BridgeBio Pharma : BBIO – Acoramidis AG10 TTR – ESC Heart Failure 2024 – ITT Sensitivity Analysis and Sub-Analysis Comparing Acoramidis and Placebo in Stage 4 CKD in ATTRibute-CM

ATTRibute-CM: ITT Sensitivity Analysis and Sub-Analysis

Comparing Acoramidis and Placebo in Stage 4 CKD

Steen Poulsen1, Julian D Gillmore2, Kevin M Alexander3, Prem Soman4, Simon D J Gibbs5, Francesco Cappelli6, Sanjiv J Shah7, Jonathan C Fox8, Leonid Katz8, Jean-François Tamby9, Xiaofan M Cao8, Ted Lystig9, Sarah A M Cuddy10, Daniel P Judge11

1Aarhus University Hospital, Aarhus, Denmark; 2University College London, United Kingdom; 3Stanford University School of Medicine, Stanford, CA, US; 4University of Pittsburgh Medical Center, Pittsburg, PA, US; 5Eastern Health, Melbourne, Australia; 6Careggi University Hospital, Florence, Italy; 7Northwestern Medicine, Chicago, IL, US; 8Eidos Therapeutics, a subsidiary of BridgeBio Pharma, San Francisco, CA, US; 9BridgeBio Pharma Inc., Palo Alto, CA, US; 10Brigham and Women's Hospital, Boston, MA, US; 11Medical University of South Carolina, Charleston, NC, US

Presenter: Steen Poulsen

Acknowledgements

• The authors would like to thank the patients who participated in the ATTRibute-CM trial and their families
• The authors would also like to thank the ATTRibute-CM investigators
• Under the direction of the authors, medical writing assistance was provided by Syneos Health Medical Communications, LLC, and supported by BridgeBio Pharma, Inc.

Background

ATTR-CM, caused by destabilization of TTR, can lead to progressive heart failure, significantly impaired quality of life, hospitalization, and premature death1,2

Acoramidis is a next-generation, investigational TTR stabilizer that demonstrated robust clinical efficacy vs placebo in a pivotal phase 3 study, ATTRibute-CM*3-5

Acoramidis treatment is associated with a 25% relative risk reduction in all-causemortality in a prespecified mITT population with eGFR ≥30 mL/min/1.73 m2 5

Patients with eGFR <30 mL/min/1.73 m2 (Stage 4 CKD) were enrolled in the trial to explore safety in this high-risk subpopulation, but were excluded from the primary mITT efficacy analysis; the ITT population was defined as the mITT population + participants with stage 4 CKD

OBJECTIVE:

We report the results of a prespecified ITT sensitivity analysis that includes a high-risk subgroup with stage 4 CKD from ATTRibute-CM

*ATTRibute-CM (NCT03860935) was a multicenter, double-blind,placebo-controlled, phase 3 ATTR-CM clinical trial. Patients were randomized 2:1 to receive 800 mg acoramidis or matching placebo twice daily for 30 months. It met its primary hierarchical endpoint of mortality, cardiovascular-related hospitalization, change in NT-proBNP and 6MWD (P<0.0001).

ATTR-CM, transthyretin amyloid cardiomyopathy; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ITT, intention-to-treat; mITT, modified ITT; NT-proBNP,N-terminalpro-B-type natriuretic peptide; TTR, transthyretin.

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. Proc Natl Acad Sci USA. 2013;110:9992-9997. 4. Miller M, et al. J Med Chem. 2018;61: 7862-7876. 5. Gillmore JD, et al.N Engl J Med. 2024;390(2):132-142.

