Davis, Margot K.

Abstract Background Age and sex influence the clinical expression of transthyretin (ATTR) amyloidosis, but limited evidence exists on their real-world impact across disease phenotypes. The prospective, multi-national MaesTTRo study, currently enrolling patients from the USA, Canada, the UK, Germany and Spain, provides a uniquely comprehensive opportunity to explore age- and sex-associated differences in routine practice. The aim of this analysis was to quantify the associations between these factors and diagnostic delay and cardiac findings. Methods Baseline data from 230 consecutively enrolled patients were analysed. Cohorts were stratified by age at diagnosis (<60 y, n = 45; ≥60 y, n = 185) and separately by sex (female n = 70; male n = 161). Clinical characteristics, laboratory values, echocardiographic parameters and Kansas City Cardiomyopathy Questionnaire (KCCQ-23) scores were compared descriptively. Additional data will be included in the presentation as enrollment continues. Results Younger patients exclusively expressed a hereditary genotype (100% vs 63%), and experienced a longer mean (+SD) diagnostic delay than older patients (48 ± 61.5 vs 40.9 ± 64.4 months). Cardiac involvement was markedly age-dependent: median NT-proBNP was 91.5 pg ml⁻¹ (IQR 48.5–307) in the <60 yrs group versus 1,393.5 pg ml⁻¹ (457–3,065) in the ≥60 yrs group. Older patients were more likely to experience New York Health Association (NYHA) class II–IV limitation than younger patients (88% vs 44%). Nonetheless, LV ejection fraction remained preserved in both cohorts (51 ± 14.8 vs 55.6 ± 9.3%). Older patients also reported a higher burden of cardiac symptoms (52% vs 33%). Patient-reported KCCQ scores were lower in the ≥60 yrs group vs <60 years (68.4 ± 22.3 vs 73.3 ± 27.4). Females were more often diagnosed with ATTRv (84% vs 63%) after longer delays (51.3 ± 80.9 vs 38.3 ± 54.6 months), despite a stronger family history (61% vs 34%), and had lower biomarkers (NT-proBNP: 589 pg ml⁻¹ [111–2,509] vs 1,220 pg ml⁻¹ [386–2,941]) and wall thickness (LV wall thickness >12 mm: 58% vs 73%), although there was no difference in LV mass index. Males reported better health status (KCCQ: 70.7 ± 22.2 vs 64.7 ± 24.4). Neurologic manifestations were common in both sexes (~70%), while musculoskeletal symptoms were more commonly reported in females (33% vs 23%). Conclusions Age and sex may independently modulate the diagnostic trajectory and cardiac presentation of ATTR amyloidosis. Advanced age and male sex are associated with more pronounced structural biomarker evidence of myocardial damage, whereas younger age and female sex are linked to delayed diagnosis of primarily hereditary ATTR amyloidosis with polyneuropathy and less cardiac involvement, especially when non-indexed echo measurements are used. These results underscore the need for age- and sex-specific approaches to prompt early clinical suspicion and diagnosis in order to enable treatment to mitigate disease progression.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.

Importance Transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive disease caused by misfolded transthyretin (TTR), occurs as wild-type (ATTRwt-CM) or variant (ATTRv-CM) forms. p.Val142Ile is the most common variant in the US, linked to rapid progression and increased mortality. Acoramidis achieves near-complete (≥90%) TTR stabilization and showed clinical benefit in the 30-month ATTRibute-CM trial and through month 42 in the ongoing open-label extension (OLE). Objective To evaluate the efficacy of acoramidis in ATTRwt-CM, ATTRv-CM, and variant subgroups (p.Val142Ile and non-p.Val142Ile). Design, Setting, and Participants This international, multicenter, phase 3, randomized placebo-controlled study took place from April 2019 to May 2023 with ongoing OLE (month 42). ATTRibute-CM enrolled 632 participants with ATTR-CM; 611 of 632 were included in the modified intention-to-treat (mITT) population. There were 380 participants who continued into the OLE. These data were analyzed from January 2025 to July 2025. Interventions Oral acoramidis, 712 mg, or placebo twice daily for 30 months, followed by 12 months of open-label treatment. Main Outcomes and Measures All-cause mortality (ACM), cardiovascular-related hospitalizations (CVH), serum TTR, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire Overall Summary score, and N-terminal pro B-type natriuretic peptide in participants with ATTRwt-CM and ATTRv-CM. Post-hoc analyses were conducted in variant subgroups, including p.Val142Ile. Results Overall, 552 participants with wild-type ATTR-CM (mean [SD] age, 78 [6.3] years; 92.0% male and 8.0% female) and 59 participants with variant ATTR-CM (mean [SD] age, 73 [7.7] years; 77.3% male and 22.7% female) were randomized (mITT population), including 35 with p.Val142Ile. Consistent efficacy was observed in wild-type and variant subgroups for ACM/CVH through month 30 and ACM through month 42. At month 30, acoramidis reduced the risk of ACM/first CVH vs placebo by 31% in ATTRwt-CM (hazard ratio [HR], 0.69; 95% CI, 0.52-0.90; P = .007) and by 59% in ATTRv-CM (HR, 0.41; 95% CI, 0.21-0.81; P = .01). ACM was reduced through month 42 with HRs of 0.70 (95% CI, 0.50-0.98; P = .04) and 0.41 (95% CI, 0.19-0.93; P = .03) in the ATTRwt-CM and ATTRv-CM groups, respectively. Consistent treatment benefit was observed in participants with ATTRwt-CM and ATTRv-CM for secondary end points. Within variant subgroups (p.Val142Ile vs non-p.Val142Ile), consistent treatment benefits were observed for ACM/CVH through month 30 and ACM through month 42. Conclusions and Relevance The beneficial effect of acoramidis was observed consistently in ATTRwt-CM and ATTRv-CM groups. These hypothesis-generating results indicate that further studies are warranted to better characterize the therapeutic benefit of acoramidis in variant subgroups. Trial Registration ClinicalTrials.gov Identifiers: NCT03860935 ; NCT04988386

