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Background Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a progressive, fatal disease associated with a substantial health care system burden. The aim of this study was to compare health care resource utilization and associated costs among individuals with ATTR‐CM, with non‐amyloid heart failure (HF), and without HF in the United States. Methods Optum's de‐identified Clinformatics Data Mart Database (January 2016 to September 2023) was used to identify patients with ATTR‐CM based on HF and/or cardiomyopathy claims within 2 years of the first ATTR diagnosis. Patients with ATTR‐CM were matched to patients with non‐amyloid HF (HF/cardiomyopathy without ATTR) and non‐HF controls using 1:1 propensity score matching. All‐cause and cardiovascular‐related hospitalizations and costs were compared during follow‐up. Results Each matched cohort included 4571 patients (mean age, 75.3–75.5 years; 56.0%–56.6% male; mean follow‐up: 2.9–3.2 years). The ATTR‐CM, non‐amyloid HF, and non‐HF cohorts had 3.3, 2.7, and 1.5 all‐cause hospitalizations per patient during follow‐up, respectively. Compared with non‐amyloid HF, patients with ATTR‐CM had a longer mean length of stay per hospitalization (all‐cause and cardiovascular‐related: 8.0 versus 7.5 days; P <0.001), more mean days hospitalized annually per patient (all‐cause: 10.6 versus 8.4; cardiovascular‐related: 10.5 versus 8.3 [both P <0.001]), and higher mean annual inpatient hospitalization costs per patient (all‐cause: $42 868 versus $36 061; cardiovascular‐related: $42 841 versus $36 027 [both P <0.001]). In ATTR‐CM subgroups, mean cardiovascular‐related length of stay and days hospitalized were higher among patients aged 46 to 64 years and 65 to 80 years (versus >80 years), Black patients (versus White patients), and patients in the Northeast or South US regions (versus West regions). Conclusions ATTR‐CM is associated with a higher health care resource utilization/cost burden than non‐amyloid HF and the general population.

Abstract Background The National Amyloidosis Centre (NAC) staging system for transthyretin amyloid cardiomyopathy (ATTR-CM) is used to classify patients into prognostic categories based on N-terminal pro-B-type natriuretic peptide (NT-proBNP) level and estimated glomerular filtration rate (eGFR). The NAC staging system has been shown to predict ongoing survival throughout the course of ATTR-CM, with survival progressively decreasing from stage I to stage III. Acoramidis, a highly selective, oral transthyretin stabilizer that achieves near-complete (≥90%) transthyretin stabilization, has recently been approved in Europe and the USA for the treatment of wild-type or variant ATTR-CM in adults. In the phase 3 ATTRibute-CM study, acoramidis treatment was well tolerated and led to a 42% relative risk reduction in the composite of all-cause mortality and recurrent cardiovascular hospitalizations over 30 months compared with placebo (p=0.0005). Purpose To evaluate the ability of acoramidis treatment, as compared with placebo, to stabilize or improve NAC stage after 30 months in participants with ATTR-CM from the ATTRibute-CM study. Methods Participants in ATTRibute-CM were randomized 2:1 to receive acoramidis or placebo for 30 months. Efficacy analyses were conducted in the modified intention-to-treat population, which consisted of all randomized participants who had received at least one dose of acoramidis or placebo, had at least one efficacy evaluation after baseline and had a baseline eGFR ≥30 mL/min/1.73 m2. NAC stage at baseline and Month 30 was assessed. Changes from baseline to Month 30 were categorized as "stable", "improved" or "worsened". The "stable" category comprised participants who stayed within the same NAC stage at baseline and Month 30. The "improved" category comprised participants who moved from a higher NAC stage at baseline to a lower stage at Month 30. The "worsened or missing" category comprised participants who moved from a lower NAC stage at baseline to a higher stage at Month 30 and participants whose Month 30 NAC stage was missing. The change in NAC stage was compared between treatment groups using a stratified Cochran-Mantel-Haenszel test with stratification factors of genotype, NT-proBNP level and eGFR as recorded in the interactive voice/web response system at randomization. Results Overall, 611 participants were analysed (acoramidis: n=409; placebo: n=202). Baseline characteristics were comparable between treatment groups. Most participants had NAC stage I at baseline (acoramidis: 58.9%; placebo: 59.4%; Table). At Month 30, NAC stage remained stable or improved in 52.1% of acoramidis participants compared with 43.1% of placebo participants (p=0.0351; Figure). Conclusions Acoramidis treatment resulted in a greater proportion of participants whose NAC stage improved or remained stable at Month 30 compared with placebo, indicating better stabilization of their disease.

