SEPSIS & SEPTIC SHOCK

Impaired vascular integrity in sepsis results in organ failure & shock


Sepsis is a life-threatening medical condition caused by an overwhelming
reaction of the immune system to a severe infection. The systemic inflammation results in an acute impairment of the vascular endothelial barrier, leading to vascular leakage and acute circulatory failure (septic shock). Diminished perfusion of internal organs with oxygens finally leads to multiple organ failure and death.

Early treatment with antibiotics and hemodynamic support represent the current standard of care in sepsis management. However, despite considerable improvement in the development of novel antibacterial agents and immunomodulatory therapies, sepsis incidence rate has doubled in the past 10 years and the mortality rate still remains high at approx. 30%. Once the patient developes a septic shock the mortality rate coverges to 50-80% [1,2].

 

ADRENOMEDULLIN

Key regulator of vascular integrity

Since its discovery in 1993, the vasoactive peptide hormone Adrenomedullin (ADM) has attracted a great deal of interest as a multifunctional regulator of the vascular system, i.a. regulating angiogenesis and cardiovascular homeostasis [3]. Adrenomedullin is mainly expressed and secreted by vascular endothelial cells and is best known for its vasodilatory activity [3]. In addition, Adrenomedullin has been extensively described as key determinant of vascular integrity [4,5,6].

Molecular Mechanism of Action

Adrenonomedullin exerts its molecular action mainly via the stimulation of cAMP formation. ADM binds the G protein–coupled receptor CRLR (calcitonin receptor-like receptor) that is expressed both on vascular smooth muscle and vascular endothelial cells. CRLR is associated with one of three different accessory single-pass transmembrane proteins called RAMP1-3 [7]. ADM only interacts with CRLR receptors that are accompanied by either RAMP2 or RAMP3 [7]. Binding of Adrenomedullin to CRLR/RAMP2 or CRLR/RAMP3 on endothelial cells triggers downstream signaling pathways that affect endothelial barrier function and blood vessel permeability [8].

ADRECIZUMAB

 

Clinical Stage First-in-Class Drug Candidate

Adrecizumab is a humanized murine monoclonalIgG1 antibody specifically binding the N-terminal region of human Adrenomedullin. It will be a first-in-class drug that targets and balances an essential reagulator of vascular activity.

  • High Preclinical Efficacy: In several resuscitated vascular integrity models (mouse, rat, pig), Adrecizumab has shown to improve all clinically relevant end points. It reduces vascular leakage, stabilizes the circulation, by restoring blood pressure, normalizing fluid balance and reducing vasopressor demand, improves renal function and reduces mortality from septic shock by 50% (For further details see below or our publication list).
  • GMP Material available: A genereic Good Manufacturing Practice (GMP) process is established and sufficient GMP material for Clinical Phases I and II is available.
  • Strong Patent Position: Adrenomed AG owns six patent families, two already issued in an EP and US patent, that effectively secures our business.
  • Excellent Safety: Regulatory (GLP) Toxicology & Safety studies in healthy rodents(rats) and non-rodents (dogs and non-human primates) showed that Adrecizumab is well tolerated and has an excellent safety profile.
  • Phase I: Safety & Tolerability in healthy subjects confirmed
  • Phase II Goal: Demonstrate Safety & Tolerability, Dose Finding & Effect Size Estimation for Phase III


Preclinical results

Adrecizumab has shown to improve all clinically relevant end points in several resuscitated animal models of vascular integrity (mouse, rat, pig). It reduces vascular leakage, stabilizes the circulation, by restoring blood pressure and reducing vasopressor demand, improves renal function and reduces mortality from septic shock by 50%.


