APEPTICO: Mechanism of the AP301-peptide discovered

Most recently, in a scientific collaboration effort between APEPTICO, the Vascular Biology Center of the Georgia Regents University (Prof. Dr. Rudolf Lucas, USA), and the Institute of Pharmacology and Toxicology of the University of Vienna (Prof. Dr. Rosa Lemmens-Gruber, Austria), the detailed mechanism has been discovered how APEPTICO’s clinically stage “AP301-peptide” (identical to the lectin-like domain of native TNF-alpha) activates the specific pulmonary ion channel “ENaC” to result in “Activation of Lung Oedema Clearance”.

In the most recent EDITORIAL in “American Journal of Respiratory Critical Care” (Am J Respir Crit Care Med Vol 190(6), pp 595–605, Sep 15, 2014; http://www.atsjournals.org/doi/abs/10.1164/rccm.201407-1364ED#.VBfyMha7ZbI) by Gary C. Sieck and Mark E. Wylam from the Mayo Clinic, Rochester, both the ground-braking scientific discoveries and the clinical-therapeutically potential of AP301 peptide have been highlighted.
In the EDITORIAL the authors summarise as follow “Previously, the lectin-like domain of TNF-alpha was shown to activate ENaC in type 2 alveolar epithelial cells (Ref. 1). Importantly, this effect has been mimicked by a small 17-amino acid circular peptide known as TNF inhibitory peptide (TIP; APEPTICO code “AP301”). A recent European study compared placebo treatment with TIP inhalation in patients with ALI/ARDS and found that TIP elicited earlier and more pronounced clearance of pulmonary edema (Ref. 2, Ref. 3). The molecular mechanism underlying TIP-induced ENaC activation remained uncertain until the study by Czikora and colleagues, published in the September 1, 2014, issue of the Journal (Ref. 4).”
The EDITORIAL makes explicate reference to APEPTICO’s most recently completed phase IIa clinical study in patients with ARDS and pulmonary oedema. During the European Respiratory Society International Conference (Munich, 6-9 September 2014), Dr. Krenn from the Department of Intensive Care Medicine, Medical University of Vienna, reported key findings of the AP301-trial in mechanically ventilated patients with pulmonary permeability oedema.
The EDITORIAL concludes, “Taken together, these basic science results provide new physiological insight into the potential role of the lectin-like domain of TNF-a (AP301 peptide) and support the novel therapeutic use of AP301 aerosols in patients with ALI/ARDS and ischemia reperfusion lung injury.”
In addition, Dr. Krenn’s presentation of the AP301 clinical trial at the ERS International Conference was immediately reflected as “Top story of the week” in Pulmonary/Respiratory Medicine (http://dgnews.docguide.com/novel-peptide-activates-pulmonary-oedema-clearance-mechanically-ventilated-patients). MUNICH, Germany -- September 10, 2014: Jenny Power reported “Novel Peptide Activates Pulmonary Oedema Clearance in Mechanically Ventilated Patients. -- Acute lung injury (ALI) mediated by acute pulmonary permeability oedema can be reduced by a novel synthetic peptide that promotes pulmonary oedema clearance by decreasing extra-vascular lung water (EVLW) among mechanically ventilated patients in the intensive care unit (ICU).”
Dr. Bernhard Fischer, CEO of APEPTICO added: ”We are very proud that Prof. Rudolf Lucas’ scientific discoveries and APEPTICO’s therapeutic approach have been rewarded an Editorial in the American Journal of Respiratory Critical Care”. “APEPTICO develops the “AP301-peptide”, a synthetic version of the lectin-like domain of TNF, as a new life-saving medicine for patients with pulmonary permeability oedema. Most recently we could demonstrate in a clinical phase II proof-of-concept study (ClinicalTrials.gov ID NCT01627613) that orally inhaled “AP301-peptide” activates alveolar liquid clearance in mechanically ventilated patients having lung oedema and ARDS,” he added.
Ref. 1: Tzotzos S, Fischer B, Fischer H, Pietschmann H, Lucas R, Dupre´ G, Lemmens-Gruber R, Hazemi P, Prymaka V, Shabbir W. AP301, a synthetic peptide mimicking the lectin-like domain of TNF, enhances amiloride-sensitive Na(1) current in primary dog, pig and rat alveolar type II cells. Pulm Pharmacol Ther 2013;26:356–363.
Ref. 2: Hartmann EK, Thomas R, Liu T, Stefaniak J, Ziebart A, Duenges B, Eckle D, Markstaller K, David M. TIP peptide inhalation in experimental acute lung injury: effect of repetitive dosage and different synthetic variants. BMC Anesthesiol 2014;14:42.
