AdrenoMed AG has announced promising results from a prespecified subgroup analysis of its Phase II AdrenOSS-2 trial for septic shock treatment. The findings, published in the Journal of Critical Care, demonstrate that enibarcimab (formerly known as Adrecizumab) significantly improved outcomes in biomarker-selected patients.
Biomarker-Guided Precision Medicine Approach Shows Strong Results
The double-blind, placebo-controlled trial utilized a novel precision medicine approach, targeting patients with elevated levels of bioactive adrenomedullin (bio-ADM >70 pg/mL) and low levels of dipeptidyl peptidase 3 (DPP3 <70 ng/mL). This dual biomarker strategy identified patients most likely to benefit from enibarcimab, a humanized non-neutralizing monoclonal antibody targeting adrenomedullin.
In the identified patient subgroup (n=128 for enibarcimab, n=141 for placebo), treatment with enibarcimab led to substantial improvements in organ function as measured by the Sequential Organ Failure Assessment (SOFA) score. The between-group difference was 1.33 points (p=0.006) in favor of enibarcimab over a seven-day period.
More importantly, the 28-day all-cause mortality rate was reduced to 18% in the enibarcimab group compared to 26% in the placebo group, corresponding to a hazard ratio of 0.65.
Prof. Dr. Peter Pickkers, Professor of Experimental Intensive Care Medicine at Radboud University Nijmegen Medical Centre and corresponding author of the study, emphasized the significance of these findings: "For too long, sepsis treatment has relied on a one-size-fits-all approach, failing to account for the complexity of this multifactorial condition. This prespecified subgroup analysis from the AdrenOSS-2 trial demonstrates that combining biomarkers results in pronounced enrichment as it identifies the patients in septic shock who will likely experience the best treatment efficacy of enibarcimab."
Addressing the Pathophysiology of Septic Shock
Septic shock is increasingly understood as a multifactorial syndrome with complex underlying pathophysiology involving different pathways. The AdrenOSS-2 trial specifically targeted vascular integrity, a critical factor in septic shock progression.
Enibarcimab works by binding to adrenomedullin (ADM), a key regulator of vascular integrity. Rather than neutralizing ADM, the antibody increases plasma levels of bioactive ADM, enhancing its beneficial effects on endothelial function and counteracting sepsis-induced vascular leakage.
Dr. Stephan Witte, Chief Medical Officer of AdrenoMed, explained: "These results highlight the critical value of a biomarker-guided precision medicine approach in sepsis. By stratifying patients based on both bio-ADM and DPP3 levels, we can more effectively target those most likely to benefit from our causal therapy."
Biomarker Rationale and Patient Selection
The dual biomarker approach used in the trial reflects the complex nature of septic shock. While elevated bio-ADM levels indicate endothelial barrier dysfunction that may respond to enibarcimab treatment, high DPP3 levels reflect a different septic shock pathology that would not benefit from the ADM-antibody.
DPP3 is a cytosolic enzyme involved in the degradation of various cardiovascular and endorphin mediators. Elevated levels indicate a high risk of organ dysfunction and mortality through a mechanistically distinct pathway from the loss of vascular integrity targeted by enibarcimab.
This strategic patient selection represents a significant advancement in sepsis clinical trial design, moving away from the traditional one-size-fits-all approach that has contributed to numerous failed trials in this therapeutic area.
Moving Toward Confirmatory Trials
Based on these promising results, AdrenoMed has designed the confirmatory BOOST clinical trial, which will apply the same precision medicine approach to obtain efficacy data supporting a future marketing authorization application.
The need for new septic shock treatments remains critical. Even with the best standard of care, mortality rates for septic shock patients remain at 30-50%. Enibarcimab holds the potential to significantly improve these outcomes by addressing one of the fundamental pathophysiological mechanisms of the condition.
Founded in 2009, AdrenoMed AG is a German privately financed, clinical-stage biopharmaceutical company focused on rescuing vascular integrity in critically ill patients. The AdrenOSS-2 trial included 301 patients with early septic shock and incorporated the biomarker-guided enrichment strategy that proved successful in identifying responders.
The full results of the prespecified subgroup analysis were published in the Journal of Critical Care in April 2025, with the citation: Knothe C, Witte S, Bergmann A, Mebazaa A, Laterre PF, Pickkers P. Enibarcimab for the treatment of septic shock in patients selected by a combination of the biomarkers bio-ADM and DPP3: A prespecified subgroup analysis of the AdrenOSS-2 trial.
