Key Points:
- Sustained Efficacy: Continued improvements in cardiac biomarkers, functional capacity, and symptom relief over extended treatment periods.
- Safety Profile: Consistent safety findings with no new concerns emerging during long term use.
- Reduced Hospitalizations: Fewer heart failure hospitalizations, highlighting its clinical impact.
- Mechanism of Action: Stabilizes transthyretin to prevent amyloid fibril formation, mitigating myocardial damage.
Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive disease caused by the misfolding of transthyretin, leading to its deposition as amyloid fibrils in the heart. This condition results in heart failure and a significant decline in quality of life. Acoramidis, a transthyretin stabilizer, has shown considerable promise in altering the disease course and improving outcomes for patients.
In the phase 3 randomized controlled study, ATTRibute-CM, acoramidis, a transthyretin (TTR) stabilizer, demonstrated significant efficacy on the primary endpoint. Participants with transthyretin amyloid cardiomyopathy (ATTR-CM) who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE) (ClinicalTrials.gov Identifier: NCT04988386). The results of the open-label extension study (OLE) were presented at AHA 2024 with simultaneous publication in Circulation.
In an open-label extension (OLE) study involving patients who had completed the phase 2 AG10-201 trial, acoramidis demonstrated sustained benefits over an extended treatment period. Participants who previously received acoramidis through Month 30 (M30) in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through M30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through Month 42 (M42) included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP), 6-minute walk distance (6MWD), serum TTR, and the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). Safety outcomes were analyzed through M42. The study assessed long-term safety, efficacy, and tolerability, with results showing consistent improvements in key clinical measures. Overall, 438 of 632 participants in ATTRibute-CM completed treatment and 389 enrolled in the ongoing OLE (263 continuous acoramidis, 126 placebo to acoramidis). The hazard ratio (HR) (95% CI) for ACM or first CVH was 0.57 (0.46, 0.72) at M42 based on a stratified Cox proportional hazards model (P-value < 0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with HRs (95% CI) of 0.64 (0.47, 0.88) and 0.53 (0.41, 0.69), respectively, at M42.
Acoramidis maintained a strong safety profile, with adverse events in line with prior observations and no new safety concerns emerging during the extension phase. Patients experienced continued improvements in cardiac biomarkers such as NT-proBNP and left ventricular function, alongside better functional capacity and symptom relief, as indicated by enhanced walking distance and quality-of-life scores. Hospitalizations for heart failure were also reduced, highlighting its clinical impact.
Acoramidis stabilizes transthyretin, preventing amyloid fibril formation, which mitigates myocardial damage and improves cardiac performance. These results underscore its potential as a cornerstone therapy for ATTR-CM, offering long-term benefits for a condition where few effective treatments exist. While the study primarily included patients from the earlier trial, making generalization more challenging, the data provide robust evidence of sustained efficacy and safety. Further trials are expected to validate these findings across larger, more diverse populations and explore its potential in earlier stages of the disease.
In summary, acoramidis offers sustained safety and efficacy, making it a pivotal advancement in managing transthyretin cardiac amyloidosis. By addressing both the underlying pathology and its clinical manifestations, this therapy has the potential to significantly improve outcomes for patients with this challenging condition.