BridgeBio Pharma : BBIO – Acoramidis AG10 TTR – ESC Heart Failure 2024 – NT-proBNP Insights from the ATTRibute-CM Study

Acoramidis Significantly Improves NT-proBNP Indices That Indicate ATTR-CM Disease Progression and Predict Subsequent Mortality: Insights From the ATTRibute-CM Study

Pablo Garcia-Pavia1, Ahmad Masri2, Kunal Bhatt3, Matthias Dupont4, Michele Emdin5, Emer Joyce6, Michel Khouri7, Timothy Sutton8, Jing Du9, Jean-François Tamby9, Maria Lucia Pecoraro10, Leonid Katz10, Jonathan C. Fox10, Julian Gillmore11

1Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain; 2Oregon Health & Science University, Portland, OR, US; 3Emory Healthcare, Atlanta, GA, US; 4Ziekenhuis Oost Limburg, Genk, Limburg, Belgium; 5Fondazione G. Monasterio, Pisa, Italy; 6Mater University Hospital, Dublin, Ireland; 7Duke Health, Raleigh, NC, US; 8Middlemore Hospital, Auckland, New Zealand; 9Bridge Bio Pharma Inc, Palo Alto, CA, US; 10Eidos Therapeutics, a subsidiary of BridgeBio Pharma Inc, San Francisco, CA, US; 11University College London, London, UK

PURPOSE

• To evaluate the rate of N-terminal prohormone of brain

natriuretic peptide (NT-proBNP) progressor indices 1

and 2 observed at various intervals in the ATTRibute-CM

efficacy population in patients with symptomatic

transthyretin amyloid cardiomyopathy (ATTR-CM)

CONCLUSIONS

• Acoramidis treatment leads to significant improvement in NT-proBNP progressor indices as compared to placebo
• These results indicate that acoramidis reduces ATTR-CM disease progression, likely resulting in the reduction of subsequent clinical events

BACKGROUND

• ATTR-CM is an infiltrative, restrictive cardiomyopathy caused by

the destabilization of transthyretin (aka prealbumin) tetramers1-5

• NT-proBNP is a biomarker of disease progression and predicts

mortality in ATTR-CM.6 The following progressor indices have

been described:

- Progressor index 1: an increase in NT-proBNP (>30% and

>300 pg/mL) can signal disease progression6

- Progressor index 2: increases in NT-proBNP >500 pg/mL

and >1000 pg/mL at Month 12 after diagnosis can predict

subsequent mortality in wild-typeATTR-CM7

• Acoramidis is a novel, investigational transthyretin oral stabilizer

for the treatment of patients with ATTR-CM8-10

• The 30-month, phase 3 study of acoramidis vs placebo in ATTR-

CM (ATTRibute-CM, NCT03860935; 90% wild-typeATTR-CM)

RESULTS

Baseline demographic and disease characteristics

• As previously reported, baseline demographics and clinical characteristics in the intent-to-treat (ITT) population were well balanced between the treatment groups (Table)10

TABLE. Baseline Demographics and Clinical Characteristics (ITT Population)10

	Acoramidis	Placebo
	N=421	N=211
Age, years, mean (SD)	77.4 (6.5)	77.1 (6.8)
Male sex, n (%)	384 (91.2)	186 (88.2)
Transthyretin genotypea,	39 (9.3)	19 (9.0)
ATTRv-CM, n (%)
NT-proBNP, pg/mL,	2326 (1332-4019)	2306 (1128-3754)
median (IQR)
eGFR, mL/min/1.73 m2,	61 (18)	61 (19)
mean (SD)
Serum transthyretin,	23 (6)	24 (6)
mg/dL, mean (SD)

• The rise in NT-proBNP from baseline to Month 30 observed with placebo was attenuated with acoramidis treatment. The ratio of the adjusted geometric mean fold change from baseline to Month 30 between the 2 treatment groups was 0.529 (95% CI: 0.463, 0.604; p<0.0001) (Figure 1)

FIGURE 1. Change in NT-proBNP Level From Baseline to Month 3010

Factor	3.0		Placebo
		Acoramidis
Baseline
2.5
Mean
1.5
Geometric
From	2.0
Change
Adjusted	1.0
	Baseline	1	3	6	9	12	15	18	21	24	27	30

• For progressor index 2 (>500 pg/mL, imputed values), a 14.5% absolute reduction in the rate of progressors was observed with acoramidis at the end of year 1 (Months 9-12)
  (p =0.0005), gradually increasing to reach 25.8% at Months 27-30 (p<0.0001) (Figure 3)
• For progressor index 2 (>1000 pg/mL, imputed values), an 8.7% absolute reduction in the rate of progressors was observed with acoramidis at the end of year 1 (Months 9-12) (p=0.0305), gradually increasing to reach 26.6% at Months 27-30 (p<0.0001) (Figure 3)

FIGURE 3. Progressor Index 2: Percent of Patients (Imputed and Observed) With NT-proBNP Increase from Baseline (>500 and >1000 pg/mL) at Various Intervalsa,b

