- Clinical data presented by Prof. Alexandre Mebazaa at ESC Congress 2019 in Paris provide evidence for a novel disease mechanism in which circulating DPP3 degrades central mediators of heart and kidney function, rapidly leading to fatal organ dysfunction.
- 4TEEN4 Pharmaceuticals GmbH licensed its diagnostic biomarker test DPP3 to SphingoTec GmbH, which today launched the IB10 sphingotest® DPP3 assay for use with the Nexus IB10 point-of-care analyser, the first CE-IVD test for DPP3.
Paris, France, and Hennigsdorf/Berlin, Germany, August 31, 2019 - 4TEEN4 Pharmaceuticals GmbH ("4TEEN4", former Sphingotec Therapeutics GmbH, Hennigsdorf/Berlin, Germany) today for the first time reported preclinical data on its lead product Procizumab, a therapeutic antibody targeting circulating Dipeptidyl Peptidase 3 (DPP3) for the treatment of patients with acute myocardial depression including acute heart failure and cardiogenic shock. The published data further emphasizes the medical utility of DPP3 as a biomarker predicting organ dysfunction and outcome in critically ill patients.
DPP3 is at the core of a recently discovered patho-mechanism of acute myocardial depression reported for the first time by Prof. Alexandre Mebazaa (Hôpital Lariboisière, Paris) at ESC Congress 2019 (organised by the European Society of Cardiology ESC, Paris)1. Data from two clinical studies (OptimaCC2 and CardShock3) presented by Prof. Mebazaa demonstrate that pathological concentrations of the newly identified myocardial depressant factor DPP3 were clearly associated with organ failure and short-term outcome of patients with cardiogenic shock, an emergency that affects around 10%4 of patients with myocardial infarction. Mebazaa's team hypothesizes that intracellular DPP3 is released from cells into the bloodstream during cell death. They provided striking evidence that DPP3 degrades the cardiovascular mediators angiotensin II and enkephalin, which are central to heart and kidney function.
In pre-clinical models, injections of DPP3 decreased cardiac output, as well as kidney hemodynamics. Administration of Procizumab, a humanized monoclonal antibody designed to block peptidase activity of DPP3, immediately normalized heart and kidney function in a pre-clinical model for acute heart failure. "Procizumab is a novel treatment approach targeting a recently identified DPP3-mediated disease mechanism in critically ill patients", said Prof. Mebazaa, whose results were also published today in the European Journal of Heart Failure5,6.
4TEEN4 is currently setting up a GMP process for Procizumab manufacturing and is expected to enter regulatory non-clinical safety studies next year.
"In ongoing preclinical efficacy studies, Procizumab has shown high therapeutic potential in certain indications, including heart failure, that are triggered by dysfunction in the cardiorenal axis mediated by low angiotensin II and enkephalin levels. Supported by excellent clinical cohort results on the DPP3 biomarker, we are now preparing for first-in-men clinical trials" said Dr. Andreas Bergmann, CEO of 4TEEN4.
The studies published today and further on-going retrospective studies show promising clinical utility of DPP3 as a biomarker in emergency settings. The company has licensed the global rights to develop DPP3-based diagnostics for near-patient and central laboratory testing to SphingoTec GmbH ("sphingotec"; Hennigsdorf, Germany). 4TEEN4 and sphingotec, together with Nexus Dx Inc. and Adrenomed AG, are part of the Medicine4Future Initiative established by serial entrepreneur Dr. Andreas Bergmann.
(1) Circulating dipeptidyl peptidase-3 is a myocardial depressant factor: Procizumab promptly and sustainably restored hemodynamics in heart failure, Prof. Alexandre Mebazaa at ESC Congress 2019, Paris
(2) clinicaltrial.gov NCT 01367743
(3) clinicaltrial.gov NCT 1374867
(4) van Diepen (2017) Contemporary Management of Cardiogenic Shock: A Scientific Statement From the American Heart Association, Circulation
(5) Takagi (2019) Circulating dipeptidyl-peptidase 3 and alteration in hemodynamics in cardiogenic shock: Results from the OptimaCC Trial, European Journal of Heart Failure
(6) Deniau (2019) Circulating dipeptidyl peptidase-3 is a myocardial depressant factor: DPP3 inhibition rapidly and sustainably improves hemodynamics, European Journal of Heart Failure
4TEEN4 Pharmaceuticals GmbH is a biopharmaceutical company developing Procizumab, a humanized antibody targeting human Dipeptidyl Peptidase 3 (DPP3) for the treatment of acute cardiovascular diseases. 4TEEN4 licenses its proprietary biomarker DPP3 to make it available for diagnostic use in indications as acute heart failure, myocardial infarction, cardiogenic shock, and septic shock. The company was established in 2013 in Hennigsdorf near Berlin, Germany, by Dr. Andreas Bergmann, CEO of 4TEEN4, as part of his Medicine4Future Initiative.
