DUBLIN – Adrenomed AG reported its anti-adrenomedullin antibody, adrecizumab, attained an absolute reduction of 9% in mortality as compared with placebo at both 14 and 28 days (D28) after treatment in a phase II trial in a large subgroup of patients with septic shock.
Hennigsdorf, Germany-based Adrenomed reported earlier this year that adrecizumab attained the primary endpoint of the study, which was based on safety and tolerability. It also reported at that time a positive trend in all-cause mortality. It reported the numbers this week at a virtual version of the International Symposium on Intensive Care and Emergency Medicine (ISI-CEM).
The study recruited 301 patients with early septic shock and assigned them to one of two drug arms or a control arm (1-to-1-to-2). Those on drug received adrecizumab as a single dose of either 2 mg/kg or 4 mg/kg of bodyweight. The biomarker-guided study only recruited patients who had elevated plasma levels (>70 picograms/ml) of the peptide hormone adrenomedullin at admission.
Adrenomedullin normally helps to maintain endothelial barrier function, but sepsis can cause levels to rise in the interstitial space outside the vasculature, where it has strong vasodilatory effects and contributes to the “leaky vessels” that are a central part of the pathology of septic shock. Adrecizumab does not eliminate adrenomedullin, but sequesters it within the lumen of blood vessels, where it exerts its beneficial effects.
The survival signal was strongest in patients who also had low plasma levels (<70 ng/ml) of dipeptidyl protease 3 (DPP3), a biomarker of cardiac dysfunction, which is independent of adrenomedullin. Those in that category who received adrecizumab (n=125) had a D14 mortality rate of 12% (15/125) as compared with 21% (29/139) for those in the control arm (n=139). That translates into a relative reduction in mortality of 45% (p=0.057).
The effect was maintained over the following two weeks. “The curves stayed absolutely parallel,” Adrenomed CEO Jens Schneider-Mergener told BioWorld. The absolute mortality levels rose during that time, however. At D28, the mortality rate for those in the drug-treatment arm was 18% vs. 27% for those in the control arm. The study was not powered to detect a survival signal but the mortality data are “very close” to statistical significance, he said. The survival benefit was statistically significant in a subgroup of patients with DPP3 levels below 60 ng/ml.
Adrecizumab did attain a significant (p<0.05) reduction in the SOFA (Sequential-related organ failure assessment) score, 24 hours after treatment. “We see a rapid onset of adrecizumab in elevating adrenomedullin, which translates into a SOFA score reduction,” Adrenomed’s co-founder and chief business officer, Frauke Hein, told BioWorld. The SOFA score assesses six organ systems affected by sepsis: lungs, heart, brain, liver and kidney, as well as blood coagulation.
Mortality is not included in the SOFA assessment, however. Patients were also evaluated on a specially designed endpoint, the Sepsis Severity Index (SSI), which combines renal, cardiovascular and pulmonary function with mortality. It failed to demonstrate any difference between the drug-treatment and control groups, however, and Adrenomed has concluded that “conceptual limitations” make it an unsuitable endpoint. “Maybe we were too clever,” Hein said.
The survival signal appears to be real, however, and the company is now considering how to build on the present study. It will conduct additional small-scale clinical and simulation studies that will help to inform the design of a phase III trial, which it aims to begin during the first half of 2022.
A key issue to consider is whether a higher dose or an additional dose would further improve the outcome. Adrecizumab has a half-life of only seven days in patients, Schneider-Mergener said, whereas its half-life is twice that in healthy volunteers. The drug appears to have a good therapeutic window – it has been dosed at twice the level used in the present trial in an ongoing trial in cardiogenic shock and on a small-scale compassionate use initiative in COVID-19
Sepsis has been a notoriously difficult indication for drug developers over the years. By developing biomarkers to help it identify likely responders, Adrenomed hopes to change that narrative. Another European firm, Paris-based Inotrem SA, is also using biomarkers to guide the development of another candidate drug for septic shock.
Nangibotide, which blocks the Trem-1 (triggering receptor expressed on myeloid cells) inflammatory pathway, is undergoing a phase II trial in 450 septic shock patients. Its primary endpoint is the change in SOFA score from baseline to D5. D28 survival and all-cause mortality are secondary endpoints. Its subgroup analysis will include a group with elevated baseline levels of Trem-1. Inotrem previously reported a D28 mortality rate of 14% (5/37) for nangibotide vs. 25% (3/12) for the placebo group in a phase IIa trial.
Immunosuppressed or immunocompromised patients are not eligible to receive the therapy, a major point of difference with Adrenomed’s approach. “We go downstream,” Hein said.