Ref. 3: Krenn K, Croize A, Klein KU, Bo¨ hme S, Markstaller K, Ullrich R, Hermann R, Lucas R, Fischer B. Oral inhalation of AP301 peptide activates pulmonary oedema clearance: initial results from a phase IIa clinical trial in mechanically ventilated ICU patients. Presented at the ERS International Congress 2014. September 6–10, Munich, Germany.
Ref. 4: Czikora I, Alli A, Bao H-F, Kaftan D, Sridhar S, Apell H-J, Gorshkov B, White R, Zimmermann A, Wendel A, et al. A novel tumor necrosis factor–mediated mechanism of direct epithelial sodium channel activation. Am J Respir Crit Care Med 2014;190:522–532.
About APEPTICO GmbH (www.apeptico.com)
APEPTICO is a privately-held biotechnology company based in Austria, developing peptide-based products targeting chronic and life-threatening diseases. The peptide molecules correspond to validated, pharmacodynamic active structures and domains of well-known proteins and biopharmaceuticals. By concentrating on synthetically produced protein structures APEPTICO avoids general risks associated with gene- and cell-technologies. APEPTICO makes use of its technology platforms PEPBASE(TM) and PEPSCREEN(TM) to significantly reduce cost and to shorten time to market.
About the AP301-peptide / TIP-peptide
The AP301-peptide (synonym to TNF-derived TIP-peptide) is a synthetic molecule whose structure is based on the lectine-like domain of the human Tumour Necrosis Factor α. The AP301 peptide is water soluble and can be administered into the lung by oral inhalation. Formulated AP301 is easily nebulised and the resulting aerosol is composed of peptide/water droplets of diameter 4 μm or less. APEPTICO’s most recent clinical phase II proof-of-concept study (ClinicalTrials.gov ID NCT01627613) demonstrated that orally inhaled AP301-peptide activates alveolar liquid clearance in mechanically ventilated patients with pulmonary permeability oedema and ARDS.
Comprehensive research and development studies conducted by Dr. Rudolf Lucas and the APEPTICO research consortium demonstrated, that AP301-peptides are effective therapeutic molecules in various forms of pulmonary oedema, such as pulmonary permeability and hydrostatic oedema, high altitude pulmonary oedema (HAPE), pulmonary oedema associated with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), pulmonary oedema resulting from pneumonia, sepsis and lung transplantation (primary graft dysfunction).
APEPTICO’s AP301 has been granted orphan drug status (i) for treatment of pulmonary permeability oedema in ALI/ARDS, (iii) for treatment of primary graft dysfunction following lung, and (iii) for treatment of high altitude pulmonary oedema by the European Commission and European Medicines Agency (EMA) and by the Food and Drug Agency (FDA).
About pulmonary oedema
Pulmonary oedema occurs when fluid leaks from the pulmonary capillary network into the lung interstitium and alveoli. There are many possible causes of lung oedema, such as heart failure (cardiac/hydrostatic lung oedema); inhaling high concentrations of smoke, toxins, or oxygen; severe burns; blood infections / sepsis; infection of the lung / pneumonia; aspirations, cerebral damage or trauma to other parts of the body and lung transplantation. Lungs contain alveoli, which are tiny air sacs where the oxygen is passed into the blood. During lung oedema, blood and fluid begin to leak into the alveoli. When this happens, oxygen cannot enter the alveoli, which means oxygen no longer passes into the blood. Because the lungs are inflamed and filled with fluid, the patient finds it increasingly difficult to breathe. The mortality rate of patients with pulmonary oedema in ALI/ARDS is 35% to 45% within two to four weeks. Currently, no specific drug treatment exists for patients suffering from pulmonary permeability oedema and patients having ARDS. ARDS is also a major economic burden to hospitals and health care budgets. It is estimated that due to a long ICU and hospital stay the cost of every saved live from ARDS is approximately $70,000 USD.

The sender takes full responsibility for the content of this news item. Content may include forward-looking statements which, at the time they were made, were based on expectations of future events. Readers are cautioned not to rely on these forward-looking statements.

As a life sciences organization based in Vienna, would you like us to promote your news and events? If so, please send your contributions to news(at)lisavienna.at.