BridgeBio Pharma : BBIO – Acoramidis AG10 TTR – ISA 2024 – Higher risk of mortality in previously hospitalized patients

Higher Risk of Mortality in Previously Hospitalized Patients: Insights From ATTRibute-CM

Ahmad Masri1, Michele Emdin2, Keyur Shah3, Kunal Bhatt4, Mazen Hanna5, Michael Johnstone6, Michel Khouri7, Noel Dasgupta8, Olakunle Akinboboye9, Dariusz Korczyk10, Kaitlyn Lam11, Prem Soman12, Jing Du13, Jean-François Tamby13, Suresh Siddhanti13, Leonid Katz13, Jonathan C. Fox13, Kevin Alexander14, Martha Grogan15

1Oregon Health & Science University, Portland, OR, US; 2Fondazione G. Monasterio, Pisa, Italy; 3Virginia Commonwealth University Health, Richmond, VA, US; 4Emory Healthcare, Atlanta, GA, US; 5Cleveland Clinic, Cleveland, OH, US; 6Steward Health Care, Dallas, TX, US; 7Duke Health, Durham, NC, US; 8Indiana University School of Medicine, Indianapolis, IN, US; 9Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Uniondale, NY, US; 10Princess Alexandra Hospital, Brisbane, Australia; 11Western Australia Advanced Heart Failure and Cardiac Transplant Service, Perth, Australia; 12University of Pittsburgh Medical Center, Pittsburgh, PA, US; 13BridgeBio Pharma, Inc., San Francisco, CA, US; 14Stanford University School of Medicine, Palo Alto, CA, US; 15Mayo Clinic, Rochester, MN, US

OBJECTIVE

• To evaluate the relationship between CVH and subsequent survival across treatment arms in ATTRibute-CM

INTRODUCTION

CONCLUSIONS

• To our knowledge, this is the first time a prospective trial has demonstrated that CVH portends a higher subsequent mortality in patients with ATTR-CM
• This suggests that effective treatment to reduce the need for CVH is critically important, and that highly effective, targeted therapy for ATTR-CM that reduces CVH can improve the prognosis of patients with ATTR-CM

• ATTR-CM, caused by the destabilization of the TTR (also known as prealbumin) tetramer, is a chronic disease characterized by

progressive heart failure, significantly impaired quality of life, hospitalization, and death1-3

• CVH is an indicator of higher mortality in patients with undifferentiated heart failure.4 Whether this association might be observed

in the ATTR-CM population has not been determined

• Acoramidis is a next-generation, investigational, near-complete TTR stabilizer (>90% vs placebo) for the treatment of patients with

ATTR-CM5-7

• In a phase 3 study (ATTRibute-CM, NCT03860935), acoramidis demonstrated improved clinical outcomes in patients with ATTR-CM,

including a 50% reduction in the risk of CVH compared to placebo over 30 months, with a positive treatment effect observed as

RESULTS

• Demographics and baseline disease characteristics were mostly comparable between patients with and without CVH (Table); patients with CVH had higher baseline NT-proBNP and lower eGFR

TABLE. Demographics and Baseline Characteristics by CVH Group (mITT Population)

Mortality over the 30-month treatment period, by CVH groups

• Patients with no CVH during the study had a 30-month survival rate of 86.7% (95% CI, 82.9%-89.7%) vs 60.1% (95% CI, 52.8%-66.7%) in patients who had at least one CVH during the study (p<0.0001) (Figure)

FIGURE. Kaplan-Meier Curve for Time to ACM Over Month 30 by CVH Groups (mITT Population)

early as 3 months7

METHODS

		Overall Population
Parameters
CVH		Non-CVH
	n=195		n=416

1.0

0.8

Non-CVH: 86.7% (82.9%, 89.7%)

CVH: 60.1% (52.8%, 66.7%)

• Details of the study design have been previously published7
• The mITT population (n=611) was the primary analysis population for efficacy endpoints and included randomized participants who received at least 1 dose of study drug and had a baseline eGFR ≥30 mL/min/1.73 m2
• ACM and cumulative CVH were considered to be the most clinically important components within the primary hierarchical endpoint
• • ACM included CEC-reviewed and -adjudicated death, heart transplant, and implantation of CMAD, defined as a durable CMAD implanted in a participant with end-stage heart failure
  • CVH was defined as a nonelective admission to an acute care setting for cardiovascular-related morbidity that resulted in at least a 24-hour stay (or a date change, if the time of admission/discharge was not available) or an unscheduled medical visit of <24 hours due to heart failure and requiring treatment with IV diuretics
• Kaplan-Meiercurves for patients with and without CVH were plotted in this post-hoc analysis

