Early Initiation of Acoramidis in ATTR-CM: Importance and Long-Term Impacts

Despite advances in diagnostic tools and therapeutic strategies, transthyretin amyloid cardiomyopathy (ATTR-CM) remains a progressive condition with significant clinical burden. The open-label extension (OLE) of the ATTRibute-CM trial provides a longer-term assessment of acoramidis, an investigational transthyretin (TTR) stabilizer, in patients previously enrolled in the phase 3 study. This follow-up aims to explore whether early and sustained treatment with acoramidis influences clinical outcomes over an extended period beyond the original 30-month study duration. Here’s a breakdown of the OLE study.

Study Snapshot: A Closer Look at Continuity and Transition
In the original ATTRibute-CM phase 3 trial, acoramidis demonstrated clinically meaningful benefits over placebo over a 30-month double-blind period. The OLE study transitioned into a single-arm, open-label design in which 389 of 438 eligible participants (89 percent) who completed ATTRibute-CM were enrolled. Those who had previously received acoramidis continued therapy in the “continuous” group, while those originally assigned to placebo were transitioned to open-label acoramidis. To minimize potential confounding factors, participants who had received tafamidis during the prior trial phase were required to discontinue its use before enrolling in the extension study.

Participants were monitored through month 42 from the original trial’s baseline, with endpoints focused on all-cause mortality (ACM) and/or first cardiovascular-related hospitalization (CVH), functional status, biomarkers, and safety.

Overall, this study showed that continuous treatment with acoramidis was associated with sustained and significant clinical benefits over the extended follow-up, with the following results:

• All-Cause Mortality (ACM) alone:
  • 23 percent of the continuous group died by month 42 vs. 34.7 percent of the placebo-to-acoramidis group.
  • Hazard ratio: 0.64 (p=0.006), indicating a 36 percent relative risk reduction.
• ACM or First CVH:
  • 42.5 percent of patients in the continuous group had ACM or first CVH compared to 64.4 percent in the placebo-to-acoramidis group.
  • Hazard ratio: 0.57 (p<0.0001), reflecting a 43 percent reduction in combined risk.
• First CVH Alone:
  • 31.5 percent of patients in the continuous group experienced first CVH vs. 53.5 percent in the placebo-to-acoramidis group.
  • Hazard ratio: 0.53 (p<0.0001), indicating a 47 percent risk reduction.
• Recurrent Events:
  • Negative binomial regression revealed a 48 percent reduction in annualized cumulative ACM or recurrent CVH events (p<0.0001).

Consistent with the earlier trial phase, biomarker and functional trajectories continued to diverge favorably with ongoing therapy, demonstrating the following results:

• NT-proBNP, a surrogate for cardiac stress:
  • By month 42, the geometric mean fold change in NT-proBNP from baseline was 1.10 for the continuous acoramidis group, compared to 2.29 in those who switched from placebo.
• 6-Minute Walk Distance (6MWD):
  • Relative preservation in the continuous arm (–24.5 meters at month 42), versus more substantial declines in the switch group.
• Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS):
  • Mean change at month 42: –4.0 points (continuous), suggesting preserved quality of life.

Additionally, serum transthyretin levels—a biochemical proxy for TTR stabilization—rose promptly and robustly upon initiation and remained elevated with continued therapy. No new safety concerns emerged during the extended follow-up. The specific adverse event findings included:

• 1.1 percent of patients in the continuous group reported treatment-related adverse events.
• No treatment-related serious adverse events were recorded.
• Discontinuations due to adverse events dropped to 1.5 percent in the continuous group, down from 9.3 percent in the original blinded phase.

These observations support the premise that the long-term use of acoramidis is not only efficacious but also well tolerated.

Clinical Takeaways
The sustained benefits observed with acoramidis over 42 months underscore an important clinical insight: earlier initiation of therapy appears to matter significantly. Patients who began treatment during the initial randomized phase and continued uninterrupted showed consistently better outcomes across mortality, hospitalization, functional capacity, and quality-of-life metrics. In contrast, those who started acoramidis later—after 30 months on placebo—did not achieve the same degree of benefit, suggesting that delays in initiating disease-modifying therapy may lead to irreversible cardiac deterioration and loss of functional reserve.

Reference:
Judge DP, Gillmore JD, Alexander KM, et al. Long-Term Efficacy and Safety of Acoramidis in ATTR-CM: Initial Report From the Open-Label Extension of the ATTRibute-CM Trial. Circulation. 2025;151(9):601-611.