Ambardekar, Amrut

Introduction: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) typically have low serum transthyretin (sTTR) levels, worsening heart failure, and increased mortality. A recent study has shown the association of sTTR levels ≥20mg/dL with reduced risk of all-cause mortality and cardiovascular mortality (CVM). It has also been shown that regardless of baseline sTTR level, greater increases in sTTR levels are associated with greater improvements in cardiovascular outcomes. Acoramidis, a near-complete (≥90%) TTR stabilizer, demonstrated a rapid and sustained increase from baseline in sTTR by Day 28 and reduced risk of cardiovascular outcomes in patients with ATTR-CM. Hypothesis: Acoramidis-mediated early increase in sTTR levels ≥20 mg/dL (lower limit of normal) at Day 28 reduces risks of CVM and cardiovascular-related hospitalizations (CVH) in patients with ATTR-CM. Methods: Analyses were conducted in the ATTRibute-CM modified intention-to-treat (mITT) population (acoramidis: 409; placebo: 202). The sTTR concentrations (normal range is 20-40 mg/dL) were assessed using an immunoturbidimetric method (Abbott ARCHITECT system) in a central laboratory. The proportion of participants with sTTR levels below normal at baseline and Day 28 were determined. The relationship between sTTR levels <20 or ≥20 mg/dL, at Day 28 across the pooled acoramidis and placebo treatment groups, and subsequent risk of CVM and of CVH over 30 months were analyzed using a stratified log-rank test. Results: At baseline about 25% of study participants had sTTR levels below normal in both treatment groups. At Day 28, less than 2% of participants had sTTR levels <20 mg/dL in the acoramidis arm compared with 26% in the placebo arm ( Table 1 ). When acoramidis and placebo treatment groups were pooled based on sTTR levels <20 or ≥20 mg/dL at Day 28, participants with sTTR ≥20 mg/dL were associated with a lower risk of the composite endpoint of CVM or first CVH at Month 30 in comparison with <20 mg/dL ( p <0.0001) ( Figure 1A ). Comparable findings were observed for the individual components (CVM, first CVH) ( Figure 1B and C ). Conclusion: Across treatment groups, sTTR levels above normal range (≥20 mg/dL) at Day 28 were associated with a lower risk of cardiovascular outcomes at Month 30, when compared with sTTR levels below normal range (<20 mg/dL). Thus, these observations demonstrate that higher sTTR levels over time may have the potential for clinical benefits in both CVM and CVH.

Introduction: Acoramidis, an oral transthyretin (TTR) stabilizer achieving near-complete (≥90%) TTR stabilization, is now approved in the USA, EU, Japan, and UK for the treatment of TTR amyloid cardiomyopathy (ATTR-CM). In the 30-month phase 3 ATTRibute-CM study, acoramidis reduced all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) vs placebo. Through Month 42 (M42) of the open-label extension (OLE; 30 months ATTRibute-CM + 12 months OLE), the clinical benefit of acoramidis was sustained, resulting in a 36% and 43% risk reduction in ACM and ACM/first CVH, respectively, compared with the placebo to acoramidis group Research Question: Are the long-term clinical benefits of acoramidis on ACM and ACM/first CVH in ATTR-CM over 42 months consistent across patient subgroups? Methods: ATTRibute-CM study design has been previously described. At the end of the 30-month double-blind period, patients enrolled into OLE continued acoramidis or switched from placebo to acoramidis; all patients received open-label acoramidis HCI 800 mg BID. Data cut was performed after 12 months in OLE. Subgroup analysis for ACM and ACM/first CVH through M42 were conducted for randomization stratification factors (genotype, NT-proBNP, and eGFR levels) and other pre-specified subgroups. ACM included death due to any cause, cardiac mechanical assist device placement, and heart transplant. CVH included CV hospitalizations (≥24 h) and urgent visits (<24 h) for decompensated heart failure requiring IV diuretics and was adjudicated by an independent Clinical Events Committee. Results: Overall, 389 patients enrolled in the OLE (263 continuous acoramidis and 126 placebo to acoramidis). The analyses of ACM/first CVH ( Figure 1 ) and ACM ( Figure 2 ) through M42 consistently favored patients initially randomized to acoramidis across all patient subgroups, including those based on sex, age, country, ATTR-CM genotype, baseline NT-proBNP, baseline eGFR, NYHA class, and NAC stage. The largest effect size for the reduction in ACM/first CVH (HR <0.50) was observed in the following subgroups: female, non-Caucasian patients, variant ATTR-CM, or NAC stage 2. Conclusions: The long-term benefit of acoramidis was consistently shown in patients initially randomized to acoramidis treatment compared with placebo to acoramidis switch after 30 months across multiple clinically relevant subgroups, underscoring the importance of early initiation of acoramidis to reduce the long-term risk of ACM or CVH.

Background: Acoramidis is a novel, potent, investigational, transthyretin (TTR) stabilizer under development for the treatment of TTR amyloidosis that results in near-complete (≥90%) TTR stabilization. In a phase 3 study, ATTRibute-CM, acoramidis demonstrated improved clinical outcomes in participants with transthyretin amyloid cardiomyopathy (ATTR-CM), including a 50% reduction in the risk of CVH compared to placebo over 30 months. The study also demonstrated that cardiovascular hospitalization (CVH) during the study predicted a higher subsequent mortality in participants with ATTR-CM. Hypothesis: CVH portends a higher risk of mortality in participants with ATTR-CM. Since acoramidis reduces CVH, it can improve the prognosis of participants with ATTR-CM. Aim: To evaluate the relationship between CVH and survival in the acoramidis group within ATTRibute-CM. Methods: In this post-hoc analysis, the relationship between those with or without CVH and survival was analyzed within the acoramidis treatment group using the Kaplan-Meier (KM) estimator method. Results: Demographics and baseline disease characteristics were mostly comparable between acoramidis-treated participants with and without CVH, although participants with CVH had a higher baseline NT-proBNP and lower eGFR. At Month 30, in acoramidis-treated participants, those without any CVH (n=300) had a higher survival [86.8% (95% CI = 82.2, 90.3)] versus 62.4% (95% CI = 52.6, 70.7) in those who had any CVH (n=109); p<0.0001 from log-rank test (Figure). Conclusion: In the ATTRibute-CM study, pts without any CVH receiving acoramidis have a higher survival rate. CVHs remain a powerful predictor of mortality. This reinforces the importance of an effective therapy that reduces CVH and in turn may improve survival in patients with ATTR-CM.