AIMS:Acoramidis is an oral transthyretin (TTR) stabilizer that achieves near-complete (≥90%) TTR stabilization. This post-hoc analysis evaluated response categories based on NT-proBNP concentration and 6-minute walk distance (6MWD) changes among participants with transthyretin amyloid cardiomyopathy (ATTR-CM) in the phase 3 ATTRibute-CM trial. METHODS AND RESULTS:Clinically meaningful improvement (CMI) was defined as a decrease from baseline to Month 30 in NT-proBNP of >700 ng/L and >30%, and separately, a 6MWD increase of >35 m. Data from 611 participants were analysed (409: acoramidis; 202: placebo). Median baseline NT-proBNP and 6MWD values were 2273 ng/L and 365 m in the acoramidis group and 2274 ng/L and 352 m in the placebo group, respectively. A significantly higher proportion of participants in the acoramidis group reached CMI in NT-proBNP or 6MWD (22.7%) compared with the placebo group (8.9%; OR 3.0, 95% CI 1.8-5.1; p < 0.001). CONCLUSION:Acoramidis led to CMI from baseline in NT-proBNP concentration or 6MWD in a considerable proportion of participants with ATTR-CM. These findings suggest that the treatment paradigm of ATTR-CM may evolve from slowing disease progression to achieving improvement.

Importance In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), acoramidis achieves near-complete (≥90%) transthyretin stabilization and reduces mortality and cardiovascular-related hospitalizations; however, its effect on patient-reported health status has not been comprehensively described. Objective To evaluate the effect of acoramidis on heart failure (HF)–related health status as assessed by the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS) in patients with ATTR-CM. Design, Setting, and Participants ATTRibute-CM was a phase 3, multicenter, international, placebo-controlled randomized clinical trial conducted from April 2019 through May 2023. Adults with ATTR-CM were eligible for inclusion. Data were analyzed from July 2023 through November 2023. Interventions Acoramidis hydrochloride (800 mg) or placebo twice daily for 30 months. Main Outcomes and Measures The prespecified secondary outcome was least-squares mean (LSM) difference in KCCQ-OS over 30 months, analyzed using a mixed-effects model for repeated measures. Post hoc analysis at month 30 included being “alive and not worse” (KCCQ-OS <5-point decrease from baseline), “alive and well” (KCCQ-OS >60 and <10-point decrease from baseline), and ”alive and better” (KCCQ-OS >5-point increase from baseline). Results Among 632 adults with ATTR-CM enrolled, 611 were included in the modified intention-to-treat population. Overall mean (SD) age was 77.2 (6.6) years, and 56 participants (9.2%) were female. Baseline mean (SD) KCCQ-OSs were 71.7 (19.4) and 70.5 (20.7) in the acoramidis (n = 409) and placebo (n = 202) groups, respectively. At month 30, a statistically significant, clinically meaningful treatment benefit was observed for acoramidis vs placebo (LSM difference, 9.9; 95% CI, 6.0-13.9; P < .001). At month 30 (acoramidis: 367; placebo: 188), 171 acoramidis recipients (47%) were “alive and not worse” vs 56 placebo recipients (30%) (odds ratio, 2.1; 95% CI, 1.4-3.1; P < .001; number needed to treat [NNT] = 6). More acoramidis recipients (168 [46%]) were “alive and well” vs placebo (59 [31%]) (odds ratio, 1.9; 95% CI, 1.3-2.8; P < .001; NNT = 7). Similarly, 93 acoramidis recipients (25%) were “alive and better” vs 26 placebo recipients (14%) (odds ratio, 2.1; 95% CI, 1.3-3.4; P = .002; NNT = 9). Conclusions and Relevance In this secondary analysis of the ATTRibute-CM randomized clinical trial, in patients with ATTR-CM, acoramidis significantly attenuated the decline in HF-related health status compared with placebo. These results suggest meaningful patient-centered benefits and clinically relevant modification of disease trajectory with acoramidis. Trial Registration ClinicalTrials.gov Identifier: NCT03860935

