Adrenomed AG reveals Adrecizumab mode of action

14. June 2018

  • Three scientific papers report how the monoclonal therapeutic antibody Adrecizumab reverses vascular hyperpermeability in sepsis.
  • Adrecizumab acts through stabilization of the vasoactive peptide hormone adrenomedullin and its redistribution from tissue into blood plasma without blocking adrenomedullin receptor signaling.
  • Adrecizumab-induced rise in adrenomedullin plasma levels attenuates vascular leakage, improves kidney function and reduces mortality.
  • Adrecizumab triggers adrenomedullin-mediated stabilization of endothelial barrier function and vessel tone which both contribute to the development of septic shock when impaired.

Hennigsdorf/Berlin (Germany) June, 14th, 2018 – Adrenomed AG today announces the publication of two landmark papers in Shock [1,2] and a letter to the editor in Critical Care [3] suggesting a novel mode of action of its first-in-class adrenomedullin-specific antibody Adrecizumab (HAM8101) in the treatment of sepsis. The first author of all papers was Christopher Geven (Department of Intensive Care Medicine, and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands) in the Group of Prof. Peter Pickkers. Data generated in two animal models for sepsis and in humans with systemic inflammation show that Adrecizumab restores the impaired vascular barrier function that causes hemodynamic instability in sepsis and leads to edema formation, organ failure and shock. The story will be the cover picture of the Shock August issue.

Treatment of endothelial dysfunction is a completely new causal approach to decrease mortality in sepsis, a condition that affects 24 million people worldwide per year and is currently managed by supportive treatment such as vasopressors, organ support etc. To date, there is no treatment to correct endothelial dysfunction, which also is a hallmark of other common conditions with high unmet medical need such as congestive heart failure.

Clinical data from more than 16,000 patients have shown that the vasoactive peptide hormone adrenomedullin is a key regulator in endothelial integrity. However, due to its short plasma half-life (22 mins) and its relaxing effect on vascular smooth muscle cells, which surround blood vessels, it was difficult to target adrenomedullin in a way that selectively supports its beneficial effects on the barrier function of the endothelium. Based on experimental evidence from preclinical models and two clinical Phase I studies, the authors suggest a mode of action of Adrecizumab that prevents vasodilation but selectively boosts endothelial integrity leading to beneficial effect on hemodynamics and mortality in sepsis:

  1. Excess Adrecizumab in the blood vessels binds most of the vasoactive 6kDA peptide adrenomedullin, which freely diffuses between the extra- and intravascular space, fixing it to the intravascular compartment where it restores the barrier function of the endothelium.
  2. Excess of Adrecizumab does not increase adrenomedullin synthesis in smooth vascular muscle and endothelial cells.
  3. Adrecizumab (plasma half-life 14d), which binds adrenomedullin N-terminally, prolongs the short half-life (22 mins) of the free peptide in the vasculature by protecting it from N-terminal proteolysis while only marginally affecting its C-terminal receptor binding activity in the endothelium.
  4. Redistribution of adrenomedullin from the extravascular space to the intravascular compartment promotes adrenomedullin’s proven intravascular effects (closing of endothelial gaps, tight junctions) while preventing its extravascular effects (vasodilation).

The proposed mode of action is supported by new animal data, published in Shock [2]. In a rat endotoxemia model (N=48) administration of Adrecizumab (0.02-2.5 mg/kg HAM8101) before induction of sepsis by bacterial lipopolysaccharide (LPS) attenuated LPS-induced vascular hyperpermeability by 40- 71% vs controls as measured by albumin leakage into the kidney. In a cecal ligation and puncture (CLP) mouse model for sepsis (N=24), a single Adrecizumab injection (0.1-20 mg/kg) prior to surgical induction of sepsis also significantly reduced albumin leakage into renal tissue (77-78% vs placebo). At the same time, levels of VEGF, a potent inducer of vascular permeability, was significantly reduced in renal tissue. Furthermore, levels of Ang1, a biomarker for improved endothelial barrier function, increased. In an additional study with CLP mice (N=60), a single injection of Adrecizumab reduced 7-day mortality by 50%, while repeated injection of the humanized antibody reduced 14-day mortality by 60%. The results provide statistically significant evidence that Adrecizumab prevents inflammation-induced vascular hyperpermeability and improves survival in mouse models for sepsis.