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

Background: Atrial fibrillation (AF) significantly impacts quality of life (QoL) and is often observed in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Acoramidis achieves near-complete (≥90%) transthyretin (TTR) stabilization and is approved in the USA, the UK, Europe and Japan for the treatment of ATTR-CM in adults. In the phase 3 ATTRibute-CM study (NCT03860935), acoramidis treatment significantly reduced the time to all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) at Month 30, and resulted in improved 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) scores and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels relative to placebo. The clinical efficacy of acoramidis has not yet been reported in patients with ATTR-CM and with an AF or atrial flutter (AFL) diagnosis at baseline. Research Question: How does acoramidis treatment affect ACM or first CVH, 6MWD, KCCQ-OS scores, and NT-proBNP levels at Month 30 in participants with ATTR-CM with or without AF/AFL diagnosis at baseline? Methods: The ATTRibute-CM study design has been previously published. This post hoc analysis included participants in the modified intention-to-treat population (N=611) grouped by AF/AFL diagnosis at baseline (defined as recorded AF medical history or the presence of AF or AFL on an ECG at enrollment). The rate of ACM or first CVH at Month 30 was compared between groups using a stratified Cox proportional hazards model. Changes from baseline to Month 30 in 6MWD, KCCQ-OS scores and NT-proBNP levels were summarized descriptively. Results: Overall, 62.8% (384/611) of participants had an AF/AFL diagnosis at baseline (acoramidis: 255/409, placebo: 129/202). These participants had lower mean 6MWD and KCCQ-OS scores and higher median NT-proBNP levels than those without AF/AFL diagnosis at baseline. Treatment with acoramidis reduced ACM or first CVH, slowed the decline in 6MWD and KCCQ-OS scores and blunted the rise in NT-proBNP compared with placebo, regardless of AF/AFL diagnosis at baseline ( Table ). Conclusions: Acoramidis improved clinical outcomes (ACM, CVH), functional status, QoL and NT-proBNP levels relative to placebo in participants with ATTR-CM, regardless of AF/AFL diagnosis at baseline.

Introduction: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) arises from amyloidogenic aggregates of destabilized TTR protein in variant (ATTRv-CM) or acquired wild-type TTR (ATTRwt-CM). The p.V142I (V122I) variant is the most common pathogenic TTR allele in the USA and has higher mortality vs wild type. Acoramidis, an oral TTR stabilizer achieving ≥90% stabilization, is approved in USA, UK, Europe, and Japan for treating ATTR-CM in adults. In ATTRibute-CM (NCT03860935), acoramidis showed a reduction in all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) vs placebo (PBO), with consistent benefit in ATTRwt-CM and ATTRv-CM (all variants). We report clinical outcomes in participants with p.V142I ATTRv-CM. Research Question: What was the efficacy of acoramidis for clinical outcomes (ACM, CVH) in participants with p.V142I ATTRv-CM in ATTRibute-CM? Methods: In ATTRibute-CM, 632 participants were randomized 2:1 to receive acoramidis HCl 800 mg or PBO twice daily for 30 months. All participants enrolled in open-label extension (OLE) received acoramidis only. Exploratory post hoc analyses were done in the p.V142I ATTRv-CM subgroup. Time-to-event analyses used a stratified Cox proportional hazards model using treatment group as an explanatory factor and baseline 6MWD as a covariate, stratified by randomization factors: serum NT-proBNP and eGFR. ACM was analyzed at Month 42 (ATTRibute-CM 30 months + 12 months OLE). Results: Of the 59 patients with ATTRv-CM reported at randomization, 35 (59.3%) had p.V142I (23 acoramidis, 12 PBO) with comparable baseline characteristics; 4 were homozygous for p.V142I (1 acoramidis, 3 PBO). Through Month 30, ACM/first CVH occurred in 43.5% (10/23) of acoramidis vs 83.3% (10/12) in PBO (HR 0.311; 95% CI 0.120–0.805; Figure 1 ). Through Month 42, ACM occurred in 26.1% (6/23) of continuous acoramidis vs 66.7% (8/12) in PBO to acoramidis (HR 0.307; 95% CI 0.097–0.973; Figure 2 ). Conclusions: In participants with p.V142I ATTRv-CM, acoramidis use was associated with 69% risk reduction in ACM/first CVH through Month 30 and ACM through Month 42 vs PBO. This is the first report of clinical benefit of this magnitude observed in this high-risk population. These findings have biologic plausibility and may reflect the near-complete stabilization observed experimentally with acoramidis in p.V142I ATTR fibrils. These observations require confirmation in larger cohort studies.

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.

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: In the phase 3 randomized controlled study ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy), acoramidis, a transthyretin stabilizer, demonstrated significant efficacy on the primary end point. Participants with transthyretin amyloid cardiomyopathy who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report the efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE. METHODS: Participants who previously received acoramidis through month 30 in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through month 30 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 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 NT-proBNP (N-terminal pro-B-type natriuretic peptide), 6-minute walk distance, serum transthyretin, and Kansas City Cardiomyopathy Questionnaire Overall Summary score. Safety outcomes were analyzed through month 42. RESULTS: Overall, 438 of 632 participants in ATTRibute-CM completed treatment, and 389 enrolled in the ongoing OLE (263 continuous acoramidis and 126 placebo to acoramidis). The hazard ratio for ACM or first CVH was 0.57 (95% CI, 0.46–0.72) at month 42 based on a stratified Cox proportional hazards model ( P <0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with hazard ratios of 0.64 (95% CI, 0.47–0.88) and 0.53 (95% CI, 0.41–0.69), respectively, at month 42. Treatment effects for NT-proBNP and 6-minute walk distance also favored continuous acoramidis. On initiation of open-label acoramidis in the placebo-to-acoramidis arm, there was a prompt increase in serum transthyretin. Quality of life assessed by Kansas City Cardiomyopathy Questionnaire Overall Summary score was well preserved in continuous-acoramidis participants compared with the placebo-to-acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation. CONCLUSIONS: Early initiation and continuous use of acoramidis in the ATTRibute-CM study through month 42 of the ongoing OLE study were associated with sustained clinical benefits in a contemporary transthyretin amyloid cardiomyopathy cohort, with no clinically important safety issues newly identified. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04988386.