Importance:Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disorder caused by destabilization of serum transthyretin (sTTR). Acoramidis, an approved therapy that achieves near-complete (≥90%) sTTR stabilization, demonstrated clinical benefit through month 30 in ATTRibute-CM, which was incremental through month 42 in the open-label extension (OLE); however, the longer-term durability of outcomes has not been reported. Objective:To evaluate the long-term efficacy and safety of acoramidis through month 54. Design, Setting, and Participants:This OLE of the ATTRibute-CM randomized clinical trial is an international, multicenter, ongoing OLE study. Data accumulated between October 2021 and April 2025 through month 24 of the OLE (month 54) are reported. Participants (aged 18-90 years) who completed ATTRibute-CM and met the OLE eligibility criteria were invited to enroll in the OLE. Data were analyzed from May 2025 through November 2025. Interventions:All OLE participants received open-label oral acoramidis, 800 mg, twice daily. Acoramidis recipients from ATTRibute-CM continued therapy (continuous acoramidis) and placebo recipients switched to acoramidis (placebo to acoramidis). Main Outcomes and Measures:The primary outcome was time to event for all-cause mortality (ACM), cardiovascular-related mortality (CVM), and first cardiovascular hospitalization (CVH), which was assessed for both groups. Biomarkers of disease progression (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), sTTR, functional capacity (6-minute walk distance [6MWD]), and heart failure-related health status (Kansas City Cardiomyopathy Questionnaire-Overall Summary [KCCQ-OS] score) were analyzed. Results:In ATTRibute-CM, 632 participants were randomized to receive acoramidis (n = 421) or placebo (n = 211); mean (SD) age was 77.3 (6.6) years, and 62 participants (9.8%) were female. Overall, 389 participants enrolled in the OLE (263 in the continuous acoramidis group; 126 in the placebo-to-acoramidis group). Continuous acoramidis treatment reduced risks of ACM (hazard ratio [HR], 0.55; 95% CI, 0.42-0.74; P < .001) and CVM (HR, 0.51; 95% CI, 0.36-0.71; P < .001) through month 54, with consistent efficacy across all prespecified subgroups. Continuous acoramidis reduced time to first CVH (HR, 0.53; 95% CI, 0.42-0.69; P < .001) through month 54. Through month 54, continuous acoramidis stabilized increases in NT-proBNP, sustained higher sTTR levels, and stabilized KCCQ-OS score and 6MWD. Switching from placebo to acoramidis at month 30 was associated with stabilization of NT-proBNP and KCCQ-OS score and improvements in sTTR and 6MWD through month 54. No new long-term safety concerns were identified. Conclusions and Relevance:In this OLE of the ATTRibute-CM randomized clinical trial, early and continuous acoramidis treatment resulted in sustained incremental reductions in ACM, CVM, and first CVH through month 54. These findings support the importance of early and continuous long-term treatment with acoramidis in ATTR-CM. Trial Registration:ClinicalTrials.gov Identifier: NCT04988386.

