Safety, tolerability and pharmacokinetics/pharmacodynamics of the adrenomedullin antibody adrecizumab in a first‐in‐human study and during experimental human endotoxaemia in healthy subjects

Geven, Christopher; Lier, Dirk van; Blet, Alice; Peelen, Roel V; Elzen, Bas ten; Mebazaa, Alexandre; Kox, Matthijs; Pickkers, Peter

doi:10.1111/bcp.13655

Cited by 42 publications

(39 citation statements)

References 41 publications

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“…Importantly, even though adrecizumab induced great increases in circulating levels of ADM, this did not cause hypotension. In a phase Ib study, where healthy subjects received an infusion of bacterial lipopolysaccharide to induce a systemic inflammatory response, administration of adrecizumab significantly reduced the perception of illness/sickness, as assessed by clinical scores …”

Section: Adrecizumab For the Treatment Of Heart Failure And Sepsismentioning

confidence: 99%

“…In a phase Ib study, where healthy subjects received an infusion of bacterial lipopolysaccharide to induce a systemic inflammatory response, administration of adrecizumab significantly reduced the perception of illness/sickness, as assessed by clinical scores. 73 A phase II proof of concept study in patients with worsening heart failure and elevated bio-ADM levels after initial stabilization is currently being considered. Patients with elevated bio-ADM have (residual) congestion and are at high risk for clinical events, and a heart failure readmission in particular.…”

Section: Adrecizumab For the Treatment Of Heart Failure And Sepsismentioning

confidence: 99%

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Adrenomedullin in heart failure: pathophysiology and therapeutic application

Voors

Kremer

Geven

et al. 2018

European J of Heart Fail

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177

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Adrenomedullin (ADM) is a peptide hormone first discovered in 1993 in pheochromocytoma. It is synthesized by endothelial and vascular smooth muscle cells and diffuses freely between blood and interstitium. Excretion of ADM is stimulated by volume overload to maintain endothelial barrier function. Disruption of the ADM system therefore results in vascular leakage and systemic and pulmonary oedema. In addition, ADM inhibits the renin–angiotensin–aldosterone system. ADM is strongly elevated in patients with sepsis and in patients with acute heart failure. Since hallmarks of both conditions are vascular leakage and tissue oedema, we hypothesize that ADM plays a compensatory role and may exert protective properties against fluid overload and tissue congestion. Recently, a new immunoassay that specifically measures the biologically active ADM (bio‐ADM) has been developed, and might become a biomarker for tissue congestion. As a consequence, measurement of bio‐ADM might potentially be used to guide diuretic therapy in patients with heart failure. In addition, ADM might be used to guide treatment of (pulmonary) oedema or even become a target for therapy. Adrecizumab is a humanized, monoclonal, non‐neutralizing ADM‐binding antibody with a half‐life of 15 days. Adrecizumab binds at the N‐terminal epitope of ADM, leaving the C‐terminal side intact to bind to its receptor. Due to its high molecular weight, the antibody adrecizumab cannot cross the endothelial barrier and consequently remains in the circulation. The observation that adrecizumab increases plasma concentrations of ADM indicates that ADM‐binding by adrecizumab is able to drain ADM from the interstitium into the circulation. We therefore hypothesize that administration of adrecizumab improves vascular integrity, leading to improvement of tissue congestion and thereby may improve clinical outcomes in patients with acute decompensated heart failure. A phase II study with adrecizumab in patients with sepsis is ongoing and a phase II study on the effects of adrecizumab in patients with acute decompensated heart failure with elevated ADM is currently in preparation.

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Section: Adrecizumab For the Treatment Of Heart Failure And Sepsismentioning

confidence: 99%

Section: Adrecizumab For the Treatment Of Heart Failure And Sepsismentioning

confidence: 99%

Adrenomedullin in heart failure: pathophysiology and therapeutic application

Voors

Kremer

Geven

et al. 2018

European J of Heart Fail

Self Cite

177

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“…Also, pretreatment with Adrecizumab improved 7-day survival in CLP-induced sepsis in mice from 10 to 50% for single and from 0 to 40% for repeated dose administration ( 151 ). Moreover, in a phase I study, excellent safety and tolerability was demonstrated: no serious adverse events were observed, no signal of adverse events occurring more frequently in Adrecizumab-treated subjects was detected, and no relevant changes in other safety parameters were found ( 152 ). Of particular interest is the proposed mechanism of action of Adrecizumab.…”

Section: Adm and Adm-targeted Therapy As Treatment Strategies Relevanmentioning

confidence: 99%

“…Both animal and human data reveal a potent, dose-dependent increase of circulating ADM following administration of this antibody. Based on pharmacokinetic data and the lack of an increase in MR-proADM (an inactive peptide fragment derived from the same prohormone as ADM), the higher circulating ADM levels cannot be explained by an increased production ( 152 ). A mechanistic explanation for this increase could be that the excess of antibody in the circulation may drain ADM from the interstitium to the circulation, since ADM is small enough to cross the endothelial barrier, whereas the antibody is not.…”

Section: Adm and Adm-targeted Therapy As Treatment Strategies Relevanmentioning

confidence: 99%

Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis

Geven

Kox²,

Pickkers³

2018

Front. Immunol.