100%	Acoramidis (N=409)		>500 pg/mL	p<0.0001	p<0.0001
90%	Placebo (N=202)
		p<0.0001	81.2	84.7
80%		p=0.0005
p=0.1048	71.3
70%		64.9
60.4
60%			54.8	58.9
53.8	50.4	54.5
50%		52	56	52
40%	43	45

met its four-step primary hierarchical endpoint of mortality,

cardiovascular-related hospitalization, change in N-terminal

pro-B-type natiuretic peptide, and six-minute walk test

(p<0.0001) in the modified intent-to-treat (mITT) population10

aGenetic status may differ from interactive voice/web response system stratification factor, as classification of a variant	No. at Risk				Months Since Randomization
for the latter was at the discretion of the investigator. For this electronic case report form, all variants were documented
as a mutation.	Acoramidis	409	365	356	361	383	382	383	393	401	395	397
From The New England Journal of Medicine, Gillmore JD, et al, Efficacy and safety of acoramidis in transthyretin amyloid	Placebo	202	184	181	180	190	190	195	199	197	189	198
cardiomyopathy, 390, 132-142. Copyright © 2024 Massachusetts Medical Society. Reprinted with permission from
Massachusetts Medical Society.	From The New England Journal of Medicine, Gillmore JD, et al, Efficacy and safety of acoramidis in transthyretin amyloid
	cardiomyopathy, 390, 132-142. Copyright © 2024 Massachusetts Medical Society. Reprinted with permission from

30%
30
20%	27	27	27	28
10%

NT-proBNP progressor indices 1 and 2 outcomes

Massachusetts Medical Society.

0%
Months 3-6	Months 9-12	Months 15-18	Months 21-24	Months 27-30

METHODS

• Details of the study design have been previously published10
• The efficacy analysis was conducted in the modified intent-to- treat (mITT) population, which consisted of randomized participants who had a baseline estimated glomerular filtration rate of ≥30 mL/min/1.73 m2 10
• Rates of NT-proBNP progressor indices 1 and 2 (imputed
  and observed) at 3-month intervals in the ATTRibute-CM study are reported. The denominators for both rates were 409 (acoramidis) and 202 (placebo)
• Cochran-Mantel-Haenszelstatistical testing was applied for the comparison of imputed values between groups

• At all 3-month intervals from end of year 1 (Months 9-12) to the end of the study (Months 27-30), the distribution for both NT-proBNP progressor indices favored acoramidis over placebo (Figures 2 and 3)
• For progressor index 1 (imputed values), a 13.5% absolute reduction in the rate of progressors was observed with acoramidis at the end of year 1 (Months 9-12) (p=0.0013) and gradually increased, reaching 28.9% at Months 27-30 (p<0.0001) (Figure 2)

FIGURE 2. Progressor Index 1: Percent of Patients (Imputed and Observed) With NT-proBNP Increase from Baseline (>30% and >300 pg/mL) at Various Intervalsa,b

					p<0.0001	p<0.0001
100%	Acoramidis (N=409)	Placebo (N=202)	p<0.0001
	87.1
90%	p=0.3174	p=0.0013		81.2
73.8
80%
70%		55.9	62.4			58.2
60%	51.6	48.9	54.8	54.0
50%		54	56	55
40%			43
30%		38
20%	26		26	27	26	27
10%
0%	Months 3-6	Months 9-12	Months 15-18	Months 21-24	Months 27-30

aThe values at the top of the bar are percentage of patients meeting the criteria after imputation (patients with missing data considered as meeting the progression criteria) bThe values in the lower base of the bars are percentage of patients meeting the criteria based on observed values

100%				Acoramidis (N=409)						>1000 pg/mL
90%				Placebo (N=202)														p<0.0001			p<0.0001
80%
																p=0.0137			77.2
70%
			p=0.5508	p=0.0305		67.3
60%				58.9							50.6
50%	45.2			47.5		41.3		50.0	48.9				48.2
40%
																									42					42
30%																				38
														29
20%								25
	20										20					19					19
10%							17
0%
		Months 3-6				Months 9-12		Months 15-18		Months 21-24		Months 27-30

aThe values at the top of the bar are imputed values (patients with missing data considered as meeting the progression criteria)

bThe values in the lower base of the bars are observed values, indicating the percentage of patients who have actually met the criteria at a given visit group

FUNDING: This study was sponsored by BridgeBio Pharma Inc, Palo Alto, CA, US.

ABBREVIATIONS: ATTR-CM, transthyretin amyloid cardiomyopathy; ATTRv-CM, variant ATTR-CM; eGFR, estimated glomerular filtration rate; ITT, intent-to-treat; mITT, modified ITT; NT-proBNP,N-terminal prohormone of brain natriuretic peptide.

ACKNOWLEDGMENTS: Under the direction of the authors, medical writing assistance was provided by Syneos Health Medical Communications, LLC, and supported by BridgeBio Pharmaceuticals, 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. Ruberg FL, et al. J Am Coll Cardiol. 2019;73(22):2872-2891.5. Grogan M, et al. J Am Coll Cardiol. 2016;68(10):1014-1020.6. Garcia-Pavia P, et al. Eur J Heart Fail. 2021a;23(6):895-905.7. Law S, et al. Heart. 2022;108(6):474-478.8. Penchala SC, et al. PNAS. 2013;110(24):9992-9997.9. Miller M, et al. Med Chem. 2018;61(17):7862-7876.10. Gillmore JD, et al. N Engl J Med. 2024;390(2):132-142.

PRESENTED AT THE EUROPEAN SOCIETY OF CARDIOLOGY CONGRESS ON HEART FAILURE, 11-14 MAY 2024; LISBON, PORTUGAL, AND VIRTUAL.