This study evaluates the efficacy of acoramidis in transthyretin amyloid cardiomyopathy with wild-type, transthyretin amyloid cardiomyopathy with variant, and variant subgroups (p.Val142Ile and non-p.Val142Ile). QuestionIs the efficacy of acoramidis similar between those with transthyretin amyloid cardiomyopathy with wild-type (ATTRwt-CM) and with a pathogenic/likely pathogenic variant (ATTRv-CM)?FindingAmong 611 participants, in this study, 9.6% had ATTRv-CM with similar reduction in all-cause mortality and first cardiovascular hospitalization compared with ATTRwt-CM at 30-month trial completion. Of 380 participants who continued in the open-label extension, 7.1% had ATTRv-CM with a similar reduction in all-cause mortality at 42-month follow-up.MeaningIn patients randomized to acoramidis and followed up in the open-label extension, reduction in all-cause mortality and cardiovascular hospitalization was similar in those with ATTRv-CM and ATTRwt-CM. ImportanceTransthyretin 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).ObjectiveTo evaluate the efficacy of acoramidis in ATTRwt-CM, ATTRv-CM, and variant subgroups (p.Val142Ile and non-p.Val142Ile).Design, Setting, and ParticipantsThis 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.InterventionsOral acoramidis, 712 mg, or placebo twice daily for 30 months, followed by 12 months of open-label treatment.Main Outcomes and MeasuresAll-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.ResultsOverall, 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 RelevanceThe 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 RegistrationClinicalTrials.gov Identifiers: NCT03860935; NCT04988386

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, often fatal disease caused by transthyretin (TTR) tetramer destabilization, leading to amyloid deposition from either age-related wild type TTR or pathogenic TTR variants. TTR variants are less stable than wild type TTR, leading to lower serum TTR (sTTR) and worse clinical outcomes. TTR stabilizers, tafamidis and acoramidis, are approved for treatment of patients with ATTR-CM. Objectives The aim of this study was to evaluate the differences in stabilizing effect and magnitude of sTTR increases for acoramidis and tafamidis using data from the ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy) trial. Methods Stabilizing potency was analyzed using sTTR as an in vivo readout and by applying 2 orthogonal pharmacodynamic assays: Western blot and fluorescent probe exclusion. In vitro analyses used blood samples from patients with variant ATTR-CM at clinically relevant concentrations of acoramidis (10 μM) and tafamidis (16-26 μM). Results In ATTRibute-CM, treatment with acoramidis (n = 234) resulted in a greater rise in sTTR from baseline to month 30 vs placebo plus tafamidis (n = 34). Acoramidis achieved greater TTR stabilization than placebo plus tafamidis at month 30 by Western blot (90.2% [n = 83] vs 60.6% [n = 6]) and fluorescent probe exclusion (99.7% [n = 71] vs 68.0% [n = 4]), although this was limited by a small sample size. Subsequent in vitro analysis corroborated acoramidis was a more effective TTR stabilizer than tafamidis across all 51 individual participant samples tested, representing 17 unique variants. Conclusions Acoramidis is a near-complete stabilizer of wild type and variant TTR. Although in vitro comparisons between acoramidis and tafamidis suggest greater stabilization by acoramidis, randomized prospective trial data comparing these TTR stabilizers are lacking, and further investigation is warranted. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935)

Importance:In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), acoramidis achieves near-complete (≥90%) transthyretin stabilization and reduces mortality and cardiovascular-related hospitalizations; however, its effect on patient-reported health status has not been comprehensively described. Objective:To evaluate the effect of acoramidis on heart failure (HF)-related health status as assessed by the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS) in patients with ATTR-CM. Design, Setting, and Participants:ATTRibute-CM was a phase 3, multicenter, international, placebo-controlled randomized clinical trial conducted from April 2019 through May 2023. Adults with ATTR-CM were eligible for inclusion. Data were analyzed from July 2023 through November 2023. Interventions:Acoramidis hydrochloride (800 mg) or placebo twice daily for 30 months. Main Outcomes and Measures:The prespecified secondary outcome was least-squares mean (LSM) difference in KCCQ-OS over 30 months, analyzed using a mixed-effects model for repeated measures. Post hoc analysis at month 30 included being "alive and not worse" (KCCQ-OS <5-point decrease from baseline), "alive and well" (KCCQ-OS >60 and <10-point decrease from baseline), and "alive and better" (KCCQ-OS >5-point increase from baseline). Results:Among 632 adults with ATTR-CM enrolled, 611 were included in the modified intention-to-treat population. Overall mean (SD) age was 77.2 (6.6) years, and 56 participants (9.2%) were female. Baseline mean (SD) KCCQ-OSs were 71.7 (19.4) and 70.5 (20.7) in the acoramidis (n = 409) and placebo (n = 202) groups, respectively. At month 30, a statistically significant, clinically meaningful treatment benefit was observed for acoramidis vs placebo (LSM difference, 9.9; 95% CI, 6.0-13.9; P < .001). At month 30 (acoramidis: 367; placebo: 188), 171 acoramidis recipients (47%) were "alive and not worse" vs 56 placebo recipients (30%) (odds ratio, 2.1; 95% CI, 1.4-3.1; P < .001; number needed to treat [NNT] = 6). More acoramidis recipients (168 [46%]) were "alive and well" vs placebo (59 [31%]) (odds ratio, 1.9; 95% CI, 1.3-2.8; P < .001; NNT = 7). Similarly, 93 acoramidis recipients (25%) were "alive and better" vs 26 placebo recipients (14%) (odds ratio, 2.1; 95% CI, 1.3-3.4; P = .002; NNT = 9). Conclusions and Relevance:In this secondary analysis of the ATTRibute-CM randomized clinical trial, in patients with ATTR-CM, acoramidis significantly attenuated the decline in HF-related health status compared with placebo. These results suggest meaningful patient-centered benefits and clinically relevant modification of disease trajectory with acoramidis. Trial Registration:ClinicalTrials.gov Identifier: NCT03860935.

