Coramitug, a Humanized Monoclonal Antibody for the Treatment of Transthyretin Amyloid Cardiomyopathy: a Phase 2, Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial

Background: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive disease caused by the deposition of transthyretin 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 ATTR-CM to receive infusions every 4 weeks of either coramitug at two dosages (10 mg/kg or 60 mg/kg) or placebo in a 1:1:1 ratio for 52 weeks. The primary endpoints were the change from baseline to week 52 in the six-minute walk test (6MWT) and N-terminal pro-brain type natriuretic peptide (NT-proBNP) levels. Safety was assessed for up to 64 weeks by assessing treatment-emergent adverse events, all-cause mortality, and number of cardiovascular (CV) events comprising hospitalization due to CV 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 ATTR-CM) were randomized and dosed: 34 to coramitug 10 mg/kg, 35 to coramitug 60 mg/kg, 35 to placebo. Median NT-proBNP was 1985 pg/mL (interquartile range: 1224, 3406 pg/mL). In total, 90% of participants were on disease-modifying therapy; 84% were treated with tafamidis and 7 (6.7%) with TTR silencers (patisiran, n=4; vutrisiran, n=3). From baseline to week 52, coramitug 60 mg/kg significantly reduced NT-proBNP levels compared with placebo (–48%; 95% CI: –65%, –22%; P =0.0017). The change in 6MWT 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 ATTR-CM, 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 6MWT within 52 weeks.