Age, years, mean (SD)	77	(6.3)	77	(6.7)
Male sex, n (%)	174	(89.2)	381	(91.6)
White race/ethnic group, n (%)	176	(90.3)	361	(86.8)
TTR genotype, ATTRwt-CM, n (%)	167	(85.6)	385	(92.5)
NYHA class, n (%)	12	(6.2)	56	(13.5)
I
149	(76.4)	295	(70.9)
II
34	(17.4)	65	(15.6)
III
Serum TTR, mg/dL, mean (SD)a	23	(6.4)	23	(5.4)
NT-proBNP, ng/L, mean (SD)	3266	(2094.6)	2573	(2025.0)
eGFR, mL/min/1.73 m2, mean (SD)	59	(16.8)	64	(17.5)

aNumber of patients with serum TTR assessments: CVH, n=191; non-CVH, n=414.

probability	0.6
Survival	0.4
	0.2							CVH		Non-CVH

p<0.0001 (log-rank test)

0.0		+Censored

0

3

6

9

12

15

18

21

24

27

30

Time since randomization (months)

Patients Remaining at Risk (Cumulative Events)

CVH	195 (0)	195 (0)	192 (3)	185 (10)	174 (21)	165 (30)	159 (36)	151 (44)	135 (60)	125 (70)	0 (77)
Non-CVH	416 (0)	413 (3)	407 (9)	404 (12)	399 (17)	392 (24)	389 (27)	382 (34)	375 (41)	367 (49)	0 (54)

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

ABBREVIATIONS: ACM, all-cause mortality; ATTR-CM, transthyretin amyloid cardiomyopathy; ATTRwt-CM;wild-type cardiomyopathy; CEC, clinical events committee; CMAD, cardiac mechanical assist device; CVH, cardovascular-related hospitalization; eGFR, estimated glomerular filtration rate; IV, intravenous; mITT, modified intent-to-treat;NT-proBNP,N-terminalpro-B-type natriuretic 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, et al. JAMA. 2024;331(9):778-791.3. Lane T, et al. Circulation. 2019;140(1):16-26.4. Bello NA, et al. Circ Heart Fail. 2014;7(4):590-595.5. Penchala SC, et al. PNAS. 2013;110(24):9992-9997.6. Miller M, et al. Med Chem. 2018;61(17):7862-7876.7. Gillmore JD, et al. N Engl J Med. 2024;390(2):132-142.

DISCLOSURES: AM: Has contributed to research for Pfizer, Ionis, Attralus, and Cytokinetics; has been a consultant, advisor, and/or speaker for Cytokinetics, BMS, BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, Akros, Prothena, BioMarin, AstraZeneca, and Tenaya. ME: No relevant financial relationships to disclose. KS: Has been a consultant, advisor, and/or speaker for Pfizer. KB: No relevant financial relationships to disclose. MH: Has been a consultant, advisor, and/or speaker for Pfizer, Alnylam, BridgeBio, Ionis, and Alexion. MJ: No relevant financial relationships to disclose. MK: Has contributed to research for Pfizer, BridgeBio, Alnylam, and Ionis; has been a consultant, advisor, and/or speaker for BridgeBio and Alnylam. ND: Has been a consultant, advisor, and/or speaker for Ionis, Akcea, Alnylam, Pfizer, BridgeBio, Intellia, and Pfizer. OA: Has been a consultant, advisor,

and/or speaker for BridgeBio, Alnylam, Pfizer, and AstraZeneca. DK: No relevant financial relationships to disclose. KL: No relevant financial relationships to disclose. PS: Has contributed to research for Pfizer; has been a consultant, advisor, and/or speaker for BridgeBio, Alnylam, Pfizer. JD, JFT, LK, JCF, and SS: Employees and shareholders of BridgeBio. KA: Has been a consultant, advisor, and/or speaker for Arbor, Attralus, Intellia, and Prothena. MG: Has contributed to research for Alnylam, BridgeBio, Janssen, and Pfizer; has been a consultant, advisor, and/or speaker for Janssen Pharmaceuticals and Novo Nordisk.

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