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.

Importance Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disorder caused by destabilization of serum transthyretin (sTTR). Acoramidis, an approved therapy that achieves near-complete (≥90%) sTTR stabilization, demonstrated clinical benefit through month 30 in ATTRibute-CM, which was incremental through month 42 in the open-label extension (OLE); however, the longer-term durability of outcomes has not been reported. Objective To evaluate the long-term efficacy and safety of acoramidis through month 54. Design, Setting, and Participants This OLE of the ATTRibute-CM randomized clinical trial is an international, multicenter, ongoing OLE study. Data accumulated between October 2021 and April 2025 through month 24 of the OLE (month 54) are reported. Participants (aged 18-90 years) who completed ATTRibute-CM and met the OLE eligibility criteria were invited to enroll in the OLE. Data were analyzed from May 2025 through November 2025. Interventions All OLE participants received open-label oral acoramidis, 800 mg, twice daily. Acoramidis recipients from ATTRibute-CM continued therapy (continuous acoramidis) and placebo recipients switched to acoramidis (placebo to acoramidis). Main Outcomes and Measures The primary outcome was time to event for all-cause mortality (ACM), cardiovascular-related mortality (CVM), and first cardiovascular hospitalization (CVH), which was assessed for both groups. Biomarkers of disease progression (N-terminal pro–B-type natriuretic peptide [NT-proBNP]), sTTR, functional capacity (6-minute walk distance [6MWD]), and heart failure–related health status (Kansas City Cardiomyopathy Questionnaire–Overall Summary [KCCQ-OS] score) were analyzed. Results In ATTRibute-CM, 632 participants were randomized to receive acoramidis (n = 421) or placebo (n = 211); mean (SD) age was 77.3 (6.6) years, and 62 participants (9.8%) were female. Overall, 389 participants enrolled in the OLE (263 in the continuous acoramidis group; 126 in the placebo-to-acoramidis group). Continuous acoramidis treatment reduced risks of ACM (hazard ratio [HR], 0.55; 95% CI, 0.42-0.74; P < .001) and CVM (HR, 0.51; 95% CI, 0.36-0.71; P < .001) through month 54, with consistent efficacy across all prespecified subgroups. Continuous acoramidis reduced time to first CVH (HR, 0.53; 95% CI, 0.42-0.69; P < .001) through month 54. Through month 54, continuous acoramidis stabilized increases in NT-proBNP, sustained higher sTTR levels, and stabilized KCCQ-OS score and 6MWD. Switching from placebo to acoramidis at month 30 was associated with stabilization of NT-proBNP and KCCQ-OS score and improvements in sTTR and 6MWD through month 54. No new long-term safety concerns were identified. Conclusions and Relevance In this OLE of the ATTRibute-CM randomized clinical trial, early and continuous acoramidis treatment resulted in sustained incremental reductions in ACM, CVM, and first CVH through month 54. These findings support the importance of early and continuous long-term treatment with acoramidis in ATTR-CM. Trial Registration ClinicalTrials.gov Identifier: NCT04988386

BACKGROUND:Acoramidis, an oral transthyretin stabilizer that achieves near-complete (≥90%) transthyretin stabilization, demonstrated significant clinical benefit over placebo in participants with transthyretin amyloid cardiomyopathy (ATTR-CM) in the phase 3 ATTRibute-CM trial (NCT03860935). METHODS:Post-hoc exploratory analyses of ATTRibute-CM were performed to evaluate associations between outpatient worsening heart failure (HF) (initiation/escalation of oral loop diuretics) and clinical outcomes, the impact of acoramidis on outpatient worsening HF, and the effect of acoramidis on clinical outcomes adjusting for time-dependent first outpatient worsening HF. RESULTS:In