Preclinical safety evaluation of the adrenomedullin-binding antibody Adrecizumab in rodents, dogs and non-human primates.

Adrenomedullin (ADM) is a vasoactive peptide in sepsis. The non-neutralizing ADM-binding antibody Adrecizumab improved outcome in animal models of systemic inflammation and sepsis. Herein, we evaluated the preclinical safety of Adrecizumab in various animal species. First, Wistar rats received vehicle, 100, 200 or 400 mg/kg/day of Adrecizumab intravenously (n = 20 each) on days 1, 4, 8 and 14. An additional set of rats received vehicle or 400 mg/kg/day (n = 10 each) on the same days and were followed for 42 days. For toxicokinetics, satellite animals received vehicle (n = 6), 100, 200, or 400 mg/kg/day Adrecizumab intravenously (n = 18 each). A hemodynamic study was performed in Beagle dogs (n = 3) receiving vehicle (day 1), 2 mg/kg (day 3), 10 mg/kg (day 5), 50 mg/kg (day 8) and 10 mg/kg Adrecizumab intravenously (day 29). In final experiments, cynomolgus monkeys received vehicle, 25, 50 or 100 mg/kg/day Adrecizumab intravenously (n = 6 each) on days 1, 4, 8 and 14. Additional groups of monkeys received vehicle or 100 mg/kg/day Adrecizumab intravenously (n = 4 each) on the same days and were followed for 42 days. No mortality or moribund conditions occurred and no toxicologically relevant effects were attributed to Adrecizumab. Adrecizumab significantly increased circulating concentrations of its target peptide ADM, consistent with previous studies and mechanistically relevant. Toxicokinetic analyses showed immediate and dose-dependent peak concentrations, slow elimination and no gender differences. In conclusion, intravenous, repeated administration of high doses of Adrecizumab appeared well-tolerated across species. These results pave the way for further investigation of Adrecizumab in humans (intended dose of 2 mg/kg).

Effects of the Humanized Anti-Adrenomedullin Antibody Adrecizumab (HAM8101) on Vascular Barrier Function and Survival in Rodent Models of Systemic Inflammation and Sepsis.

PURPOSE: Adrenomedullin (ADM) is an important regulator of endothelial barrier function during sepsis. Administration of a murine antibody targeted against the N-terminus of ADM (HAM1101) resulted in improved outcome in models of murine sepsis. We studied the effects of a humanized form of this antibody (HAM8101, also known as Adrecizumab) on vascular barrier dysfunction and survival in rodent models of systemic inflammation and sepsis. METHODS: Rats (n=48) received different dosages of HAM8101 or placebo (n = 8 per group), directly followed by administration of lipopolysaccharide (5 mg/kg). Twenty-four hours later, Evans Blue dye was administered to assess vascular leakage in kidney and liver tissue. Furthermore, mice (n = 24) were administered different dosages of HAM8101 or placebo (n = 6 per group), immediately followed by cecal ligation and puncture (CLP). Eighteen hours later, albumin, vascular endothelial growth factor (VEGF), and angiopoietin-1 were analyzed in the kidney. Finally, effects of single and repeated dose administration of HAM1101, HAM8101 and placebo on survival were assessed in CLP-induced murine sepsis (n = 60, n = 10 per group). RESULTS: Dosages of 0.1 and 2.5 mg/kg HAM8101 attenuated renal albumin leakage in endotoxemic rats. Dosages of 0.1, 2.0, and 20 mg/kg HAM8101 reduced renal concentrations of albumin and the detrimental protein VEGF in septic mice, whereas concentrations of the protective protein angiopoietin-1 were augmented. Both single and repeated administration of both HAM1101 and HAM8101 resulted in improved survival during murine sepsis. CONCLUSIONS: Pretreatment with the humanized anti-ADM antibody HAM8101 improved vascular barrier function and survival in rodent models of systemic inflammation and sepsis.

Designing phase 3 sepsis trials: application of learned experiences from critical care trials in acute heart failure.

Substantial attention and resources have been directed to improving outcomes of patients with critical illnesses, in particular sepsis, but all recent clinical trials testing various interventions or strategies have failed to detect a robust benefit on mortality. Acute heart failure is also a critical illness, and although the underlying etiologies differ, acute heart failure and sepsis are critical care illnesses that have a high mortality in which clinical trials have been difficult to conduct and have not yielded effective treatments. Both conditions represent a syndrome that is often difficult to define with a wide variation in patient characteristics, presentation, and standard management across institutions. Referring to past experiences and lessons learned in acute heart failure may be informative and help frame research in the area of sepsis. Academic heart failure investigators and industry have worked closely with regulators for many years to transition acute heart failure trials away from relying on dyspnea assessments and all-cause mortality as the primary measures of efficacy, and recent trials have been designed to assess novel clinical composite endpoints assessing organ dysfunction and mortality while still assessing all-cause mortality as a separate measure of safety. Applying the lessons learned in acute heart failure trials to severe sepsis and septic shock trials might be useful to advance the field. Novel endpoints beyond all-cause mortality should be considered for future sepsis trials.