Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial

• Published in: Intensive care medicine Vol. 47; no. 11; pp. 1284 - 1294
• Main Authors: Laterre, Pierre-François, Pickkers, Peter, Marx, Gernot, Wittebole, Xavier, Meziani, Ferhat, Dugernier, Thierry, Huberlant, Vincent, Schuerholz, Tobias, François, Bruno, Lascarrou, Jean-Baptiste, Beishuizen, Albertus, Oueslati, Haikel, Contou, Damien, Hoiting, Oscar, Lacherade, Jean-Claude, Chousterman, Benjamin, Pottecher, Julien, Bauer, Michael, Godet, Thomas, Karakas, Mahir, Helms, Julie, Bergmann, Andreas, Zimmermann, Jens, Richter, Kathleen, Hartmann, Oliver, Pars, Melanie, Mebazaa, Alexandre
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2021; Springer; Springer Nature B.V; Springer Verlag
• Subjects: Adrenomedullin; Adverse events; Anesthesiology; Antibodies; Antibodies, Monoclonal, Humanized - therapeutic use; Belgium; Biomarkers; Clinical trials; Comparative analysis; Confidence intervals; Critical Care Medicine; Double-Blind Method; Emergency Medicine; Ethylenediaminetetraacetic acid; France; Germany; Health aspects; Hemodynamics; Humans; Infection; Intensive; Intensive care; Life Sciences; Medicine; Medicine & Public Health; Mortality; NCT; NCT03085758; Original; Pain Medicine; Patients; Pediatrics; Pharmaceutical sciences; Placebos; Pneumology/Respiratory System; Randomization; Rankings; Safety; Sepsis; Septic shock; Shock, Septic - drug therapy; Treatment Outcome; Viral antibodies; Belgium; France; Germany; Adrenomedullin; Septic shock; Endothelial function; Adrecizumab (HAM8101); Enibarcimab
• ISSN: 0342-4642; 1432-1238
• DOI: 10.1007/s00134-021-06537-5

Purpose Investigate safety and tolerability of adrecizumab, a humanized monoclonal adrenomedullin antibody, in septic shock patients with high adrenomedullin. Methods Phase-2a, double-blind, randomized, placebo-controlled biomarker-guided trial with a single infusion of adrecizumab (2 or 4 mg/kg b.w.) compared to placebo. Patients with adrenomedullin above 70 pg/mL, < 12 h of vasopressor start for septic shock were eligible. Randomization was 1:1:2. Primary safety (90-day mortality, treatment emergent adverse events (TEAE)) and tolerability (drug interruption, hemodynamics) endpoints were recorded. Efficacy endpoints included the Sepsis Support Index (SSI, reflecting ventilator- and shock-free days alive), change in Sequential-related Organ Failure Assessment (SOFA) and 28-day mortality. Results 301 patients were enrolled (median time of 8.5 h after vasopressor start). Adrecizumab was well tolerated (one interruption, no hemodynamic alteration) with no differences in frequency and severity in TEAEs between treatment arms (TEAE of grade 3 or higher: 70.5% in the adrecizumab group and 71.1% in the placebo group) nor in 90-day mortality. Difference in change in SSI between adrecizumab and placebo was 0.72 (CI −1.93–0.49, p  = 0.24). Among various secondary endpoints, delta SOFA score (defined as maximum versus minimum SOFA) was more pronounced in the adrecizumab combined group compared to placebo [difference at 0.76 (95% CI 0.18–1.35); p  = 0.007]. 28-day mortality in the adrecizumab group was 23.9% and 27.7% in placebo with a hazard ratio of 0.84 (95% confidence interval 0.53–1.31, log-rank p  = 0.44). Conclusions Overall, we successfully completed a randomized trial evaluating selecting patients for enrolment who had a disease-related biomarker. There were no overt signals of harm with using two doses of the adrenomedullin antibody adrecizumab; however, further randomized controlled trials are required to confirm efficacy and safety of this agent in septic shock patients.