the modified-intention-to-treat population, 287/611 participants (46.97%) experienced outpatient worsening HF, which was associated with an increased risk of all-cause mortality (ACM)/recurrent cardiovascular hospitalization (CVH) (hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.51-2.51), first CVH (HR 2.78, 95% CI 1.95-3.95), ACM (HR 1.64, 95% CI 1.14-2.36), and cardiovascular mortality (HR 1.63, 95% CI 1.08-2.46) through month 30. Acoramidis was associated with a 41% risk reduction of first outpatient worsening HF versus placebo (HR 0.59, 95% CI 0.46-0.75); Kaplan-Meier curves separated early, nominal statistical significance was first reached at day 30 (HR 0.562, 95% CI 0.317-0.998; p = 0.0492), and sustained nominal statistical significance was achieved at day 134 through month 30. When adjusting for time-dependent first outpatient worsening HF over 30 months, acoramidis reduced the risk of ACM/recurrent CVH and first CVH versus placebo. CONCLUSIONS:Outpatient worsening HF was associated with clinical outcomes in ATTR-CM. Acoramidis reduced the risk of outpatient worsening HF; effects emerged early and persisted throughout follow-up.

Introduction Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) occurs due to a pathogenic TTR variant (ATTRv-CM) or aging-related misfolding of wild-type protein (ATTRwt-CM). ATTRv-CM occurs at a younger age and progresses faster. Acoramidis, an oral TTR stabilizer achieving ≥90% stabilization, is approved in the USA and Europe for the treatment (Tx) of ATTR-CM. In the phase 3 ATTRibute-CM study, acoramidis reduced all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) risk by 36% and annual CVH frequency by 50%. Results at month 42 (M42; 30 months ATTRibute-CM + 12 months open-label extension [OLE]) showed continuous acoramidis Tx was associated with statistically significant risk reductions (RRs) of 36% in ACM and 43% in ACM/first CVH vs placebo to acoramidis switch. Hypothesis Early and continuous acoramidis Tx is associated with a lower risk of ACM and ACM/first CVH vs delayed Tx initiation in both ATTRv-CM and ATTRwt-CM. Methods At the end of ATTRibute-CM, participants (pts) enrolled into OLE continued or switched to acoramidis HCL 800 mg BID (712 mg active ingredient); tafamidis was not allowed in OLE. Risk of ACM and CVH at M42 was assessed for early and continuous use of acoramidis vs delayed Tx. ACM included death due to any cause, cardiac mechanical assist device placement, and heart transplant. CVH was adjudicated by an independent clinical events committee and included CV hospitalizations (≥24 h) and urgent visits (<24 h) for decompensated heart failure requiring IV diuretics. Forest plots for HRs by genotype (Figure) used stratified Cox models with baseline 6-minute walk distance, Tx, genotype subgroup, and Tx by genotype interaction stratified by NT-proBNP and eGFR at randomization. Results Among 611 ATTR-CM pts (552 wild-type, 59 variant) in the M42 analysis (full-analysis set), 389 completed ATTRibute-CM and entered OLE (362 wild-type, 27 variant). In pts with ATTRv-CM, continuous acoramidis Tx showed RRs at M42 of 59% (HR 0.41, 95% CI 0.19-0.93, p = 0.0320) for ACM, 65% (HR 0.35, 95% CI 0.18- 0.67, p = 0.0017) for ACM/first CVH, and 70% (HR 0.30, 95% CI 0.15-0.61, p = 0.0009) for first CVH. In pts with ATTRwt-CM, continuous acoramidis Tx showed RRs at M42 of 30% (HR 0.70, 95% CI 0.50-0.98, p = 0.0371) for ACM, 40% (HR 0.60, 95% CI 0.47-0.77, p < 0.0001) for ACM/first CVH, and 42% (HR 0.58, 95% CI 0.44-0.76, p = 0.0001) for first CVH. Conclusions At M42, continuous acoramidis Tx was associated with lower risk of ACM, first CVH, and ACM/first CVH vs placebo to acoramidis switch in both ATTRwt-CM and ATTRv-CM, highlighting the importance of early and continuous acoramidis Tx regardless of TTR genotype.

