The ADESTE trial: A phase 2 study of enibarcimab, a monoclonal antibody targeting adrenomedullin, in acute heart failure.

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This study aimed to conduct a phase 2 proof-of-concept and safety study to evaluate the effect of ENIBARCIMAB (EN), a non-neutralizing humanized monoclonal antibody targeting the N-terminus of adrenomedullin (ADM), administered immediately after stabilization with standard of care (SoC) treatment, in patients hospitalized for acute heart failure (AHF). This prospective, open-label, controlled, interventional, multicenter, dose-escalation study was conducted at two cardiology sites in Indonesia. Patients were divided into two interventional groups sequentially receiving 0.5mg/kg (SoC+EN 0.5mg/kg, n=10; first cohort) and 2mg/kg (SoC+EN 2mg/kg, n=10; second cohort) of EN via 1-h intravenous (IV) infusion within 48h after admission for AHF. The control group (n=10) was treated with SoC therapy for AHF therapy. All patients were monitored continuously within 24h post-infusion and subsequent daily until discharge. Treatment-related serious adverse events (SAEs) were recorded during hospitalization and up to 90days after discharge. Both EN dosages were well-tolerated, and no significant safety issues were identified during hospitalization and up to 90days of follow up. SAEs occurred in 10% of patients in each EN group but were deemed not related to treatment. No significant differences in the occurrence of SAEs were found between the groups. Five deaths occurred: three (30%) in the control group as compared with two deaths (20%) in the SoC+EN 2mg/kg group. EN led to a significant increase in plasma bio-ADM levels within 24h post-infusion, with the SoC+2mg/kg group showing the highest increase. Within 1h from IV EN infusion, SoC+EN 2mg/kg compared with 0.5mg/kg, resulted in a significant percentage reduction in systolic, diastolic blood pressure, and mean arterial pressure. However, it did not result in severe hypotension and the need for drug discontinuation. In this pilot safety study of patients hospitalized for AHF, IV infusion of EN 0.5 and 2mg/kg increased circulating plasma bio-ADM levels and was well-tolerated without treatment-related SAEs occurring during hospitalization and up to 90days after discharge.