team observed a continuous biomarker-risk gradient, and mediation analyses revealed that the effect of acoramidis treatment on all-cause mortality and cardiovascular hospitalization was associated with an HR of 0.66.¹

Ultimately, Januzzi and colleagues concluded that, while these data may reflect an effective and accurate predictor of cardiovascular risk in ATTR-CM, several potential study limitations may hamper the ratio’s accuracy in real-world practice. To this end, they determined that further research is necessary to fully validate the biological pathway linking these targets with long-term clinical benefit with acoramidis.¹

“I think the most important thing that we can say is that biomarker testing really can be extremely informative, not just about the presence and severity of ATTR-CM, but also with respect to its response to treatment,” Januzzi said. “We need more data about the role of biomarkers to help people manage transthyretin cardiomyopathy, but I would argue that the future is very bright in this regard.”

Editors’ Note: Januzzi reports disclosures with Abbott Laboratories, AbbVie, Inc., Eli Lilly, AstraZeneca Pharmaceuticals, Jana Care, Siemens, and others.

References

1. Myhre P, Murtagh G, Gaggin H, et al. Implications of Serum Transthyretin to NT-proBNP Ratio in Transthyretin Amyloid Cardiomyopathy: Insights From ATTRibute-CM. J Am Coll Cardiol HF. null2026, 0 (0). https://doi.org/10.1016/j.jchf.2026.103493

2. Gillmore JD, Judge DP, Cappelli F, et al. Efficacy and safety of ACORAMIDIS in transthyretin amyloid cardiomyopathy. New England Journal of Medicine. 2024;390(2):132-142. doi:10.1056/nejmoa2305434

3. Eidos Therapeutics. Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM). ClinicalTrials.gov Identifier: NCT03860935. Updated June 27, 2026. Accessed October 14, 2026. https://clinicaltrials.gov/study/NCT03860935