“Endothelial dysfunction and vasodilation are hallmarks of sepsis,” commented Dr. Andreas Bergmann, Founder and Chief Scientific Officer of Adrenomed AG. “The unique mode of action of Adrecizumab has large potential to add significant benefit to the treatment of sepsis and early septic shock.“ An interim analysis of a proof-of-concept Phase II study with Adrecizumab in 300 patients with septic shock is expected in

Q4/2018. Furthermore, Adrenomed is planning a Phase II proof-of-concept study in patients with acute decompensated heart failure.

About Adrenomed
Adrenomed AG is a privately financed biopharmaceutical company, based in Hennigsdorf near Berlin, Germany, with a clear mission to improve survival by improving vascular integrity in critically ill patients. Its lead candidate, Adrecizumab, a monoclonal antibody therapy targeting the vasoactive adrenomedullin system, is in clinical testing for early septic shock. Impaired vascular integrity is a pathology observed in a variety of medical conditions. A further indication besides sepsis and early septic shock is acute decompensated heart failure.

About adrenomedullin
Adrenomedullin is a strong vaso-regulatory hormone released by smooth muscle cells and the endothelium. It is a key regulator of blood pressure and vascular tone and plays a pivotal role in the development of septic shock.

About Adrecizumab
Adrecizumab is a proprietary humanized monoclonal adrenomedullin-specific antibody, as first-in-class therapy for the treatment and prevention of impaired vascular integrity, which is a hallmark of septic shock. Adrecizumab showed excellent safety & tolerability as well as high efficacy in a variety of preclinical animal models, mimicking human standard of care treatment on ICU. In several resuscitated vascular integrity models (mouse, rat, pig), Adrecizumab reduced vascular leakage, stabilized the circulation, by restoring blood pressure, normalized fluid balance and reduced vasopressor demand, improved renal function and reduced mortality from septic shock by 50%. The excellent tolerability and safety of Adrecizumab was confirmed in two clinical Phase-I studies in healthy subjects with and without LPS challenge. Adrecizumab is currently tested in a double-blind, placebo-controlled, randomized, multicenter proof of concept and dose-finding phase II study using two doses of ADRECIZUMAB in patients with early septic shock and a bio-ADM plasma concentration at admission of > 70 pg/ml (AdrenOSS-2, ClinicalTrials.gov Identifier: NCT03085758).

Septic shock
is defined as a life-threatening organ dysfunction due to dysregulated host response to a proven or suspected infection which leads to a decline of Mean Arterial Pressure (MAP) < 65 mmHg, which is refractory to fluid resuscitation and requires vasopressors. Refractoriness to fluid resuscitation is defined as a lack of response to the administration of 30 mL of fluid per kilogram of body weight or is determined according to a clinician’s assessment of inadequate hemodynamic results.

About animal models for Sepsis
In the the cecal ligation and puncture (CLP) model, peritonitis is surgically induced by ligature of the cecum and puncture with a tiny needle. Subsequently, cecal contents is pressed through the wound.

In the endotoxemia model, mice received a 5mg/kg injection of bacterial lipopolysaccharide (LPS).

References

  • Geven C, Bergmann A, Kox M, Pickkers P. Vascular effects of adrenomedullin and the anti-adrenomedullin antibody adrecizumab in sepsis. Shock 2018 Publish Ahead of Print
  • Geven C, Peters E, Schroedter M, Struck J, Bergmann A, McCook O, et al. Effects of the humanized anti-adrenomedullin antibody adrecizumab (HAM8101) on vascular barrier function and survival in rodent models of systemic inflammation and sepsis. Shock 2018; Publish Ahead of Print
  • Geven C and Pickkers P. The mechanism of action of the adrenomedullin-binding antibody adrecizumab. Critical Care 2018; 22:159

Contact

Frauke Hein, Ph.D. (CBO)
Adrenomed AG
phone: +49 (0)3302 2077814
fhein@adrenomed.com
www.adrenomed.com