Endothelial disruption: From bench to bedside
Late in 2017, key opinion leaders (KOLs) in the field of heart failure (AHF) and sepsis presented data supporting that elevated levels of the vasoactive peptide hormone adrenomedulin (ADM) indicate when blood vessels become leaky and that such endothelial dysfunction precedes bad outcomes in congestive heart failure (AHF) and septic shock. New clinical data presented at the 2nd Scientific Symposium on Endothelial Disruption (18 December 2018, Berlin, Germany) demonstrated that the first diagnostic test measuring the biologically active form of adrenomedullin (Sphingotest® bio-ADM®, Sphingotec GmbH, Hennigsdorf, Germany) is on a good way to be translated to bedsite very rapidly as key opinion leaders at the meeting confirmed actionable clinical utility of bio-ADM testing in sepsis and AHF.
From clinical trails to routine testing
New data on pilot routine testing of bio-ADM in patients with sepsis presented at the meeting in Berlin suggest that the new diagnostic concept could enter broader routine testing very soon. According to representative case studies, elevated blood levels of bio-ADM at admission, which remained high, were a strong predictor for mortality. Daily monitoring of bio-ADM levels identified the outcome and response to therapy in sepsis patients: if bio-ADM levels remained high or rised above the cut-off value of 70 pg/ml, patients died. When bio-ADM levels dropped below the cut-off, patients survived. Even when inflammation biomarkers such as PCT or CRP pointed to recovery, high bio-ADM levels were an independent predictor of bad outcome and non-response to therapy, the study leaders told European Biotechnology pointing to the need of those patients to receive immediate critical care. The medical interest was to generate data from clinical practice and translate them into therapy decisions, they said. Routine tests with more patients, even in AHF, are already in planning stage.
Automated test to be launched in H1/2019
While the routine testing was conducted with a manual version of a bio-ADM sandwich immunoassay (see photo), confirmatory data may be generated with a fully automated test that runs on the established Nexus IB 10 point-of-care (POC) testing platform of German Sphingotec GmbH. The company announced at the meeting that it will launch such a fully automated bio-ADM test particularly suited to the needs of ICUs and EDs in H1/2019 latest. Nexus IB 10 is a market-established microfluidic POC testing platform currently used by over 1,000 hospitals including ICUs/EDs that allows measurement of a test panel of up to five acute care blood biomarkers.
Academic leaders in emergency medicine reported further progress regarding clinical utility with the biomarker of endothelial dysfunction. Several lectures in Berlin confirmed the diagnostic and therapeutic utility of bio-ADM monitoring of therapy response.
“In septic shock patients, bio-ADM levels reflect the pathophysiological relaxation of vascular tone 1-2 days before clinical signs of shock appear”, stressed Prof. Dr. Salvatore Di Somma, Head of Emergency Medicine (ED) at University La Sapienza, Rome. According to Di Somma, data from a clinical multicenter study on approx. 1.000 sepsis patients (ALBIOS) admitted to the ED demonstrated that plasma bio-ADM levels increased with the severity of disease, correlated with the requirement for intensive care such as immediate vasopressor therapy and 28-day mortality rate. Di Somma confirmed that, “serial measurement of bio-ADM may add important information to levels measured at admission”. Almost 100% of sepsis patients with high bio-ADM levels at admission whose bio-ADM blood level dropped below 70 pg bio-ADM/ml blood 4 days post-admission survived.
Medical utility in AHF patients
According to further data presented at the meeting, bio-ADM testing also cuts time to diagnosis and appropriate treatment in the medically underserved area of congestive acute heart failure (AHF). “Monitoring of this biomarker of endothelial dysfunction can inform clinical decision making in order to reduce patients’ mortality, in-hospital length of stay and rehospitalisation rate,” stressed Di Somma pointing to results ofto multi-center studies that proved that bio-ADM levels identified patients with residual congestion before discharge – a main cause of mortality, kidney damage, and re-hospitalisaton of AHF patients.
“The issue in heart failure is congestion and thus the identification of patients that require immediate diuretics therapy”, explained heart failure biomarker and critical care expert Prof. Dr. Alexandre Mebazaa (Head AP-HP, Hôpital Lariboisière Paris) pointing to data from a meta-analysis of studies on 3,000 patients with acute heart failure in which elevated bio-ADM levels at admission preceded development of life-threatenting pulmonary edema and/or interstitial edema. Data from PD Dr. Hans-Dirk Duengen proved that elevated/rising bio-ADM levels identified high-risk patients with worsening heart failure requiring immediate diuretics therapy. He supported Di Somma’s view that bio-ADM monitoring might help to support discharge decisions in acute heart failure by diagnosing residual congestion.
Enhancing medical utility by therapeutic targeting of bio-ADM
Speaking in Berlin, Prof. Dr. Pierre François Laterre, St Luc Hospital, Brussels, told European Biotechnology that bio-ADM testing definitely provides an added value to sepsis patients, as the biomarker determines the amount of vasopressors needed by sepsis patients early in the process and thus helps prevent bad outcomes. In AHF patients bio-ADM was the first blood biomarker capable to diagnose residual congestion prior to discharge of AHF patients that did not sufficiently respond to diuretics therapy resulting in rehospitalisation, death and kidney damage, he said.
Laterre, added that medical utility of diagnostic bio-ADM monitoring is set improve in the future. A clinical Phase II trail assessing efficacy of adrecizumab (Adrenomed AG, Hennigsdorf, Germany), a therapeutic antibody targeting bio-ADM, conducted by Laterre, will have Phase II read-out in sepsis patients this summer. The target is reduction of mortality in 300 sepsis patients with bad prognosis as identified by a bio-ADM level above 70 pg /ml at admission. This would qualify bio-ADM as companion diagnostic to targeted antibody therapy resolving endothelial dysfunction
According to data published in 2018, adrecizumab binds adrenomedullin at its C-terminus and doesn’t affect receptor-binding and subsequent cAMP signaling, which had been previously shown to support vascular integrity and block vascular leakage. Adrecizumab thus repairs endothelial dysfunction, providing a targeted therapy to improve outcomes both in sepsis but also in AHF.
According to preclinical and Phase I data provided by Tobias Schürholz (Unversity Rostock) and the group of Peter Pickkers (University Nijmegen), binding to adrecizumab additionally protects bio-ADM from proteolytic degradation thus improving the half-life of the vasoactive peptide hormone in blood. A Phase II trial will start enrolment of 300 AHF patients this year to evaluate the clinical safety and efficacy of adrecizumab in patients with AHF.
Experts such as Allan Jaffe from Mayo Clinic in Rochester or Prof Dr Michael Bauer from University Jena, stressed that bio-ADM as a companion diagnostic would enable an optimal therapy choice both in sepsis as well as in patients with congestive heart failure.
A new way of personalized medicine
According to serial entrepreneur Dr. Andreas Bergmann, founder of Sphingotec and Adrenomed, bio-ADM is just the first in a series of blood biomarkers/therapeutic targets set to improve outcomes in medically underserved conditions. “Our strategy is to identify protein biomarkers indicating severe medical disorders in the blood of patients. These biomarkers enable us to look for potential therapeutic targets and validate if these have an effect on humans following the blood biomarker read-out.” Bergmann, who co-founded and sold BRAHMS AG for €330m to ThermoFisher Scientific, said his companies have the financial freedom to quit unsuccessful projects early and follow just the best approach that adds value to current medical standards. “We are thus delighted about the positive feedback from the scientific community on our bio-ADM approach”, commented Bergmann the outcome of the symposium.