BridgeBio Pharma : BBIO – Acoramidis AG10 TTR – ISA 2024 – Acoramidis treatment related increase in serum TTR is associated with lower cardiovascular mortality in ATTR CM

Treatment-Related Early Increase in Serum TTR is Associated With Lower Cardiovascular Mortality in ATTR-CM: Insights From ATTRibute-CM

Amrut Ambardekar1, Nitasha Sarswat2, Justin L. Grodin3, Julian D. Gillmore4, Steen H. Poulsen5, Jorg Taubel6, Jan Krejci7, Jose Nativi-Nicolau8, Richard Wright9, Frederick L. Ruberg10, Noemi Horvath11, Matthias Dupont12, Jing Du13, Jean-François Tamby13, Maria Lucia Pecoraro13, Leonid Katz13, Satish Rao13, Uma Sinha13, Jonathan C. Fox13, Mathew S. Maurer14

1Division of Cardiology, University of Colorado, Aurora, CO, US; 2Division of Cardiovascular Medicine, University of Chicago Medicine, Chicago, IL, US; 3Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, US; 4National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Hospital, London, UK; 5Department of Internal Medicine, Division of Cardiology, Haderslev Hospital, Haderslev, Denmark; 6Aarhus University Hospital, Aarhus N, Denmark; 7Department of Cardiovascular Diseases, St. Anne's University Hospital, Brno, Czech Republic; 8Transplant Center, Cardiovascular Medicine, Mayo Clinic, Rochester, MN, US; 9Cardiology, Heart Failure, and Transplantation Cardiology, Pacific Heart Institute, Santa Monica, CA, US; 10Cardiovascular Medicine, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, US; 11Department of Haematology, Royal Adelaide Hospital, Adelaide, Australia; 12Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium; 13BridgeBio Pharma, Inc., San Francisco, CA, US; 14Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, US

OBJECTIVE

• To prospectively evaluate the impact of treatment-related early increase in serum TTR (also known as prealbumin) on CVM among participants with ATTR-CM from the ATTRibute-CM clinical trial

CONCLUSIONS

• This analysis demonstrated that an early and greater increase in serum TTR is significantly associated with lower risk of CVM in ATTR-CM
• To our knowledge, this is the first demonstration of the relationship between change from baseline in serum TTR and subsequent risk of CVM in patients with ATTR-CM in a prospective randomized trial

INTRODUCTION

• ATTR-CM,a progressive disease caused by the destabilization of the TTR tetramer, is associated with poor quality of life and leads to heart failure, hospitalization, and death1-3
• Patients with ATTR-CM can have lower circulating serum TTR levels, which are associated with worsening of cardiac function and increased risk of CVM4
• Acoramidis is a next-generation, investigational, near-complete (>90%) TTR stabilizer that increases serum TTR levels for the treatment of patients with ATTR-CM3,5-7
• ATTRibute-CM(NTC03860935), the phase 3 study of acoramidis vs placebo, met its 4-step primary hierarchical endpoint of mortality, cardiovascular-related hospitalization, change in NT-proBNP, and 6MWT (p<0.0001)7
• • Acoramidis was also more effective than placebo in increasing circulating serum TTR levels, and was generally well tolerated

METHODS

• Details of the study design have been previously reported7
• Analysis was conducted in the mITT population (N=611; acoramidis, n=409; placebo, n=202), which was the primary analysis population for efficacy endpoints
• CVM was defined as any death due to a cardiovascular or undetermined cause as determined by the Clinical Events Committee up to the 30-month duration. Receiving a heart transplant or a cardiac mechanical assist device was treated as CVM
• The change from baseline in TTR levels was analyzed using the MMRM with J2R method, with treatment group, visit, genotype (ATTRvariant-CM vs ATTRwild type-CM,NT-proBNP levels (≤ 3000 vs >3000 pg/mL), eGFR levels (≥45 vs <45 mL/min/1.73 m2), treatment group-by-visit interaction as factors, and baseline value as covariate. The genotype, NT-proBNP levels, and eGFR levels randomization stratification factors were based on information from an IXRS
• The relationship between change from baseline in Day 28 serum TTR levels and CVM was analyzed using a stratified Cox proportional hazards model. The model included baseline 6MWT and change from baseline in TTR levels at Day 28 as covariates, and was stratified by treatment group, baseline TTR group (≥20 vs <20), and randomization stratification factors of genotype, NT-proBNP levels, and eGFR levels

RESULTS

• Baseline characteristics were comparable across treatment groups (Table 1)7

TABLE 1. Demographics and Baseline Characteristics (mITT Population)

mITT Population

N=611

	Acoramidis	Placebo
	n=409	n=202
Age, years, mean (SD)	77	(6.5)	77	(6.7)
Sex, n (%)
Male	374	(91.4)	181	(89.6)
Female	35	(8.6)	21	(10.4)
NYHA class, n (%)
I	51 (12.5)	17	(8.4)
II	288	(70.4)	156	(77.2)
III	70 (17.1)	29	(14.4)
eGFR, mL/min/1.73 m2
Mean (SD)	62 (17.4)	63	(17.5)
Median (IQR)	62 (49, 74)	61 (48, 74)
NT-proBNP, pg/mL
Mean (SD)	2865 (2149.6)	2650	(1899.5)
Median (IQR)	2273 (1315, 3872)	2274 (1128, 3590)
Genetic status, n (%)*
Wild type	370	(90.5)	182	(90.1)
Variant	39	(9.5)	20	(9.9)

• The change from baseline in the LSM difference observed between the acoramidis and placebo arms on Day 28 and at Month 30 was 9.6 mg/dL and 7.1 mg/dL, respectively (Figure)

FIGURE. Change From Baseline in TTR Levels - MMRM (With J2R) (mITT Population)7*

10.0

ChangeLSM From Baseline(mg/dL)(± SE)	7.5	Acoramidis
0.0	Placebo
	5.0
	2.5
	-2.5

	Baseline Day28	3	6	9	12	15	18	21	24	27	30
			Months Since Randomization
No. at Risk
Acoramidis 406 367	359	353	357	378	376	381	387	398	391	397
Placebo	199 178	177	173	177	188	185	192	195	194	187	197

*Serum TTR levels were analyzed with the use of a MMRM with J2R.

