Tsujita, Kenichi

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy is a progressive disease caused by the deposition of transthyretin (TTR) as amyloid in the myocardium. Current therapies may slow disease progression but do not clear existing deposits. Coramitug is a humanized monoclonal antibody that targets misfolded transthyretin, designed to promote clearance of transthyretin amyloid through antibody-mediated phagocytosis. METHODS: This phase 2, double-blind, placebo-controlled trial randomized participants with transthyretin amyloidosis with cardiomyopathy to receive infusions every 4 weeks of either coramitug at 2 dosages (10 mg/kg or 60 mg/kg) or placebo in a 1:1:1 ratio for 52 weeks. The primary end points were the change from baseline to week 52 in the 6-minute walk test and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Safety was assessed for up to 64 weeks by assessing treatment-emergent adverse events, all-cause mortality, and number of cardiovascular events (comprising hospitalization caused by cardiovascular events or urgent heart failure visits). RESULTS: In total, 104 participants (median age, 77 years; 93% men; 84% New York Heart Association class II; 13% with variant transthyretin amyloidosis with cardiomyopathy) were randomized and dosed: 34 to 10 mg/kg of coramitug, 35 to 60 mg/kg of coramitug, and 35 to placebo. Median NT-proBNP was 1985 pg/mL (interquartile range, 1224, 3406). In total, 90% of participants were receiving disease-modifying therapy; 84% were treated with tafamidis and 7 (6.7%) with transthyretin silencers (patisiran, n=4; vutrisiran, n=3). From baseline to week 52, 60 mg/kg of coramitug significantly reduced NT-proBNP levels compared with placebo (–48% [95% CI, –65% to –22%]; P =0.0017). The change in 6-minute walk test from baseline to week 52 was not statistically different from placebo with either dose. Coramitug (60 mg/kg) was associated with improved functional echocardiographic parameters and was well tolerated. CONCLUSIONS: This phase 2 trial showed that coramitug, an antibody targeting misfolded transthyretin in transthyretin amyloidosis with cardiomyopathy, was well tolerated and, at a dose of 60 mg/kg, resulted in a statistically significant reduction in NT-proBNP, a validated marker of disease progression, with no statistically significant effect on 6-minute walk test within 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05442047.

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.

Objective Grip strength is a well-characterised measure of weakness and of poor muscle performance, but there is a lack of consensus on its prognostic implications in terms of cardiac adverse events in patients with cardiac disorders. Methods Articles were searched in PubMed, Cochrane Library, BioMed Central and EMBASE. The main inclusion criteria were patients with cardiac disorders (ischaemic heart disease, heart failure (HF), cardiomyopathies, valvulopathies, arrhythmias); evaluation of grip strength by handheld dynamometer; and relation between grip strength and outcomes. The endpoints of the study were cardiac death, all-cause mortality, hospital admission for HF, cerebrovascular accident (CVA) and myocardial infarction (MI). Data of interest were retrieved from the articles and after contact with authors, and then pooled in an individual patient meta-analysis. Univariate and multivariate logistic regression was performed to define predictors of outcomes. Results Overall, 23 480 patients were included from 7 studies. The mean age was 62.3±6.9 years and 70% were male. The mean follow-up was 2.82±1.7 years. After multivariate analysis grip strength (difference of 5 kg, 5× kg) emerged as an independent predictor of cardiac death (OR 0.84, 95% CI 0.79 to 0.89, p<0.0001), all-cause death (OR 0.87, 95% CI 0.85 to 0.89, p<0.0001) and hospital admission for HF (OR 0.88, 95% CI 0.84 to 0.92, p<0.0001). On the contrary, we did not find any relationship between grip strength and occurrence of MI or CVA. Conclusion In patients with cardiac disorders, grip strength predicted cardiac death, all-cause death and hospital admission for HF. Trial registration number CRD42015025280.