Effect of coramitug on diuretic use in transthyretin amyloid cardiomyopathy (ATTR CM): a post-hoc analysis from a phase 2 randomised, placebo-controlled study

Background In a phase 2 double blinded study of 104 participants with ATTR-CM, 60 mg/kg of coramitug, a monoclonal antibody targeting misfolded transthyretin, significantly reduced NT-proBNP as compared to placebo and showed a trend towards improvement in echocardiographic parameters. The aim of this retrospective analysis of the study is to assess the impact of coramitug on diuretic dosing, which might be a sensitive indicator of worsening heart failure symptoms. Methods Participants were randomized to receive infusions every 4 weeks of either placebo, 10 mg/kg of coramitug or 60 mg/kg of coramitug for a total of 52 weeks. Diuretic dose was recorded, and the mean number of increases in diuretic dose over 52 weeks was assessed. In addition, estimated glomerular filtration rate (eGFR; mL/min/1.73m2) was assessed by the CKD-EPI formula adjusted for BSA, with an analysis of patients with an eGFR < 60 also explored. Results 104 participants (median age, 77 years; 93% men; 84% New York Heart Association class II) were randomized. The mean number of instances of increased diuretic doses are shown in the graph. As can be seen, those receiving placebo were more likely to have their dose increased as compared to those receiving 60 mg/kg (rate ratio [RR] 0.48, 95% CI 0.19 to 1.20, p=0.12) or 10 mg/kg (RR 0.56, 95% CI 0.20 to 1.55, p=0.26) of coramitug. Differences between groups developed after approximately one-half year. eGFR tended to decrease more with placebo (–4.6 ± 8.0; 95% CI –7.53 to –1.63) than with 10 mg/kg (–2.4 ± 9.7; 95% CI –6.14 to 1.42) or 60 mg/kg (–1.8 ± 11; 95% CI –5.84 to 2.22) of coramitug (placebo vs coramitug p=0.20). In those with baseline eGFR < 60, eGFR decreased –2.1 ± 6.0 (95% CI –5.17 to 1.05) with placebo, –0.80 ± 4.2 (95% CI –3.79 to 2.19) with 10 mg/kg, but increased 7.0 ± 15 (95% CI –4.17 to 18.17) with 60 mg/kg of coramitug (placebo vs coramitug p=0.10). Conclusions This exploratory analysis suggests that fewer diuretic dose increases were needed with 60 mg/kg of coramitug. Further, less deterioration of renal function was observed with coramitug 60 mg/kg versus placebo and a subgroup with pre-existing kidney disease showed a numerical improvement. While needed to be confirmed in larger studies, less diuretic needs might serve as a sensitive surrogate for symptomatic benefit in heart failure. Further studies should demonstrate whether coramitug promotes clearance of transthyretin amyloid through antibody-mediated phagocytosis with subsequent clinical benefit.