Methods

ATTRibute-CM:

study design, key eligibility criteria, and primary endpoint1

mITT Population†

Stage 4 CKD participants

Key eligibility criteria

• Participants with diagnosed ATTR-CM (WT or variant)
• NYHA class I-III
• ATTR-positivebiopsy or 99mTc scan
• Light-chainamyloidosis excluded if diagnosis by 99mTc

Screening and randomization

30-month primary endpoint*:

Hierarchal analysis consisting of all-cause mortality, cumulative frequencyof CVH, change from baseline in NT-proBNP, and change from baseline in 6MWD

12-month primary endpoint*:

Change in 6MWD

Acoramidis 800 mg BID1

n=421

Placebo BID1

n=211

Efficacy assessment included 611 participants in the

prespecified mITT population (eGFR ≥30 mL/min/1.73 m2)

Part A	Part B
	(tafamidis usage allowed)

(N=611)	(N=21)
(Acoramidis, n=409; placebo, n=202)	(Acoramidis, n=12; placebo, n=9)
Participants with baseline	Participants with baseline
eGFR ≥30 mL/min/1.73 m2	eGFR <30 mL/min/1.73 m2‡

ITT Population (N=632)

(Acoramidis, N=421; placebo, N=211)

All randomized participants

*Primary analysis assessed using the Finkelstein-Schoenfeld method.

• Incidence of all-cause mortality in the mITT and ITT populations was evaluated using Cox model; prespecified sensitivity analyses included stratified log-rank and Cochran-Mantel-Haenszel tests

† Efficacy set. ‡Cohort included 1 patient with eGFR <15 mL/min/1.73 m2.

6MWD, 6-minute walk distance; 99mTc, technetium-labeled pyrophosphate or bisphosphonate; ATTR-CM, transthyretin amyloid cardiomyopathy; BID, twice daily; CKD, chronic kidney disease; CVH, cardiovascular-related hospitalization; eGFR, estimated glomerular filtration rate; ITT, intention-to-treat; mITT, modified ITT; NT-proBNP,N-terminalpro-B-type natriuretic peptide; NYHA, New York Heart Association; WT, wild-type.

1. Gillmore JD, et al. N Engl J Med. 2024;390(2):132-142.

Baseline Characteristics of the mITT and the High-Risk Stage 4 CKD Populations

ITT Population (N=632)

		mITT Population			High-Risk Stage 4 CKD Population
	(eGFR ≥30 mL/min/1.73 m2); N=611	(eGFR <30 mL/min/1.73 m2)*; N=21
	Acoramidis		Placebo	Acoramidis	Placebo
	n=409		n=202	n=12*	n=9
Mean (SD) age, years	77	(6.5)		77	(6.7)	79 (5.6)	80 (7.0)
Sex, n (%)
Male	374	(91.4)		181 (89.6)	10 (83.3)	5 (55.6)
Female	35	(8.6)		21 (10.4)	2 (16.7)	4 (44.4)
NYHA Class, n (%)
I	51 (12.5)		17	(8.4)	0 (0)	0 (0)
II	288	(70.4)		156	(77.2)	5 (41.7)	6 (66.7)
III	70 (17.1)		29 (14.4)	7 (58.3)	3 (33.3)
eGFR, mL/min/1.73 m2, mean (SD)	62 (17.4)		63 (17.5)	26 (5.9)	26 (2.3)
NT-proBNP ≤3000 pg/mL, n (%)	268	(65.5)		133	(65.8)	4 (33.3)	3 (33.3)
NT-proBNP >3000 pg/mL, n (%)	141	(34.5)		69 (34.2)	8 (66.7)	6 (66.7)
Genetic status**, n (%)
Wild type	370	(90.5)		182 (90.1)	10 (83.3)	9 (100.0)
Variant	39	(9.5)		20	(9.9)	2 (16.7)	0 (0)

*Cohort included 1 patient in acoramidis group with eGFR = 8 mL/min/1.73 m2. ** From IXRS Stratification Factors

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ITT, intention-to-treat; IXRS, interactive voice/web response system; mITT, modified ITT; NT-proBNP,N-terminalpro-B-type natriuretic peptide; NYHA, New York Heart Association.

