(T1230-05-32) Acoramidis Lowers NT-proBNP in a Larger Proportion of ATTRibute-CM Study Participants with Transthyretin Amyloid Cardiomyopathy Compared with Placebo, Independent of Atrial Fibrillation Status

Purpose: Atrial fibrillation/flutter (AF/AFL) is a frequent complication of heart failure in transthyretin amyloid cardiomyopathy (ATTR-CM) and its increasing incidence is a marker of disease progression. Increasing N-terminal B-type natriuretic peptide (NT-proBNP) levels are also an independent indicator of ATTR-CM progression and higher NT-proBNP levels are seen in ATTR-CM with superimposed AF. Acoramidis achieves near-complete (≥90%) TTR stabilization,¹ and is approved in the USA, Europe, Japan, and the UK for the treatment of ATTR-CM in adults. Acoramidis blunts the progressive rise in NT-proBNP, compared with placebo in patients with ATTR-CM.² The purpose of this study was to assess the effect of acoramidis treatment on ATTR-CM disease progression based on NT-proBNP levels in the presence or absence of AF/AFL.

Methods: The ATTRibute-CM (NCT03860935) study has been published. This post hoc analysis was conducted in the modified intention-to-treat population who had baseline (BL) and Month 30 NT-proBNP assessments (n=413). Categories defined were: 1) presence or absence of AF/AFL diagnosis at BL (defined as recorded AF medical history or presence of AF/AFL on ECG at enrollment), 2) incidence of AF/AFL treatment-emergent adverse event (TEAE) during the study, and 3) AF/AFL at any time (defined as [1] or [2]). Improvement at Month 30 was defined as a reduction of >300 pg/mL and >30% in NT-proBNP from BL. AF/AFL TEAEs were identified using ‘atrial fibrillation’, ‘atrial flutter’ and ‘cardiac flutter’ MedDRA preferred terms.

Results: At study entry, participants with BL AF/AFL had lower 6-minute walk distances, left ventricular ejection fractions and Kansas City Cardiomyopathy Questionnaire Overall Summary scores, higher NT-proBNP levels and were more frequently categorized in higher National Amyloidosis Centre stages versus those without BL AF/AFL. Other BL characteristics were comparable between groups. At Month 30, a higher proportion of participants had improved NT-proBNP with acoramidis than with placebo, regardless of AF/AFL status at BL and/or development of AF/AFL during the study (Table).

Conclusion: In ATTRibute-CM, the proportion of participants with improved NT-proBNP at Month 30 was consistently around 15 percentage points higher with acoramidis than placebo, regardless of AF/AFL status at BL or during the study. The ongoing open-label extension study may offer insights into the durability of this effect and its long-term clinical consequences.

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

Acknowledgements:

Funding: 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 Adam Castaño, Jean-François Tamby and Jonathan C. Fox as authors from the original author group. Conflicts of interest:
M.S.M. has acted as a researcher for NIH (R01HL139671 and R01AG081582-01), Alnylam Pharmaceuticals, Attralus, BridgeBio Pharma, Inc., Intellia Therapeutics, Ionis Pharmaceuticals, and Pfizer; and as a consultant or advisor for Akcea Therapeutics, Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio Pharma, Inc., Intellia Therapeutics, Ionis Pharmaceuticals, Novo Nordisk, and Pfizer. K.M.A. has acted as a consultant, advisor, or speaker for Arbor Biotechnologies, Attralus, Intellia Therapeutics, and Prothena Biosciences.
L.O. has acted as a consultant, advisor, or speaker for Alnylam Pharmaceuticals, AstraZeneca, BridgeBio Pharma, Inc., Ionis Pharmaceuticals, Novo Nordisk, Pfizer, and Sobi – Swedish Orphan Biovitrum. S.H.P. has received consulting fees from Bayer A/S, BridgeBio Pharma, Inc., Pfizer A/S, and research support from Novo Nordisk A/S. J.L.J. has received research grants or held a contract with Abbott Diagnostics, Applied Therapeutics, AstraZeneca, BMS, HeartFlow, and Novartis; has acted as a consultant, advisor, or speaker for Abbott, Abbvie, AstraZeneca, Bayer, Beckman-Coulter, Boehringer-Ingelheim, Bristol-Myers, CVRx, Intellia, Jana Care, Novartis, Pfizer, Merck, Roche Diagnostics, Siemens and Takeda; and has stock interest in Fibrosys, Imbria, Jana Care and Prevencio. R.W. has received research grants or held a contract with Pfizer, Alnylam, BridgeBio Pharma, Inc., Novo Nordisk, Alexion, Astra Zeneca, Intellia; and has acted as a consultant for Pfizer, Alnylam, BridgeBio Pharma, Inc., Novo Nordisk, Alexion, Astra Zeneca. W.J. has acted as a consultant for Boston Scientific and Pfizer. Y.B. has received an educational grant with Pfizer; and has served on advisory boards for BridgeBio Pharma, Inc. K.V. is an employee and stakeholder of Bayer AG. D.W. is an employee and stakeholder of BridgeBio Pharma, Inc. S.M. reported receiving advisory board fees from Alnyalm, Pfizer, Bridge Bio, and AstraZeneca outside the submitted work. M.H. has served on advisory boards for Alnylam, BridgeBio, Alexion, Ionis, ATTRALUS, and Novo Nordisk, and Pfizer. B.W.S. has acted as a speaker for Pfizer and a consultant for Alnylam, AstraZeneca and BridgeBio Pharma, Inc.

Table. Median NT-proBNP at baseline and proportion of participants with improvements in NT-proBNP from baseline to Month 30 according to AF/AFL status at baseline and/or AF/AFL TEAE status during the study; mITT population (N=611).