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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.

Abstract Background/Introduction Patients with ATTR-CM can have lower circulating TTR levels, which is associated with worsening of cardiac function and increased risk of cardiovascular mortality.[1] Acoramidis has been shown to reduce cardiovascular mortality and hospitalization, while increasing circulating TTR levels, in the ATTRibute-CM phase 3 study.[2] Purpose I. Evaluate serum TTR levels in participants (pts) receiving acoramidis vs those who received tafamidis in the placebo group in ATTRibute-CM at Month 30. II. Evaluate serum TTR levels in pts who transitioned from placebo+tafamidis to acoramidis in the open-label long term extension (OLE) study. Methods ATTRibute-CM study: Eligible pts with ATTR-CM were randomized in a 2:1 ratio to receive acoramidis or placebo for 30 months. Pts in both groups had the option of initiating open-label, commercially available tafamidis after 12 months in the study. Upon completion of Month 30, pts were invited to participate in the OLE study. In OLE, pts who had previously received acoramidis continued acoramidis, and those who had previously received placebo+tafamidis were switched to acoramidis-only treatment. All pts in the OLE study received acoramidis only. Change in serum TTR levels in ATTRibute-CM and OLE at data cutoff (Oct 9, 2023) are summarised using descriptive statistics. Results In the phase 3 study, efficacy analyses were performed in 611 pts, of which 61 of 409 (14.9%) and 46 of 202 (22.8%) received tafamidis in acoramidis and placebo groups, respectively. The median time until tafamidis initiation was 17.8 and 16.1 months, respectively; median exposure duration was 11.6 and 10.5 months, for acoramidis and placebo groups, respectively.[3] Change from baseline (CFB) in serum TTR levels remained unchanged at Month 30 in the placebo-only group (mean [SD] = –0.4 [4.92] mg/dL). Characteristics of pts analysed are described in Fig. 1. A total of 380/611 pts (62.2%) entered the OLE study (229 pts continued acoramidis only, and 23 switched from placebo+tafamidis to acoramidis). At the time of data cutoff, 214 pts who had received acoramidis only completed Month 6 in OLE versus 18 who switched from placebo+tafamidis to acoramidis. At Month 30 in ATTRibute-CM, CFB in serum TTR levels were higher for patients who received acoramidis only than those receiving placebo+tafamidis (Fig 2A). Serum TTR levels increased further in pts who switched from placebo+tafamidis to acoramidis in OLE (Fig. 2B). The OLE study is ongoing, and this analysis includes pts who completed the Month 6 visit at time of data-cut. Conclusion(s) CFB in serum TTR levels were higher in pts receiving acoramidis only than those receiving placebo+tafamidis at Month 30 in the double-blind study. A further significant increase in serum TTR levels was observed in those who received placebo+tafamidis and switched to acoramidis in OLE.

Abstract Introduction Transthyretin–mediated (ATTR) amyloidosis is a progressive and fatal disease. Patients with hereditary or wild–type ATTR amyloidosis frequently develop cardiomyopathy (CM). Patisiran, an IV RNAi therapeutic that inhibits synthesis of wt and variant TTR, is approved for the treatment of hATTR amyloidosis with polyneuropathy. Methods In APOLLO–B, patients were 18–85 yrs old with evidence of cardiac amyloidosis by echocardiography, ATTR amyloid deposition on tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with CM, and had prior hospitalization for heart failure (HF) due to ATTR amyloidosis or clinical evidence of HF. Patients were randomized 1:1 to patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. The primary endpoint was change from baseline in 6–MWT at Month 12 (M12) with patisiran vs placebo. Exploratory parameters at M12 included changes in cardiac biomarkers, echocardiography and Tc scintigraphy. Results APOLLO–B enrolled 360 patients (patisiran, n=181; placebo, n=179): median age, 76.0 yrs; male, 89%; wtATTR, 80%; on tafamidis at baseline, 25%. Patisiran showed a significant benefit compared with placebo in 6–MWT (median [95% CI] change from baseline: patisiran, –8.15 [–16.42, 1.50]; placebo, –21.35 [–34.05, –7.52]; HL estimate of median difference: 14.69 [0.69, 28.69]; p=0.0162). Patisiran demonstrated favorable trends in change from baseline of NT–proBNP (mean fold change ratio [95% CI]: 0.80 [0.73, 0.89]; p=1.825×10–5) and troponin I (mean fold change ratio [95% CI]: 0.87 [0.80, 0.95]; p=0.0011) at M12 vs placebo. Patisiran also demonstrated a trend towards benefit in change from baseline of most evaluated echocardiographic parameters at M12 vs placebo. Patisiran–treated patients evaluable for scintigraphy (n=37) experienced a reduction (37.8%) or no change (62.2%) in Perugini grade at M12 compared with baseline. Among placebo patients (n=28) at M12, none experienced a reduction from baseline in Perugini grade, and 1 (3.6%) increased in grade. Patisiran demonstrated an acceptable safety profile; AEs were mostly mild or moderate in severity, and there were no cardiac safety concerns. Conclusions Exploratory analyses after 12 months provide further evidence for the potential benefit of patisiran treatment on cardiac biomarkers and manifestations of cardiac amyloid involvement in patients with ATTR amyloidosis. The long–term impact of patisiran will be assessed in the ongoing APOLLO–B open–label extension.