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

Abstract

Aims: 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).

Methods and results: 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 0.5 mg/kg (SoC + EN 0.5 mg/kg, n = 10; first cohort) and 2 mg/kg (SoC + EN 2 mg/kg, n = 10; second cohort) of EN via 1-h intravenous (IV) infusion within 48 h after admission for AHF. The control group (n = 10) was treated with SoC therapy for AHF therapy. All patients were monitored continuously within 24 h post-infusion and subsequent daily until discharge. Treatment-related serious adverse events (SAEs) were recorded during hospitalization and up to 90 days after discharge. Both EN dosages were well-tolerated, and no significant safety issues were identified during hospitalization and up to 90 days 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 2 mg/kg group. EN led to a significant increase in plasma bio-ADM levels within 24 h post-infusion, with the SoC + 2 mg/kg group showing the highest increase. Within 1 h from IV EN infusion, SoC + EN 2 mg/kg compared with 0.5 mg/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.

Conclusions: In this pilot safety study of patients hospitalized for AHF, IV infusion of EN 0.5 and 2 mg/kg increased circulating plasma bio-ADM levels and was well-tolerated without treatment-related SAEs occurring during hospitalization and up to 90 days after discharge.