BACKGROUND:Acoramidis achieves near-complete (≥90%) transthyretin stabilization and is approved to reduce cardiovascular-related mortality and hospitalization in transthyretin amyloid cardiomyopathy. Its effects on kidney function are not well characterized. METHODS:Data from randomized phase 2 (N=49) and phase 3 (N=632) studies in transthyretin amyloid cardiomyopathy were included. The estimated glomerular filtration rate (eGFR) slope was generated using a linear spline mixed-effects model. The urinary albumin-to-creatinine ratio was measured longitudinally. Relationships between changes in kidney function and clinical outcomes were explored using Cox proportional hazards models. RESULTS:Acoramidis initiation resulted in a modest acute dip in eGFR that was dose-dependent, reversible, and not associated with adverse kidney-related events. At Day 28, the mean (±SE) dip in eGFR from baseline with acoramidis was 8.5±0.48 mL/min per 1.73 m2; the placebo-corrected reduction in the urinary albumin-to-creatinine ratio was 15.5% (95% CI, 0.4%-28.4%; P=0.044). The rate of decline in kidney function (chronic eGFR slope) was significantly improved with acoramidis versus placebo (-1.01 versus -3.48 mL/min per 1.73 m2 per year; P<0.001), and the reduction in the urinary albumin-to-creatinine ratio was sustained (13.7% [95% CI, 1.7%-24.2%]; P=0.026) over time. Concomitant tafamidis use did not influence the chronic eGFR slope in either arm. Comparing acoramidis versus placebo subgroups with acute eGFR dips ≥ the median (4.89 mL/min per 1.73 m2) favored acoramidis for all-cause mortality or cardiovascular-related hospitalization (hazard ratio, 0.42 [95% CI, 0.22-0.78]; P=0.006; P interaction=0.043) and cardiovascular-related hospitalization (hazard ratio, 0.34 [95% CI, 0.17-0.66]; P=0.002, P interaction=0.025). Within the placebo arm, eGFR dips portended worse outcomes. CONCLUSIONS:Acoramidis initiation resulted in an acute dip in eGFR and reductions in both the chronic eGFR slope and urinary albumin-to-creatinine ratio versus placebo without adverse kidney-related events. Acoramidis effects on kidney function may be mediated through direct kidney-protective hemodynamic effects. Importantly, the acute dip in eGFR was associated with a reduced risk of adverse clinical outcomes within the first year. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03458130, NCT03536767, NCT03860935, NCT04988386.

