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.
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BridgeBio Pharma Inc. published this content on 13 May 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 13 May 2024 10:07:10 UTC.