Adrecizumab restores blood pressure Blood pressure [in mmHg] of healthy rats (Healthy) and of rats after sepsis induction (CLP model), either treated with Adrecizumab or an unspecific control antibody (control). Adapted from Blet et al. Intensive Care Med Exp 2015, 3(Suppl 1):A618.
Adrecizumab reduces mortality by 50% Survival rate of rats after sepsis induction (CLP model), either treated with Adrecizumab or an unspecific control antibody. Adapted from Struck et al. Intensive Care Medicine Experimental 2013, 1:3.For further results and details please see our publication list or contact Dr. Frauke Hein  

Adrecizumab restores blood pressure

Blood pressure [in mmHg] of healthy rats (Healthy) and of rats after sepsis induction (CLP model), either treated with Adrecizumab or an unspecific control antibody (control). Adapted from Blet et al. Intensive Care Med Exp 2015, 3(Suppl 1):A618.

 

Adrecizumab reduces mortality by 50%

Survival rate of rats after sepsis induction (CLP model), either treated with Adrecizumab or an unspecific control antibody. Adapted from Struck et al. Intensive Care Medicine Experimental 2013, 1:3.

COMPANY PROFILE

Adrenomed AG is a privately-financed biopharmaceutical company with a clear mission: to improve vascular integrity in order to improve survival. Adrenomed was established in 2009 by Dr. Bernd Wegener and Dr. Andreas Bergmann, co-founders & former executive managers of BRAHMS AG. They changed the standard of care in sepsis by developing Procalcitonin (B.R.A.H.M.S. PCTTM), the diagnostic gold standard sepsis biomarker.

We are focusing on the discovery and development of monoclonal antibody therapies that target the vasoactive Adrenomedullin system as a new strategy for causative and safe treatment of acute circulatory failure, e.g. septic shock. Our lead product is the first-in-class drug candidate Adrecizumab, a humanized monoclonal Adrenomedullin-specific antibody . Adrenomedullin is a vasoactive peptide hormone released by vascular endothelial cells. During sepsis, the impairment of the endothelial barrier leads to collapse of blood pressure (septic shock) which frequently results in multiple organ failure and death. Adrenomedullin is a key regulator of vascular integrity and plays a pivotal role in the development of septic shock. Adrecizumab has an innovative mode of action that spatially controls Adrenomedullin activity, thereby reducing vascular leakage, stabilizing the circulation and lowering mortality.

Board of Directors

Dr. Gerald Moeller | Chief Executive Officer (CEO)

Dr. Andreas Bergmann  | Chief Scientific Officer (CSO)

Senior Management

The virtual nature of the company leads to a very lean personnel structure that mainly focusses on project management. The key competences for planning and evaluation of the preclinical and clinical study program as well as CMC development are in-house capabilities; all operational resources are third party based capacities. The experienced sepsis research for decades resulted in an extensive network with key opinion leaders worldwide in cardiovascular disease and sepsis that support Adrenomed’s clinical research.

Dr. Jens Zimmermann  | Chief Medical Officer (CMO)

Dr. Frauke Hein | Chief Business Officer (CBO)

Dr. Joachim Struck | Head of Research & Development

Regulatory Consultants

Granzer Regulatory Consulting & Services

Supervisory Board

Renke Lührs (Chairman) | Corporate Lawyer & Partner of Buse Heberer Fromm Rechtsanwälte Steuerberater Partnerschaftsgesellschaft in Berlin

Dr. Bernd Wegener | Co-founder of Adrenomed with over 35 years of Management Experience in the Diagnostic and Pharmaceutical Industry

Dr. Metod Miklus | CEO of ExpoCapital GmbH and Co-founder of BRAHMS

Publications

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

    Alexandre Mebazaa, Pierre François Laterre, James A. Russell, Andreas Bergmann, Luciano Gattinoni, Etienne Gayat, Michael O. Harhay, Oliver Hartmann, Frauke Hein, Anne Louise Kjolbye, Matthieu Legrand, Roger J. Lewis, John C. Marshall, Gernot Marx, Peter Radermacher, Mathias Schroedter, Paul Scigalla, Wendy Gattis Stough, Joachim Struck, Greet Van den Berghe, Mehmet Birhan Yilmaz and Derek C. Angus, IJournal of Intensive Care 2016, 4:24 | PDF | PubMed
  •  
  • Epitope specificity of anti-Adrenomedullin antibodies determines efficacy of mortality reduction in a cecal ligation and puncture mouse model

