Berlin (Germany) - 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 diurectics. While sepsis supportive treatment causes annual healthcare cost of nearly $24bn, congestive heart failure treatment and rehospitalisation 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, rehospitalisation 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 rehospitalisation 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. Pharmakokinetic 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.
About the speakers at the scientific symposium
Prof. Dr. Inder Anand, Department of Cardiovascular Medicine, University of Minnesota Medical School,
VA Medical Center Minneapolis MN and San Diego, USA
Prof. Dr. Aw Tar Choon, Changi General Hospital, Singapore
Prof. Dr. Javed Butler, Chief of the Cardiology Divisionat Stony Brook School of Medicine, USA
Prof. Dr Salvatore Di Somma, Director Emergency Medicine, University La Sapienza, Rome, Italy
Asj-Prof. Dr. Hans-Dirk Düngen, Head Multicentric Studies Cardiology, Charité Berlin, Germany
Prof. Dr. Mina Hur, Director Department of Laboratory Medicine, Konkuk University Seoul, Korea
Prof. Dr Pierre-Francois Laterre, Head of the medical-surgical intensive care unit at St. Luc Hospital, Brussels, Belgium
Dr. Roberto Latini, Istituto di Ricerche Farmacologiche Mario Negri Milano, Italy
Prof. Dr. Gernot Marx, Director Operative Intensive Care and Intermediate Care, University Clinic Aachen, Germany
Prof. Alexandre Mebazaa, Head AP-HP, Hôpital Lariboisière Paris, France
Prof. Dr. Olle Melander, Principal investigator at Hypertension and Cardiovascular Disease, Lund University Malmö, Sweden
Prof. Dr. Marco Metra, Department of Medical and Surgical Specialties. Universita degli Studi di Brescia, Italy
Prof. Leong L. Ng, Principal Investigator, Department of Cardiovascular Sciences, University Leicester, UK
Prof. Dr. Peter Pickkers, Department of Intensive Care. Radboud University, Nijmegen, The Netherlands
Prof. Adriaan A. Voors, Director of the Heart Failure Clinic and the Outpatient Clinic of the.Department of Cardiology, UMC Groningen, The Netherlands
About congestive heart failure:
About 5 million US-Americans suffer from congestive heart failure. The characteristic loss of pump function of the heart triggers cardiac remodeling - the heart gets stiffer, fibrotic, and cannot pump enough blood into the circulatory system. The lower pump efficacy causes lower oxygen saturation and results in congestion, which means that blood returning to the heart through the veins backs up, resulting in higher venous pressure and causing fluids to build up in the tissues (edema). About 80% of patients with congestive heart failure are also at risk to develop edema, because their microvasculature becomes leaky due to venous hypertension. Physicians try to prevent the worst case - deadly lung edemas - by administration of loop diuretics, which can reduce hypertension by increasing water excretion. However, not all patients fully respond to diuretics. Incomplete response to diuretics therapy is the most common cause of re-hospitalization and post discharge mortality in patients with congestive heart failure. It's not yet fully understood why patients with congestive heart failure often experience acute kidney injury (AKI). However, there is growing evidence that AKI can be attributed to congestion („cardio-renal syndrome") and that, vice versa, AKI can trigger heart problems. Management of fluid balance with loop diuretics is challenging - if too much fluid is excreted from tissues, this will support development of AKI. On the other hand, if too little fluid is excreted, lung edemas could return. Besides that, a large proportion of patients with congestive heart failure does not fully respond to diuretics treatment, leading to undetected residual congestion. To date, physicians have no means to identify these patient group at discharge, resulting in high re-hospitalization and post-discharge mortality rates.
About septic shock
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
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 regulation of the endothelial barrier function.
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.
About sphingotec GmbH:
sphingotec GmbH (Hennigsdorf, Germany) develops innovative biomarkers for prediction, diagnosis and therapy monitoring of AKI, congestive heart failure and septic shock. The company, founded by Dr. Andreas Bergmann in 2002, has also in its portfolio biomarkers which can predicts risks of obesity, breast cancer and cardiovascular diseases.
Adrenomed AG is a privately financed biopharmaceutical company, based in Hennigsdorf near Berlin, Germany, with the 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.