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107

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Sepsis remains a major medical challenge, for which, apart from improvements in supportive care, treatment has not relevantly changed over the last few decades. Vasodilation and vascular leakage play a pivotal role in the development of septic shock, with vascular leakage being caused by disrupted endothelial integrity. Adrenomedullin (ADM), a free circulating peptide involved in regulation of endothelial barrier function and vascular tone, is implicated in the pathophysiology of sepsis. ADM levels are increased during sepsis, and correlate with extent of vasodilation, as well as with disease severity and mortality. In vitro and preclinical in vivo data show that administration of ADM exerts anti-inflammatory, antimicrobial, and protective effects on endothelial barrier function during sepsis, but other work suggests that it may also decrease blood pressure, which could be detrimental for patients with septic shock. Work has been carried out to negate ADMs putative negative effects, while preserving or even potentiating its beneficial actions. Preclinical studies have demonstrated that the use of antibodies that bind to the N-terminus of ADM results in an overall increase of circulating ADM levels and improves sepsis outcome. Similar beneficial effects were obtained using coadministration of ADM and ADM-binding protein-1. It is hypothesized that the mechanism behind the beneficial effects of ADM binding involves prolongation of its half-life and a shift of ADM from the interstitium to the circulation. This in turn results in increased ADM activity in the blood compartment, where it exerts beneficial endothelial barrier-stabilizing effects, whereas its detrimental vasodilatory effects in the interstitium are reduced. Up till now, in vivo data on ADM-targeted treatments in humans are lacking; however, the first study in septic patients with an N-terminus antibody (Adrecizumab) is currently being conducted.

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“…The loss of vascular integrity plays a pivotal role in the development of vascular leakage and organ dysfunction leading to septic shock [24][25][26]. Several animal studies have proven that ADM shows strong anti-inflammatory properties, improves the cardiomyocyte survival in myocardial ischemia, and has a marked anti-apoptotic effect on cardiomyocytes [27,28].…”

Section: Adrecizumab and Shockmentioning

confidence: 99%

Targeting Endothelial Dysfunction in Eight Extreme-Critically Ill Patients with COVID-19 Using the Anti-Adrenomedullin Antibody Adrecizumab (HAM8101)

Karakas

Jarczak

Becker³

et al. 2020

Biomolecules

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Recently, the stabilization of the endothelium has been explicitly identified as a therapeutic goal in coronavirus disease 2019 (COVID-19). Adrecizumab (HAM8101) is a first-in-class humanized monoclonal anti-Adrenomedullin (anti-ADM) antibody, targeting the sepsis- and inflammation-based vascular and capillary leakage. Within a “treatment on a named-patient basis” approach, Adrecizumab was administered to eight extreme-critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). The patients received a single dose of Adrecizumab, which was administered between 1 and 3 days after the initiation of mechanical ventilation. The SOFA (median 12.5) and SAPS-II (median 39) scores clearly documented the population at highest risk. Moreover, six of the patients suffered from acute renal failure, of whom five needed renal replacement therapy. The length of follow-up ranged between 13 and 27 days. Following the Adrecizumab administration, one patient in the low-dose group died at day 4 due to fulminant pulmonary embolism, while four were in stable condition, and three were discharged from the intensive care unit (ICU). Within 12 days, the SOFA score, as well as the disease severity score (range 0–16, mirroring critical resources in the ICU, with higher scores indicating more severe illness), decreased in five out of the seven surviving patients (in all high-dose patients). The PaO2/FiO2 increased within 12 days, while the inflammatory parameters C-reactive protein, procalcitonin, and interleukin-6 decreased. Importantly, the mortality was lower than expected and calculated by the SOFA score. In conclusion, in this preliminary uncontrolled case series of eight shock patients with life-threatening COVID-19 and ARDS, the administration of Adrecizumab was followed by a favorable outcome. Although the non-controlled design and the small sample size preclude any definitive statement about the potential efficacy of Adrecizumab in critically ill COVID-19 patients, the results of this case series are encouraging.

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Safety, tolerability and pharmacokinetics/pharmacodynamics of the adrenomedullin antibody adrecizumab in a first‐in‐human study and during experimental human endotoxaemia in healthy subjects

Abstract: Administration of adrecizumab is safe and well tolerated in humans, both in the absence and presence of systemic inflammation. These findings pave the way for further investigation of adrecizumab in sepsis patients.

Cited by 42 publications

References 41 publications

Adrenomedullin in heart failure: pathophysiology and therapeutic application

Adrenomedullin in heart failure: pathophysiology and therapeutic application

Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis

Targeting Endothelial Dysfunction in Eight Extreme-Critically Ill Patients with COVID-19 Using the Anti-Adrenomedullin Antibody Adrecizumab (HAM8101)

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