    Joachim Struck, Frauke Hein, Siegmund Karasch, Andreas Bergmann, Intensive Care Medicine Experimental 2013, 1:3 | PDF | PubMed
  •  
  • Adrenomedullin binding improves catecholamine responsiveness and kidney function in resuscitated murine septic shock

    Katja Wagner, Ulrich Wachter, Josef A Vogt, Angelika Scheuerle, Oscar McCook, Sandra Weber, Michael Gröger, Bettina Stahl, Michael Georgieff, Peter Möller, Andreas Bergmann, Frauke Hein, Enrico Calzia, Peter Radermacher, Florian Wagner, Intensive Care Medicine Experimental 2013, 1:2 | PDF | PubMed
  •  
  • Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis

    Rossella Marino, Joachim Struck, Alan S Maisel, Laura Magrini, Andreas Bergmann and Salvatore Di Somma, Critical Care 2014, 18(1):R34 | PDF | PubMed
  •  
  • Hemodynamics effects of Adrecizumab in sepsis rat Blet A, Sadoune M , Polidano E , Merval R, Bernard C , Samuel JL and Mebazaa A, Intensive Care Medicine Experimental, 2015, 3(Suppl 1):A618 | PDF
  •  
  • Endothelial Barrier Injury is directly related to Kidney Dysfunction in resuscitated murine shock model

    Zink F, Stenzel T, Wachter U, Vogt J, McCook O, Radermacher P.,  Shock 2015, 44 Suppl 2:15-6. | WebsiteF1000Prime
  •  
  • Adrenomedullin: it's double-edged sword during sepsis slices yet again

    Kox M, Pickkers P, (Editorial) Intensive Care Medicine Experimental, 2014, 2:1 | PDF
  •  
  • Sepsis bekämpfen - Leben retten

    Andreas Bergmann in |transkript 3/2016 | Website (german)

Press Releases

  • September 25, 2017: Researchers to Present New Preclinical and Clinical Data on Lead Candidate Adrecizumab at Upcoming ESICM (European Society of Intensive Care Medicine) Conference | download

  • August 11, 2017: Adrenomed AG receives approval to conduct proof of concept study with Adrecizumab to treat patients with Early Septic Shock | download

  • March 08, 2017: Phase I successfully completed | Adrecizumab is safe, well tolerated and shows additional therapeutic potential in acute heart failure | download

References

  • Angus et al. (2010) The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med 2010; 36(2): 222-231.
  •  
  • U.S. National Hospital Discharge Survey (2008) www.cdc.gov
  •  
  • Kitamura et al. (1993) Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun, 192: 553-60.
  •  
  • Temmesfeld-Wollbrück et al. (2007) Adrenomedullin and endothelial barrier function. Thromb Haemost. 98(5): 944-51.
  •  
  • Temmesfeld-Wollbrück et al. (2007) Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock. Intensive Care Med. 33(4): 703-10.
  •  
  • Koyama et al. (2013) Vascular endothelial adrenomedullin-RAMP2 system is essential for vascular integrity and organ homeostasis. Circulation. 127(7): 842-53.  
  •  
  • Wagner et al. (2012) Adrenomedullin binding improves catecholamine responsiveness and kidney function in resuscitated murine septic shock, Intensive Care Medicine Experimental, 1:2.
  •  
  • Karpinich et al. (2011) Adrenomedullin Function in Vascular Endothelial Cells: Insights from Genetic Mouse Models. Curr Hypertens Rev, 7(4):228-239.

Contact

Contact Info

+49 (0) 3302 20 77 8 0

+49 (0) 3302 20 77 8 15
info@adrenomed.com
ADRENOMED AG
Neuendorfstraße 15A
Hennigsdorf b. Berlin
D-16761, Germany

I agree to the usage and progressing of my personal data