Human Dipeptidyl Peptidase 3 (DPP3) is an ubiquitously expressed and highly conserved enzyme. DPP3 cleaves various bioactive peptides, such as such as angiotensin II, enkephalins. The most prominent substrate of DPP3 is angiotensin II, the central effector of the renin-angiotensin system (RAS), implicating extracellular DPP3 in the regulation of the RAS. The RAS is activated in cardiovascular diseases, sepsis and septic shock and angiotensin II, in particular, has been shown to modulate many cardiovascular functions including the control of blood pressure and cardiac remodelling.
Procizumab is a humanized monoclonal antibody in pre-clinical development specifically binding circulating Dipeptidyl peptidase 3 (DPP3). It will be a first-in-class drug that targets and modulates DPP3 as an essential regulator of cardiovascular function. Procizumab has an innovative mode of action, relevant in acute diseases. Massive cell death and release of DPP3 into the blood stream lead to degradation of its substrates including angiotensin II and enkephalin, that are responsible for cardio and renal function regulation. Procizumab inhibits the activity of DPP3, thereby reducing bioactive peptide degradation, stabilizing cardiovascular function and potentially increasing survival chances e.g. in acute heart failure. Preclinical studies of Procizumab in models of cardiovascular failure showed instant efficacy. As an example - injection of Procizumab in a model with shock-induced cardiovascular failure (low blood pressure, low shortening fraction) leads to an instant increase of shortening fraction.
About Acute Heart Failure
Heart failure is a state of reduced cardiac output, in which the heart cannot pump blood through the body effectively. When symptoms appear suddenly, or a person experiences rapid worsening of existing symptoms of heart failure, this is called acute heart failure (AHF) or acute decompensated heart failure (ADHF). This condition can be life threatening and should be urgently evaluated by a physician, as outcomes can be affected by early and appropriate treatment. Heart failure is a common condition affecting more than 30 million people world-wide. Typical symptoms of acute heart failure include shortness of breath, tiredness and swelling of the feet and legs (congestion). Treatment typically involves supporting breathing and adjusting the blood pressure and, where necessary, removing excess fluid from the body by diuretic treatment. There is no cure, but long-term treatment involving medications and rehabilitation can improve the heart's function.
About Cardiogenic Shock
Cardiogenic shock is an emergency with mortality rates up to 50 %. Most cases of cardiogenic shock occur after myocardial infarction and are defined by persistent low cardiac output state resulting in arterial hypotension, shortness of breath, reduced organ perfusion. Refractory cardiogenic shock presents as persistent organ hypoperfusion despite the administration of vasoactive treatments. Early initiation of mechanical circulatory support, early percutaneous coronary intervention, inotropes, and heart transplantation may improve outcomes for patients with Cardiogenic shock.
About Medicine4Future Initiative
The companies of the Medicine4Future Initiative, SphingoTec GmbH, 4TEEN4 Pharmaceuticals GmbH, Adrenomed AG and Nexus Dx Inc., have the common goal to improve the management of critically ill patients and, in future, help preventing the manifestation of common diseases by developing first-in-class diagnostics and targeted therapies in a hypothesis-driven approach that is deeply rooted in a profound understanding of disease biology. Starting from assay development and growing evidence from large cohort studies, blood biomarkers are associated with relevant patient outcomes in underserved medical conditions. Based on data that prove that a biomarker can reliably monitor outcomes, antibodies are subsequently developed to validate if the biomarker also represents a druggable target. If so, drug candidates are tested in appropriate pre-clinical models and consecutively enter first in-men clinical trials. The Medicine4Future Initiative was established by Dr. Andreas Bergmann, one of the founders and former Chief Scientific Officer of B.R.A.H.M.S. AG where he was responsible for the development of the "gold standard" sepsis biomarker Procalcitonin (B.R.A.H.M.S. PCT™).
Dr. Karine Santos
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Takagi (2019) Circulating dipeptidyl-peptidase 3 and alteration in hemodynamics in cardiogenic shock: Results from the OptimaCC Trial, European Journal of Heart Failure https://www.ncbi.nlm.nih.gov/pubmed/31472039
Deniau (2019) Circulating dipeptidyl peptidase-3 is a myocardial depressant factor: DPP3 inhibition rapidly and sustainably improves hemodynamics, European Journal of Heart Failure https://www.ncbi.nlm.nih.gov/pubmed/31472040
Link to press release titled "Dipeptidyl Peptidase 3 (DPP3) cause of acute myocardial depression": https://www.eurekalert.org/pub_releases/2019-08/sg-dp3082919.php
European Journal of Heart Failure