• Approximately 14.9% and 21.3% of participants receiving acoramidis or placebo, respectively, experienced CVM (6.4% absolute risk reduction; 30% relative risk reduction) (Table 2)

• The HR from the CVM Cox proportional hazards model for acoramidis vs placebo was 0.709 (95% CI: 0.476, 1.054; nominal p=0.0889), indicating a trend with a 29.1% HR reduction in the risk of CVM compared with placebo

TABLE 2. Summary of CVM (mITT Population)

	Acoramidis		Placebo
	(n=409)*		(n=202)*
Participants who experienced CVM, n (%)	61 (14.9)		43 (21.3)†
	Cox HR for CVM in the mITT population
HR		0.709
p value		0.089
Cochran-Mantel-Haenszel test		0.037

*Sample represents all participants in the mITT analysis set.

† 1 participant received heart transplantation and 1 participant received a cardiac mechanical assist device.

• Each 1 mg/dL change from baseline TTR increase at Day 28 post-therapeutic intervention was associated with a 5.5% reduction in CVM risk over 30 months. These observations are across the baseline TTR and treatment groups (Table 3)

TABLE 3. Cox Proportional Hazards Model of CVM for Each 1 mg/dL Change From Baseline in Serum TTR at Day 28* (mITT Population)

Acoramidis	Placebo
(n=409)†	(n=202)†

HR

0.945

95% CI

0.901, 0.922

p value

0.021

*Stratified Cox proportional hazards model included baseline 6MWT and change from baseline in TTR levels at Day 28 as covariates, and was stratified by treatment group and randomization stratification factors of genotype, NT-proBNP levels, and eGFR levels as recorded in IXRS and baseline TTR group (≥20 vs <20).

† Sample represents all participants in the mITT analysis set.

*From IXRS stratification factors.

FUNDING: This study was sponsored by BridgeBio Pharma, Inc., San Francisco, CA, US.

ABBREVIATIONS: 6MWT, 6-minutewalk test; ATTR-CM,transthyretin amyloid cardiomyopathy; CVM, cardiovascular mortality; eGFR, estimated glomerular filtration rate; HR, hazard ratio; IQR, interquartile range; IXRS, interactive voice/web response system; J2R, jump to reference; LSM, least squares mean; mITT, modified intent-to-treat;MMRM, mixed model for repeated measures; NT-proBNP, N-terminal pro-B-typenatriuretic peptide; NYHA, New York Heart Association; TTR, transthyretin.

ACKNOWLEDGMENTS: Under the direction of the authors, medical writing assistance was provided by Syneos Health Medical Communications, LLC, and supported by BridgeBio Pharma, Inc. Editorial support and critical review provided by Shweta Rane of BridgeBio Pharma, Inc.

REFERENCES: 1. Rapezzi C, et al. Nat Rev Cardiol. 2010;7(7):398-408.2. Ruberg FL, Maurer MS. JAMA. 2024;331(9):778-791.3. Penchala SC, et al. PNAS. 2013;110(24):9992-9997.4. Hanson JLS, et al. Circulation: Heart Fail. 2018;11(2):1-9.5. Miller M, et al. Med Chem. 2018;61(17):7862-7876.6. Judge DP, et al. J Am Coll Cardiol. 2019;74(3):285-295.7. Gillmore JD, et al. N Engl J Med. 2024;390(2):132-142.

DISCLOSURES: AA: No relevant financial relationships to disclose. NS: Has contributed to research for Pfizer; has been a consultant, advisor, and/or speaker for BridgeBio, Alnylam, Pfizer. JLG: No relevant financial relationships to disclose. JDG: Has been a consultant, advisor, and/or speaker for Alnylam, AstraZeneca, Attralus, BridgeBio, Ionis, Intellia, and Pfizer; SHP, JT, JK, JNN: No relevant financial relationships to disclose. RW: Has been a

consultant, advisor, and/or speaker for Alnylam, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, BridgeBio, Cytokinetics, Lexicon, Lilly, Myokardia, and Novartis. FLR: Has contributed to research for Pfizer, Alnylam, and Akcea; has been a consultant, advisor, and/or speaker for Attralus and AstraZeneca. NH, MD: No relevant financial relationships to disclose. JD, JFT, MLP, LK, SR, US, and JCF Employees and shareholders of BridgeBio.

MSM: Has contributed to research for NIH NIH R01HL139671 and R01AG081582-01, Alnylam, Pfizer, BridgeBio, Prothena, and Ionis; has been a consultant, advisor, and/or speaker for AstraZeneca, Akcea, Intellia, Novo Nordisk, Alnylam, Pfizer, BridgeBio, Prothena, and Ionis.

PRESENTED AT THE 2024 INTERNATIONAL SYMPOSIUM ON AMYLOIDOSIS, MAY 26-30; ROCHESTER, MN, US, AND VIRTUAL.