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.
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BridgeBio Pharma Inc. published this content on 11 May 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 11 May 2024 14:41:00 UTC.