BACKGROUND:Hereditary variant transthyretin amyloidosis (ATTRv) is caused by > 140 pathogenic TTR gene variants. The heterogeneous presentation of ATTRv clinical phenotypes complicates diagnosis and staging of patients. Tools that improve early detection of ATTRv symptoms and signs and identify risk of transition to clinically detectable disease are needed. METHODS:A retrospective, multicenter study at amyloid centers in France, Spain, Portugal, and the United Kingdom (December 2023-December 2024) assessed asymptomatic carriers (ACs) and ACs who transitioned to symptomatic disease within the previous 2 years (newly symptomatic carriers [NSCs]). A new 23-question asymptomatic carrier neurologic assessment (ACNA) was developed to screen for the potential transition to clinically detectable ATTRv-polyneuropathy (PN). Question topics spanned sensory, autonomic, and systemic signs and symptoms. Fisher's exact tests were conducted to evaluate the association between each individual question and disease status (i.e., NSC vs. AC). Logistic regression models with a Firth correction were used to estimate odds ratios and corresponding 95% confidence intervals. RESULTS:The study included 217 carriers (AC, n = 128; NSC, n = 89) with 18 unique transthyretin variants; 166 (76.5%) had p.Val50Met. Of 23 ACNA questions, 17 were significantly associated with transition to symptomatic disease for all patients. The pattern of neurologic signs and symptoms found to be associated with p.Val50Met and other common variants reflected what is known about variant-specific symptomatology. Confounding factors included age, medical center of treatment, and variant type. CONCLUSION:The ACNA questionnaire may be a clinically valuable tool to screen ACs for risk of transition to symptomatic ATTRv-PN but requires validation.

BACKGROUND:Transthyretin amyloid cardiomyopathy (ATTR-CM) carries high risk for all-cause mortality (ACM), cardiovascular mortality (CVM), and cardiovascular hospitalization (CVH). NT-proBNP (N-terminal pro-B-type natriuretic peptide) and serum TTR (sTTR) are prognostic biomarkers in transthyretin amyloid cardiomyopathy, but their combined value for integrated risk stratification remains unknown. We evaluated the relationship between baseline NT-proBNP and sTTR and their prognostic value in ATTRIBUTE-CM (Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy). METHODS:ATTRIBUTE-CM was a phase 3, randomized, double-blind, placebo-controlled trial. Among 632 participants randomized to acoramidis or placebo, baseline NT-proBNP and sTTR concentrations were evaluated post hoc for associations with baseline characteristics, Kansas City Cardiomyopathy Questionnaire overall scores, 6-minute walk distance, National Amyloidosis Center stage, Geriatric Nutritional Risk Index score, and subsequent time to ACM/first CVH and CVM/first CVH through Month 30. RESULTS:Higher baseline NT-proBNP and lower sTTR were associated with greater disease severity and were inversely correlated. Using multivariable linear regression, sTTR remained inversely correlated with NT-proBNP. Using multivariable Cox analyses, baseline NT-proBNP and sTTR were each independently associated with ACM/first CVH and CVM/first CVH. Higher baseline NT-proBNP combined with lower sTTR conferred higher risk and shorter time to event. Acoramidis reduced risk of ACM/first CVH and CVM/first CVH regardless of baseline NT-proBNP/sTTR, National Amyloidosis Center stage, or Geriatric Nutritional Risk Index. CONCLUSIONS:Baseline NT-proBNP and sTTR were additively prognostic for ACM/first CVH and CVM/first CVH in patients with transthyretin amyloid cardiomyopathy. Their joint measurement may be useful for enhanced staging, risk stratification, and prognostication in transthyretin amyloid cardiomyopathy. Acoramidis demonstrated consistent clinical efficacy regardless of baseline NT-proBNP/sTTR status. REGISTRATION:URL: https://clinicaltrials.gov/study/NCT03860935; Unique Identifier: NCT03860935. Registered: February 2019.

