Abstract Body (Do not enter title and authors here): Background: ATTR-CM is a progressive, underdiagnosed disease caused by amyloid fibril deposition in the heart. Current therapies slow progression but do not clear existing deposits. Coramitug is a humanized monoclonal antibody that targets disease-specific forms of transthyretin and may promote clearance of amyloid through antibody-mediated phagocytosis.
Methods: This phase 2, double blind, placebo-controlled trial randomized participants with heart failure (NYHA Class II or III) due to ATTR-CM to receive intravenous 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 NT-proBNP. Safety was assessed for up to 64 weeks by treatment-emergent adverse events, all-cause mortality, number of cardiovascular (CV) events comprising CV-related hospitalization or urgent heart failure visits.
Results: A total of 104 participants were randomized and dosed: 34 to coramitug 10 mg/kg, 35 to coramitug 60 mg/kg, 35 to placebo. Mean age was 76 years; 93% were men; 84% and 16% were in NYHA class II and III, respectively; and 62%, 21%, 14% and 3% were NAC stage 1–4, respectively. Overall, 13% had variant type ATTR-CM; median NT-proBNP was 1985 pg/mL (range: 371 to 12,890 pg/mL); and 90% of participants were on disease-modifying therapy. Baseline characteristics were generally well balanced across the treatment arms. From baseline to week 52, coramitug 60 mg/kg was associated with a significant reduction in NT-proBNP compared with placebo (–48%; 95% CI: –65% to –22%; p=0.0017), whereas coramitug 10 mg/kg was not associated with a significant reduction (–28%; 95% CI: –51% to +7%; p=0.1043) (see also Figure A). There was no statistically significant difference in the change in 6MWT from baseline to week 52 with either dose compared with placebo (Figure B). Coramitug was well tolerated. Treatment-emergent adverse events were numerically less frequent with coramitug 60 mg/kg (216 events) and coramitug 10 mg/kg (257 events), compared with placebo (311 events).
Conclusions: In the first phase 2 trial of an antibody targeting misfolded transthyretin, treatment with the humanized antibody coramitug 60 mg/kg in ATTR-CM was well tolerated and resulted in a statistically significant reduction in NT-proBNP, a validated marker of disease progression.