Early Increase in Serum TTR Linked to Lower Cardiovascular Hospitalizations in ATTR-CM Patients

A recent study presented at the 2024 International Symposium on Amyloidosis revealed that treatment-related early increase in serum transthyretin (TTR) levels is associated with reduced cardiovascular-related hospitalizations (CVH) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This research provides critical insights from the ATTRibute-CM study (NCT03860935). The study was sponsored by BridgeBio Pharma, Inc.

ATTR-CM, characterized by the deposition of misfolded TTR proteins in the heart, leads to progressive cardiac dysfunction. Patients with ATTR-CM often exhibit lower circulating serum TTR levels, which correlate with worsening cardiac function and higher cardiovascular mortality risks. Acoramidis, a next-generation investigational TTR stabilizer, has shown promise in previous studies, reducing the cumulative frequency of CVH and improving clinical outcomes.

The primary objective of this study was to evaluate the association between changes in serum TTR levels and the risk of first CVH in patients treated with acoramidis compared with placebo.

The analysis was part of ATTRibute-CM, a phase 3 pivotal study, which involved a modified intent-to-treat population of 611 patients (acoramidis, n=409; placebo, n=202). The change from baseline (CFB) in serum TTR level was assessed using a mixed model for repeated measures. The study examined the association between early changes in serum TTR at day 28 and the risk of first CVH over 30 months using a stratified Cox proportional hazards model. CVH was defined as a nonelective admission to an acute care setting for cardiovascular-related morbidity resulting in at least a 24-hour stay or an unscheduled medical visit of <24 hours due to heart failure requiring intravenous diuretic treatment.

The baseline demographics and clinical characteristics were comparable between the treatment groups (91% male; mean age, 77 years). A key finding was that each 1-mg/dL increase in serum TTR at day 28 post-treatment was associated with a 4.7% lower risk of first CVH over 30 months. Specifically, 109 (26.7%) acoramidis-treated patients experienced a first CVH compared with 86 (42.6%) in the placebo group. The Kaplan-Meier curves indicated a significant and early separation in the time to first CVH, starting as early as month 3 and increasing through month 30. Acoramidis demonstrated a statistically significant treatment effect, with a least squares mean difference in serum TTR of 9.6 mg/dL at day 28, which remained stable through month 30.

The early and sustained increase in serum TTR levels following acoramidis treatment is a promising indicator of reduced CVH in ATTR-CM patients. These findings support the efficacy of acoramidis and highlight the importance of early therapeutic intervention in improving clinical outcomes for this patient population.

Key Takeaways

• Early increases in serum TTR levels at day 28 were significantly associated with lower CVH risk over 30 months.
• Acoramidis treatment resulted in a 40% reduction in the time to first CVH, with benefits observed as early as month 3.
• This study is the first to prospectively analyze the relationship between CFB in TTR levels and CVH risk in ATTR-CM patients.
• The findings underscore the potential of acoramidis as a transformative therapy for reducing cardiovascular morbidity in ATTR-CM.