BACKGROUND:Transthyretin amyloid cardiomyopathy (ATTR-CM) causes heart failure, often leading to death, and it may be associated with low serum transthyretin (sTTR) levels. Acoramidis, a near-complete (≥90%) TTR stabilizer, increases sTTR levels and has demonstrated clinical efficacy in ATTR-CM. This report evaluates the association between the acoramidis-related early change from baseline in sTTR (ΔTTR) and cardiovascular-specific outcomes. METHODS:The 611 participants in the phase 3 (ATTRibute-CM) trial (NCT03860935; Efficacy and Safety of Acoramidis in Participants With Transthyretin Amyloid Cardiomyopathy) (acoramidis [409], placebo [202]) received oral acoramidis hydrochloride (800 mg) or placebo twice daily. Outcomes through month 30 included time to cardiovascular mortality (CVM) or first cardiovascular-related hospitalization (CVH), CVM alone, ΔTTR (day 28 until month 30), and the association between early ΔTTR (at day 28) and cardiovascular risk, including a mediation analysis. RESULTS:Acoramidis reduced the risk of CVM or first CVH vs placebo (33.3% vs 48.5%; hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.48-0.80; P < .001). A trend toward lower CVM with acoramidis was observed (14.9% vs 21.3%; HR 0.71; 95% CI 0.47, 1.05; P = .09). Cardiovascular benefits appeared to be mediated by acoramidis-induced ΔTTR (mean [standard error], 9.2 [0.25] mg/dL). Each 1- and 5-mg/dL increase in acoramidis-mediated early ΔTTR was associated with a 5.5% and 24.5% reduction in CVM and a 4.1% and 19.0% reduction in first CVH, respectively, over 30 months. CONCLUSIONS:In ATTRibute-CM trial, acoramidis led to early ΔTTR, which mediated, in part, reduced risks of CVM and first CVH over 30 months. This suggests that sTTR may serve as a clinically informative biomarker for ATTR-CM cardiovascular risk assessment following stabilizer initiation. TWEET: #Acoramidis led to an early increase in serum TTR (sTTR) that reduced risk of cardiovascular (CV) #mortality and first #CV-hospitalization over 30 months, suggesting that #sTTR may be a clinically informative biomarker after stabilizer initiation. @BridgeBioPharma.

BACKGROUND:Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed chronic disease associated with progressive heart failure that results in impaired quality of life, repeated hospitalizations, and premature death. Acoramidis is a selective, oral transthyretin stabilizer recently approved by the U.S. Food and Drug Administration for the treatment of ATTR-CM. In a phase 3, randomized, double-blind study (ATTRibute-CM [Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy]), acoramidis was well tolerated and showed clinical efficacy in improving the primary endpoint, a hierarchical combination of all-cause mortality (ACM), cardiovascular-related hospitalization (CVH), N-terminal pro-B-type natriuretic peptide level, and 6-minute walk distance. OBJECTIVES:The goal of this study was to characterize the efficacy of acoramidis on ACM and CVH. METHODS:In ATTRibute-CM, participants with ATTR-CM were randomized 2:1 to receive acoramidis hydrochloride (800 mg twice daily) or placebo for 30 months. Efficacy analyses were conducted in the modified intention-to-treat population (participants with a baseline estimated glomerular filtration rate ≥30 mL/min/1.73 m2). CVH and the composite of ACM or first CVH were plotted by using Kaplan-Meier curves and summarized with a stratified Cox proportional hazards model. The annualized frequency of CVH was analyzed by using a negative binomial regression model. Subgroup analyses were conducted for the composite of ACM or first CVH. RESULTS:Of the 632 participants randomized to treatment, 611 (97%) were included in efficacy analyses (acoramidis, n = 409; placebo, n = 202). Compared with placebo, acoramidis reduced the occurrence of the composite of ACM or first CVH (acoramidis, 35.9%; placebo, 50.5%; HR: 0.64; 95% CI: 0.50-0.83; P = 0.0008) and of first CVH (acoramidis, 26.7%; placebo, 42.6%; HR: 0.60; 95% CI: 0.45-0.80; P = 0.0005), with Kaplan-Meier curves separating at month 3 and continuing to diverge through month 30. Annualized frequency of CVH was reduced with acoramidis compared with placebo (acoramidis, 0.22; placebo, 0.45; relative risk ratio: 50%; 95% CI: 0.36-0.70; P < 0.0001). The efficacy of acoramidis on the composite of ACM or first CVH was consistent across subgroups. Acoramidis was well tolerated, with no safety signals of potential clinical concern identified. CONCLUSIONS:In participants with ATTR-CM, acoramidis reduced the composite of ACM or first CVH vs placebo, with an early effect driven by a reduction in CVH. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935).