Adrenomed AG

Company Profile

Adrenomed AG is a biopharmaceutical company with a clear mission: to improve vascular integrity in order to improve survival.

Adrenomed was established in 2009 and focuses on the discovery and development of monoclonal antibody therapies that target the vasoactive Adrenomedullin system. Adrenomedullin is a vasoactive peptide hormone released by vascular endothelial cells. Adrenomedullin is a key regulator of vasodilation and vascular integrity and plays a pivotal role in the development of septic shock.

The company’s lead product is the new first-in-class clincial stage drug candidate Adrecizumab, a humanized monoclonal antibody against Adrenomedullin. Adrecizumab has an innovative mode of action that controls the activity of Adrenomedullin and stabilizes blood circulation in sepsis, leading to lower mortality.

AdreCIZUMAB

Targeted therapy to improve vascular integrity in septic shock and beyond...

Adrecizumab is a humanized monoclonal antibody specifically binding the vasoactive peptide hormone Adrenomedullin, without blocking its biological activity. Adrenomedullin is a protective factor of blood vessel integrity that is known to counteract vascular leakage. Blood vessel integrity is compromised in a variety of medical condition, e.g. sepsis. The inflammation-induced loss of vascular integrity during sepsis frequently results in septic shock. Septic shock is a fatal drop in blood pressure that leads to diminished supply with oxygen and multiple organ failure and causes over 60,000 deaths per year in Germany alone.

Adrecizumab is the first drug candidate able to stabilize the entire circulatory system during septic shock 

Adrecizumab is intended for the secure and causal treatment of septic patients in intensive care units. During drug development, Adrenomed used the most suitable preclinical animal models for sepsis that mimic the actual conditions on ICUs. The results are very promising: The treatment with Adrecizumab restores kidney function and fluid balance, stabilizes blood pressure, reduces the inflammatory response and vascular damages - on top of standard of care. Finally, the mortality decreased by 50%.

Adrecizumab has an excellent safety and tolerability profile. The single short-term infusion of Adrecizumab in healthy volunteers (Phase-I) lead to rapid elevation of plasma ADM levels, in order to improve vascular integrity. 

Phase-II: Clinical Study with Adrecizumab in patients with early septic shock initiated. Second Phase-II study in congestive feart failure planned.


Preclinical results

Blood pressure of healthy rats in mmHg (Healthy Control) 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
Blood pressure of healthy rats in mmHg (Healthy Control) 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
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.
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.
 
ADRENOMED AG

Executive Board

Dr. Gerald Möller | Chief Executive Officer

Dr. Andreas Bergmann  | Chief Scientific Officer

 

Literature

Wagner et al. Intensive Care Medicine Experimental 2013, 1:2

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 Med Exp. 2013, 1:2

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ABSTRACT

PURPOSE: Adrenomedullin (ADM) has been referred to as a double-edged sword during septic shock: On one hand, ADM supplementation improved organ perfusion and function, attenuated systemic inflammation, and ultimately reduced tissue apoptosis and mortality. On the other hand, ADM overproduction can cause circulatory collapse and organ failure due to impaired vasoconstrictor response and reduced myocardial contractility. Since most of these data originate from un-resuscitated shock models, we tested the hypothesis whether the newly developed anti-ADM antibody HAM1101 may improve catecholamine responsiveness and thus attenuate organ dysfunction during resuscitated murine, cecal ligation and puncture (CLP)-induced septic shock.

METHODS: Immediately after CLP, mice randomly received vehicle (phosphate-buffered saline, n = 11) or HAM1101 (n = 9; 2 μg·g(-1)). Fifteen hours after CLP, animals were anesthetized, mechanically ventilated, instrumented, and resuscitated with hydroxyethylstarch and continuous i.v. norepinephrine to achieve normotensive hemodynamics (mean arterial pressure > 50 to 60 mmHg).

RESULTS: HAM1101 pretreatment reduced the norepinephrine infusion rates required to achieve hemodynamic targets, increased urine flow, improved creatinine clearance, and lowered neutrophil gelatinase-associated lipocalin blood levels, which coincided with reduced expression of the inducible nitric oxide synthase and formation of peroxynitrite (nitrotyrosine immunostaining) in the kidney and aorta, ultimately resulting in attenuated systemic inflammation and tissue apoptosis.

CONCLUSIONS: During resuscitated murine septic shock, early ADM binding with HAM1101 improved catecholamine responsiveness, blunted the shock-related impairment of energy metabolism, reduced nitrosative stress, and attenuated systemic inflammatory response, which was ultimately associated with reduced kidney dysfunction and organ injury.

