Adrenomedullin could serve as biomarker, therapeutic target in disorders caused by leaky blood vessels

Disorders caused by a leaky vasculature are more common than most people think. Despite ICU treatment, one third of the 27 million patients globally that suffer from sepsis, and up to 20% of the more than 5 million US patients with congestive heart failure die every year from their condition. Other disorders that involve a disturbed barrier function of the endothel , the innermost cell layer of blood vessels, include diabetes, migraine or inflammatory diseases. Medical opinion leaders have now confirmed evidence that adrenomedullin, a central regulator of endothelial function, could serve both as a diagnostic biomarker and a therapeutic target in disorders caused by endothelial dysfunction.

Until now, physicians had no means to identify patients with bad sepsis prognosis and those heart failure patients with congestion who relapse due to residual disease at discharge. International medical leaders have now compiled clinical data from more than 10,000 patients suffering from sepsis and congestive heart failure, whose survival was linked to blood levels of the peptide hormone adrenomedullin. Results presented in Berlin identify the active form of adrenomedullin, dubbed bio-ADM, as a biomarker that predicts development of septic shock and for the first time allows doctors to identify heart failure patients, who will relapse despite decongestive treatment with loop diuretics. While sepsis supportive treatment causes annual healthcare cost of nearly $24bn, congestive heart failure treatment and rehospitalization costs due to unidentified residual disease totaled at $31bn in the US alone. The latter annual cost is expected to double by 2030.

A diagnostic test for bio-ADM , developed and marketed by diagnostics company Sphingotec in Europe and China, is already in place. An adrenomedullin-specific therapeutic antibody, developed by Berlin-based Adrenomed AG, has just entered proof-of-concept studies in septic shock patients; a Phase II study in patients with decompensated heart failure is expected to start in 2018. According to serial entrepreneur Andreas Bergmann, founder of both companies and co-founder of BRAHMS (taken over in 2009), "bio-ADM is a general indicator for endothelial dysfunction and the need of vascular repair."

Clinical data from more than 4,000 Caucasian and Asian sepsis patients presented at the scientific symposium "Endothelial dysfunction - Adrenomedullin as a diagnostic and therapeutic target" demonstrate that low bio-ADM plasma levels (<70pg/mg) at baseline were linked to a good outcome. In contrast, bio-ADM levels above that cut-off value were linked to significantly higher mortality (up to 13-fold), organ dysfunction and high vasopressor demand. As bio-ADM levels rose 24+ hours before septic shock occurred it allowed both early intervention and therapy monitoring. bio-ADM indicated endothelial integrity in sepsis patients at emergency departments, ICUs and patients with surgical sepsis.

Further clinical data from more than 6,000 patients with acute and chronic heart failure suffering from congestion and edema caused by high venous pressure and vascular fluid leakage, demonstrate that high bio-ADM levels predicted residual congestion, rehospitalization and 180-day mortality. Measuring bio-ADM levels is the very first method that allows identification of patients with acute heart failure that have residual congestion and mustn't be discharged in order to prevent rehospitalization and death.

Using adrenomedullin as a therapeutic target seems to be a next logical step. Preclinically, Adrecizumab, a humanized antibody that binds adrenomedullin without affecting its receptor binding in the endothel, led to a 40% survival benefit in mice. In two Phase I trials the first-in-class antibody showed excellent safety and tolerability in sepsis patients. Pharmacokinetic and pharmacodynamic data suggest that antibody stabilizes adrenomedullin's half-life from 22 minutes to several days and that antibody binding leads to a redistribution from the vessel interstitium to its lumen, where is closes in gaps in the endothelium and thus restores the blood vessels barrier function. A Phase II trail on 300 patients with early septic shock is underway, while a Phase II study in congestive heart failure patients is in preparation and is expected to start in 2018.

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