Introduction: Patients with variant transthyretin (TTR) amyloid cardiomyopathy (ATTRv-CM) experience early onset disease, rapid progression, and poor outcomes due to amyloid aggregated from destabilized tetrameric TTR. Acoramidis, a highly selective, oral TTR stabilizer, achieves ≥90% TTR stabilization and is approved in the USA, EU, Japan, and UK for adults with wild-type (ATTRwt-CM) or ATTRv-CM. In the phase 3 ATTRibute-CM study and its open-label extension (OLE), acoramidis reduced both the risk of all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) through Month 30 and risk of ACM through Month 42 by 36%. Research Question: Is acoramidis efficacy in ATTRv-CM consistent with that observed in the overall ATTRibute-CM population? Methods: In ATTRibute-CM, participants with ATTR-CM were randomized 2:1 to acoramidis HCl 800 mg or PBO, twice daily (BID) for 30 months. After Month 30, all participants enrolled in the OLE received acoramidis HCl 800 mg BID. Genotype (ATTRwt-CM or ATTRv-CM) was captured at randomization; efficacy was analyzed separately in ATTRv-CM. Time-to-event analyses used a stratified Cox model with terms for treatment, baseline 6MWT, genotype, genotype×treatment interaction, stratified by randomization NT-proBNP and eGFR levels. ACM was analyzed at Month 42 (ATTRibute-CM 30 months + OLE 12 months). Results: The ATTRv-CM group comprised 59 patients (39 acoramidis, 20 PBO). Baseline characteristics were mostly similar in both groups ( Table ). The three most common variants reported were p.V142I (n=35), p.I88L (n=7), and p.T80A (n=5). Compared with PBO, acoramidis reduced the risk of ACM/first CVH through Month 30 by 59% (acoramidis, 46.2%; PBO, 75.0%; HR 0.41; 95% CI 0.21–0.81; P =0.011; Fig 1 ) and ACM through Month 42 by 59% (continuous acoramidis, 30.8%; PBO to acoramidis, 60.0%; HR 0.41; 95% CI 0.19–0.93; P =0.032; Fig 2 ) , with Kaplan–Meier curves separating at Months 5 and 10, respectively. Conclusions: In ATTRibute-CM, acoramidis use was associated with clinical benefit in the ATTRv-CM group as demonstrated by a 59% risk reduction in both ACM/first CVH at Month 30, and ACM at Month 42 compared to PBO. These previously unreported findings support the hypothesis that near complete TTR stabilization observed experimentally with acoramidis across multiple TTR mutations translates into improvement in long-term outcomes. Further validation by individual TTR variant is warranted.

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.

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.

Abstract Aims To evaluate the effect of long-term tafamidis treatment on health-related quality of life (HRQoL) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) enrolled in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension (LTE) study. Methods and results We examined change from baseline in Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) and clinical summary (KCCQ-CS) scores in patients who received tafamidis meglumine 80 mg for 30 months in ATTR-ACT and tafamidis (meglumine 80 mg or bioequivalent free acid 61 mg) for 30 months in the LTE study, and in patients who received placebo for 30 months in ATTR-ACT and tafamidis for 30 months in the LTE study. In ATTR-ACT, 176 and 177 patients were randomized to tafamidis 80 mg and placebo, respectively. Patients who continuously received tafamidis had a 6- to 7-point reduction in least squares (LS) mean (standard error) KCCQ-OS and KCCQ-CS scores at month 30 (−6.25 [1.53] and −7.48 [1.39]), with little or no further decline over the next 30 months (−5.92 [1.77] and −9.21 [1.88] at month 60). Patients who received placebo in ATTR-ACT had a 20-point reduction in LS mean KCCQ-OS and KCCQ-CS scores at month 30 (−19.60 [1.94] and −19.90 [2.01]), but the decline slowed after initiating tafamidis (−24.70 [3.04] and −25.30 [3.36] at month 60). Conclusion Tafamidis reduced HRQoL decline in patients with ATTR-CM. Patients continuously treated with tafamidis for 60 months demonstrated stabilized HRQoL. In patients who initially received placebo in ATTR-ACT, tafamidis reduced the decline in HRQoL during the LTE study.