Acoramidis was Associated With Fewer Observed Deaths Than Placebo in Both eGFR Groups (≥30 and <30 mL/min/1.73 m2)

	mITT Population	High-Risk Stage 4 CKD Population	Overall Population (ITT)
	(eGFR ≥30 mL/min/1.73 m2)	(eGFR <30 mL/min/1.73 m2)
	N=632
	N=611		N=21
	Acoramidis		Placebo	Acoramidis		Placebo	Acoramidis		Placebo
	n=409		n=202	n=12		n=9	n=421		n=211
All-cause mortality, n (%)	79 (19.3)		52 (25.7)	5 (41.7)		5 (55.6)	84 (20.0)		57 (27.0)
Cox proportional hazard model
Hazard Ratio (vs placebo)		0.772		NA*	0.762
95% CI	(0.542, 1.102)		NA*	(0.524, 1.072)
p value		0.1543		NA*	0.1184
Log-rank test		0.0754		NA*	0.0520
Cochran-Mantel-Haenszel test		0.0569		NA*	0.0390
Any TEAEs, n (%)	402 (98.3)		197 (97.5)	11 (91.7)		9 (100)	413 (98.1)		206 (97.6)

*Inferential analysis comparing two groups within the pts

CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; ITT, intention-to-treat; mITT, modified ITT; NA, not available; TEAEs, treatment-emergent adverse events.

Conclusions

ATTRibute-CM is the first ATTR-CM outcomes study to include participants with eGFR <25 mL/min/1.73 m2

In high-risk participants with stage 4 CKD, acoramidis treatment was associated

with 25% relative risk reduction in deaths at Month 30 versus placebo,

consistent with the observations in mITT population, and with no safety signals of potential clinical concern

In a prespecified sensitivity analysis applied to the ITT population (mITT + stage

4 CKD), acoramidis significantly reduced all-cause mortality (HR = 0.762;

p=0.039, Cochran-Mantel-Haenszel test)

ATTR-CM, transthyretin amyloid cardiomyopathy;CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ITT, intention-to-treat.

Thank you

Baseline Characteristics of the mITT, High-Risk Stage 4 CKD, and ITT Populations

		mITT Population		High-Risk Stage 4 CKD Population	Overall Population (ITT)
	(eGFR ≥ 30 ml/min/1.73 m2)	(eGFR < 30 ml/min/1.73 m2)
			N=632
		N=611			N=21
	Acoramidis	Placebo	Acoramidis		Placebo	Acoramidis		Placebo
	n=409	n=202	n=12		n=9	n=421		n=211
Mean (SD) age, years	77	(6.5)	77	(6.7)	79 (5.6)		80 (7.0)	77	(6.5)		77 (6.8)
Gender, n(%)
Male	374	(91.4)	181	(89.6)	10 (83.3)		5 (55.6)	384	(91.2)		186 (88.2)
Female	35	(8.6)	21 (10.4)	2 (16.7)		4 (44.4)	37	(8.8)		25 (11.8)
NYHA Class, n(%)
I	51 (12.5)	17	(8.4)	0 (0)		0 (0)	51 (12.1)		17 (8.1)
II	288	(70.4)	156	(77.2)	5 (41.7)		6 (66.7)	293	(69.6)		162 (76.8)
III	70 (17.1)	29 (14.4)	7 (58.3)		3 (33.3)	77 (18.3)		32 (15.2)
eGFR, ml/min/1.73 m2 , mean (SD)	62 (17.4)	63 (17.5)	26 (5.9)		26 (2.3)	61 (18)		61 (19)
NT-proBNP, ng/L, mean (SD)	2865 (2149.6)	2650 (1899.5)	N/A		N/A	2946 (2226)		2725 (1971)
NT-proBNP ≤3000 pg/mL, n(%)	268 (65.5)	133 (65.8)	4 (33.3)		3 (33.3)	N/A		N/A
NT-proBNP >3000 pg/mL, n(%)	141	(34.5)	69 (34.2)	8 (66.7)		6 (66.7)	N/A		N/A
Genetic Status, n(%)
Wild type	370 (90.5)	182 (90.1)	10 (83.3)		9 (100.0)	380	(90.3)		191 (90.5)
Variant	39	(9.5)	20	(9.9)	2 (16.7)		0 (0)	41 (9.7)		20 (9.5)

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ITT, intent-to-treat; mITT, modified intent-to-treat;NT-proBNP,N-terminalpro-B-type natriuretic peptide; NYHA, New York Heart Association.