Positive Results from Adrenomed's AdrenOSS-2 Phase II trial evaluating Adrecizumab (HAM8101) in Septic Shock presented during e-ISICEM

DGAP-News: Adrenomed AG / Key word(s): Study results/Conference
16.09.2020 / 07:30
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Positive Results from Adrenomed's AdrenOSS-2 Phase II trial evaluating Adrecizumab (HAM8101) in Septic Shock presented during e-ISICEM

- Primary endpoint of AdrenOSS-2 achieved: Adrecizumab was well tolerated and showed a favorable safety profile

- In this biomarker-guided trial, Adrecizumab demonstrated significant and fast improvement of organ function and a substantial reduction on short-term mortality (45% relative reduction at day 14)

- Mode of Action confirmed: Adrecizumab rapidly increased plasma levels of bioactive Adrenomedullin, a key hormone restoring vascular integrity and endothelial function

Hennigsdorf/Berlin (Germany), September 16, 2020 - Adrenomed AG, the vascular integrity company, announced that data from its proof-of-concept AdrenOSS-2 Phase II clinical trial were presented at today's sepsis session during e-ISICEM, the International Symposium on Intensive Care and Emergency Medicine. AdrenOSS-2 evaluated the safety, tolerability and efficacy of Adrecizumab (HAM8101), a first-in-class antibody targeting the vasoprotective peptide Adrenomedullin to restore and maintain vascular integrity in patients with septic shock.

Sepsis is characterized by severe organ dysfunction, caused by the body's dysregulated response to infection. Loss of vascular integrity is a key driver for organ failure and mortality in sepsis. Patients affected can be identified by measuring plasma adrenomedullin (bio-ADM) levels. Sepsis and septic shock are the main causes of death in hospitals worldwide.^[1]

The AdrenOSS-2 Phase II trial (NCT03085758^[2]) achieved its primary endpoint: No differences in serious or possibly related Treatment Emergent Adverse Events (TEAEs) between Adrecizumab and placebo were observed. As already demonstrated in previous Phase I trials, Adrecizumab exhibited a favorable safety and tolerability profile in septic shock patients.^[3]

28-day all-cause mortality analysis including all patients (n=301) showed a trend towards a survival benefit for Adrecizumab treated patients. Comparison of different follow-up times revealed mortality reduction by Adrecizumab treatment was most pronounced within the first 14 days and sustained for the 28-day follow-up period. In a sensitivity biomarker-guided (bio-Adrenomedullin; Dipeptidyl Peptidase 3) analysis this early beneficial trend on survival of Adrecizumab was substantiated. At day 14, a relative mortality reduction of 45% was observed (p=0.057, n=264).

Data for the validated and broadly established SOFA (Sequential Organ Failure Assessment) score demonstrated that treatment with Adrecizumab led to a rapid improvement in organ function. A significant reduction within 24h (p<0.05) was observed. The SOFA score is based on evaluation of six organ systems affected by sepsis: respiration, coagulation, cardiovascular, central nervous system, as well as liver and kidney function.^[4]
A novel designed exploratory endpoint, the Sepsis Support Index (SSI), did not prove to be a suitable efficacy endpoint in septic shock due to conceptual limitations. This newly developed composite endpoint combines mortality and organ dysfunction and had been used for the first time in AdrenOSS-2. No difference between Adrecizumab and placebo-treated patients was observed.

The mode of action was confirmed: administration of Adrecizumab led to a rapid increase of plasma bio-ADM without affecting its de novo synthesis. The increase of bio-ADM within 24h correlated with the early beneficial treatment effect of Adrecizumab on organ function.

"The positive trend on early survival by Adrecizumab is a particularly important finding since the reduction of mortality in septic shock is of utmost importance especially in the acute phase during the first days in ICU. This early effect on survival correlates with the rapid improvement in organ function which was observed after treatment with Adrecizumab," commented Prof. Pierre-François Laterre, MD, Head of medical surgical intensive care unit at Saint-Luc University Hospital at the Université Catholique de Louvain, Brussels (Belgium). "The outcome of the AdrenOSS-2 trial is an important step towards a new therapeutic in septic shock treatment by addressing the loss of vascular integrity as the root cause. I very much look forward to seeing this urgently needed product candidate advance further through clinical development and into ICU wards."