Struck et al. Intensive Care Medicine Experimental 2013, 1:3

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 Med Exp. 2013, 1:3 

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ABSTRACT

INTRODUCTION: Adrenomedullin (ADM), a circulating vasodilatory peptide, plays an important role in the development of sepsis-associated hemodynamic and microcirculatory disorders. While administration of exogenous ADM had beneficial effects in several septic animal models, elevated ADM concentrations are associated with a bad outcome. This prompted us to test the effect of various anti-ADM antibodies in a cecal ligation and puncture (CLP) mouse model.

METHODS: To gain new potential compounds for the treatment or prevention of septic shock we followed an alternative strategy to influence the ADM system: High-affinity anti-ADM antibodies with different epitope specificities were developed and their antagonist activity in vitro and their ability to reduce mortality in a CLP mouse model were assessed.

RESULTS: An anti-ADM antibody directed against the N-terminus substantially increased the survival of mice in a CLP model (HR = 0.077 (CI = 0.0189 to 0.315), p = 0.0004), whereas other antibodies with similar affinities but different epitope specificities were much less potent. The efficacious antibody, in contrast to an anti-C-terminal antibody, only partially inhibited ADM agonist activity in vitro. Healthy mice were not negatively affected by the N-terminal antibody. CONCLUSIONS: An anti-N-terminal ADM antibody, as opposed to antibodies with other epitope specificities, strongly reduces mortality in CLP mice.

Marino et al. Critical Care 2014, 18(1):R34

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

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ABSTRACT

INTRODUCTION: The incidence of death among patients admitted for severe sepsis or septic shock is high. Adrenomedullin (ADM) plays a central role in initiating the hyperdynamic response during the early stages of sepsis. Pilot studies indicate an association of plasma ADM with the severity of the disease. In the present study we utilized a novel sandwich immunoassay of bioactive plasma ADM in patients hospitalized with sepsis in order to assess the clinical utility.

METHODS: We enrolled 101 consecutive patients admitted to the emergency department with suspected sepsis in this study. Sepsis was defined by fulfillment of at least two systemic inflammatory response syndrome (SIRS) criteria plus clinical suspicion of infection. Plasma samples for ADM measurement were obtained on admission and for the next four days. The 28-day mortality rate was recorded.

RESULTS: ADM at admission was associated with severity of disease (correlation with Acute Physiology and Chronic Health Evaluation II (APACHE II) score: r = 0.46; P <0.0001). ADM was also associated with 28-day mortality (ADM median (IQR): survivors: 50 (31 to 77) pg/mL; non-survivors: 84 (48 to 232) pg/mL; P <0.001) and was independent from and additive to APACHE II (P = 0.02). Cox regression analysis revealed an additive value of serial measurement of ADM over baseline assessment for prediction of 28-day mortality (P < 0.01). ADM was negatively correlated with mean arterial pressure (r = -0.39; P <0.0001), and it strongly discriminated those patients requiring vasopressor therapy from the others (ADM median (IQR): no vasopressors 48 (32 to 75) pg/mL; with vasopressors 129 (83 to 264) pg/mL, P <0.0001).

CONCLUSIONS: In patients admitted with sepsis, severe sepsis or septic shock plasma ADM is strongly associated with severity of disease, vasopressor requirement and 28-day mortality.

Blet et al. Intensive Care Med Exp 2015, 3(Suppl 1):A618

Hemodynamics effects of Adrecizumab in sepsis rat

Blet A, Sadoune M , Polidano E , Merval R, Bernard C , Samuel JL and Mebazaa A

Intensive Care Med Exp 2015, 3(Suppl 1):A618

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ABSTRACT

Introduction: Sepsis and septic shock still represent major health issues, with persisting high morbidity and mortality rates in critically ill patients. Cardiac dysfunction occurs frequently during severe sepsis. Adrenomedullin (ADM) has been identified as a key mediator in vascular tone regulation. A newly developed anti-ADM antibody Adrecizumab (ADZ) may improve hemodynamic dysfunction during resuscitated murine, cecal ligation and puncture (CLP)-induced septic shock.

Objective: To determine the beneficial role of ADZ on hemodynamic impairment in a rat model of acute sepsis.

Method: For induction of polymicrobial sepsis, cecal ligation and puncture (CLP)[3] was performed in Wistar male rats. ADZ (2 mg/kg) was injected IV 24 h after the surgery. There were 7 animals per group. Invasive blood pressure and cardiac function (by echocardiography) were assessed until 2 hours after ADZ injection. Statistical analysis was performed with 2 ways ANOVA.

Result: Septic rats had lower mean arterial pressure (MAP) (p < 0.0001) 24 h after surgery (at baseline) compared to sham. Septic animas with ADZ had a trend to have a greater MAP. A transient decrease of SF was observed 15 min and 1 h after injection of ADZ (p = 0.05). On the other hand cardiac output seems to be increased by ADZ (p = 0.61).

Conclusion: During sepsis in rats, treatment by ADZ seems to have a beneficial effect on cardiac and vascular dysfunction. These preliminary results need to be confirmed in preclinical and clinical studies.

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