(M1230-05-33) Serum Transthyretin Levels at Day 28 are Associated with Cardiovascular Outcomes: Insights from the ATTRibute-CM Study

Purpose: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) typically have low serum transthyretin (sTTR) levels, worsening heart failure, and increased mortality. A recent study has shown the association of sTTR levels ≥20mg/dL with reduced risk of all-cause mortality and cardiovascular mortality (CVM).¹  It has also been shown that regardless of baseline sTTR level, greater increases in sTTR levels are associated with greater improvements in cardiovascular outcomes.¹ Acoramidis, a near-complete (≥90%) TTR stabilizer,² demonstrated a rapid and sustained increase from baseline in sTTR by Day 28 and reduced risk of cardiovascular outcomes in patients with ATTR-CM.^1,3 The purpose of this study was to assess the effect of acoramidis-mediated early increase in sTTR levels ≥20 mg/dL (lower limit of normal) at Day 28 on the risks of CVM and cardiovascular-related hospitalizations (CVH) in patients with ATTR-CM.

Methods: Analyses were conducted in the ATTRibute-CM modified intention-to-treat (mITT) population (acoramidis: 409; placebo: 202). The sTTR concentrations (normal range is 20-40 mg/dL) were assessed using an immunoturbidimetric method (Abbott ARCHITECT system) in a central laboratory. The proportion of participants with sTTR levels below normal at baseline and Day 28 were determined. The relationship between sTTR levels < 20 or ≥20 mg/dL, at Day 28 across the pooled acoramidis and placebo treatment groups, and subsequent risk of CVM and of CVH over 30 months were analyzed using a stratified log-rank test.

Results: At baseline about 25% of study participants had sTTR levels below normal in both treatment groups. At Day 28, less than 2% of participants had sTTR levels < 20 mg/dL in the acoramidis arm compared with 26% in the placebo arm (Table 1). When acoramidis and placebo treatment groups were pooled based on sTTR levels < 20 or ≥20 mg/dL at Day 28, participants with sTTR ≥20 mg/dL were associated with a lower risk of the composite endpoint of CVM or first CVH at Month 30 in comparison with < 20 mg/dL (p < 0.0001) (Figure 1A). Comparable findings were observed for the individual components (CVM, first CVH) (Figure 1B and C).

Conclusion: Across treatment groups, sTTR levels above normal range (≥20 mg/dL) at Day 28 were associated with a lower risk of cardiovascular outcomes at Month 30, when compared with sTTR levels below normal range ( < 20 mg/dL). Thus, these observations demonstrate that higher sTTR levels over time may have the potential for clinical benefits in both CVM and CVH.

References: 1. Maurer MS, et al. J Am Coll Cardiol. 2025;85(20):1911-1923.
2. Judge DP, et al. J Am Coll Cardiol. 2019;74(3):285-295.
3. Gillmore JD, et al. N Engl J Med. 2024;390;132-142.

Acknowledgements: This study was sponsored by BridgeBio Pharma, Inc., San Francisco, CA, USA. Under the direction of the authors, medical writing assistance was provided by Oxford PharmaGenesis, Inc., and was funded by BridgeBio Pharma, Inc. We thank Chris Chen, Alan Ji, Jean-François Tamby, Uma Sinha, and Jonathan C. Fox as authors from the original author group. Conflicts of interest: N.S. has acted as a researcher for Pfizer; and has been a consultant, advisor, and/or speaker for Alnylam, AstraZeneca, BridgeBio Pharma, Inc., Novo Nordisk, and Pfizer. A.V.A. has no relevant financial relationships to disclose. R.W. has acted as a consultant, advisor, or speaker for Alnylam Pharmaceuticals, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, BridgeBio Pharma, Inc., Cytokinetics, Lexicon Pharmaceuticals, Lilly, MyoKardia, and Novartis. M.K.D. has no relevant financial relationships to disclose. J.D.G. has acted as a consultant, advisor, or speaker for Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio Pharma, Inc., Intellia Therapeutics, Ionis Pharmaceuticals, Lycia Therapeutics, and Pfizer. J.L.G. has received grant support from BridgeBio Pharma Inc., the National Heart, Lung, and Blood Institute (R01HL160892), Pfizer, and the Texas Health Resources Clinical scholarship; and has acted as a consultant, advisor, or speaker for Alexion, Alnylam, AstraZeneca, BridgeBio Pharma Inc., Intellia, Lumanity, Novo Nordisk, Pfizer, Tenax Therapeutics, and Ultromics. J.D.M. has received research support from Abbott Laboratories and Myocardial Solutions; and has acted as a consultant, advisor or speaker for Alnylam Pharmaceuticals, Astrazeneca, BridgeBio Pharma, Inc.,and Pfizer. D.M. has acted as a consultant, advisor, or speaker for Pfizer. J.N-N. has acted as a researcher for Alnylam Pharmaceuticals, AstraZeneca, BridgeBio Pharma, and Pfizer. F.L.R. has acted as a researcher for Anumana, Alnylam, BridgeBio Pharma, National Heart, Lung, and Blood Institute (R01HL139671), Pfizer and TriNetX; and as a consultant/advisor to AstraZeneca and Attralus. D.W. is an employee and stakeholder of BridgeBio Pharma, Inc. M.M. has acted as a researcher for the National Institutes of Health (R01HL139671 and R01AG081582-01), Alnylam Pharmaceuticals, Attralus, BridgeBio Pharma, Intellia Therapeutics, Ionis Pharmaceuticals, and Pfizer; and as a consultant or advisor for Akcea Therapeutics, Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio Pharma, Intellia Therapeutics, Ionis Pharmaceuticals, Novo Nordisk, and Pfizer. R.K.C. has no relevant financial relationships to disclose.

Table 1. Distribution of participantsa with serum TTR <20mg/dL between treatment groups, mITT population

Figure 1. Time to CVM or first CVH (A), CVM (B), and First CVH (C) by sTTR level at Day 28 in pooled treatment groups (acoramidis and placebo).