"Treatment of septic shock still represents a high unmet medical need. We therefore consider the favorable safety profile as well as the effects of Adrecizumab on the clinical outcome as highly encouraging," stated Dr. Jens Zimmermann, CMO of Adrenomed.

"The AdrenOSS-2 data clearly show that the use of a biomarker guided, precision medicine concept is urgently needed in the fight of a multicomplex disease like sepsis. The biomarker bio-ADM specifically enables the identification of sepsis patients suffering from loss of vascular integrity," commented Dr. Andreas Bergmann, CSO and co-founder of Adrenomed.

"As loss of vascular integrity is a major driver of organ dysfunction and mortality in sepsis, we are delighted to see these promising data. These results will pave the way for further clinical development of Adrecizumab," said Dr. Jens Schneider-Mergener, CEO of Adrenomed."

Further data from the AdrenOSS-2 study will be submitted for publication in a peer-reviewed journal later this year.

About AdrenOSS-2 study design & analysis

The biomarker-guided, randomized, multicenter, double-blind, placebo-controlled AdrenOSS-2 Phase II trial (NCT03085758²) enrolled a total of 301 patients with early septic shock and elevated blood levels of Adrenomedullin (bio-ADM) throughout Belgium, France, Germany and The Netherlands.^[5] Patients received Adrecizumab or placebo in addition to standard of care. The primary endpoints were safety and tolerability of Adrecizumab over a 90-day period. The exploratory efficacy endpoints included amongst others mortality rate at day 28, change in Sequential Organ Failure Assessment (SOFA) Score and the novel Sepsis Support Index (SSI).
In the sensitivity analysis, the biomarker dipeptidyl peptidase 3 (DPP3) was used to identify patients suffering from organ dysfunction by a mechanism that involves myocardial depression and is not addressed by Adrecizumab.^[6],[7]

About Adrecizumab and Adrenomedullin^[8]

Adrenomedullin (ADM) is a free-circulating peptide that is mainly expressed and secreted by vascular endothelial cells. It shows vasoprotective activity inside blood vessels, where it closes the gaps between endothelial cells, subsequently preventing intravascular fluid and other compounds from uncontrolled leakage into the interstitium/extravascular space (= vascular leakage). In the interstitium, however, ADM has vasodilatory properties and causes hypotension when present in higher concentrations, which, in sepsis patients, leads to worsening and progression of the disease. Adrenomed's first-in-class drug candidate, Adrecizumab, targets bioactive Adrenomedullin (bio-ADM) to restore endothelial barrier function (= vascular integrity). Binding of the monoclonal antibody Adrecizumab to ADM in the blood traps and stabilizes the peptide-hormone, resulting in increased ADM concentrations within the blood vessels. The complex of ADM and Adrecizumab in the blood is still active. This way, Adrecizumab treatment boosts ADM's protective effects on the endothelial barrier.

About Adrenomed

Adrenomed AG is a German privately financed, clinical-stage biopharmaceutical company. Adrenomed's mission is to rescue vascular integrity in order to save the lives of critically ill patients with limited treatment options. Founded in 2009 by a management team with decades of in-depth experience in sepsis and deep knowledge in diagnostics and drug development, the company's lead product candidate Adrecizumab is a first-in-class monoclonal antibody. Adrecizumab targets the vasoprotective peptide Adrenomedullin, an essential regulator of vascular integrity. Adrecizumab has successfully completed a biomarker-guided, double-blinded, placebo-controlled, randomized, multicenter proof-of-concept Phase II trial with 301 patients suffering from septic shock. For further information, please visit www.adrenomed.com and follow us on LinkedIn and Twitter.

^[1] https://jamanetwork.com/journals/jama/fullarticle/1873131
^[2] clinicaltrials.gov/ct2/show/NCT03085758?term=NCT03085758&rank=1
^[3] BJCP, 2018:84(9):2129-2141
^[4] https://ccforum.biomedcentral.com/articles/10.1186/s13054-019-2663-7
^[5] BMJ Open, 2019;9:e024475
^[6] Eur J Heart Fail, 2020:22(2):290-299
^[7] J Appl Lab Med, 2019:3(6):943-953
^[8] Shock, 2018;50(6):648-654

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