In a combined research effort between the Department of Pharmacology and Toxicology of the University of Vienna and APEPTICO Research & Development, Vienna, a unique ENaC-dependent mechanism was unveiled that mimics fluid transport in the lung, which is not only relevant to pathological mechanism of lung oedema but might also present physiological means of acutely activating ENaC in the lung and other organs.
Consequently, this study was undertaken to determine whether the Epithelial Sodium-ion Channel “ENaC” is the specific target of APEPTICO’s synthetic peptide AP301. The effect of AP301 in pulmonary A549 cells as well as in human embryonic kidney cells and Chinese hamster ovary cells heterologously expressing human ENaC subunits ({Alpha}, {Beta}, {Gamma}, and {Delta}) was measured in patch clamp experiments. AP301 increased current in proteolytically activated (cleaved) but not near-silent (uncleaved) ENaC in a reversible manner. {Alpha}{Beta}{Gamma}- or {Delta}{Beta}{Gamma}-ENaC co-expression was required for maximal activity. No increase in current was observed after deglycosylation of extracellular domains of ENaC. Thus, our data suggest that the specific interaction of AP301 with both endogenously and heterologously expressed ENaC requires precedent binding to glycosylated extracellular loop(s).
APEPTICO develops the AP301 peptide compound for the activation of pulmonary oedema clearance in various forms of life-threatening oedematous respiratory failure. In 2011, APEPTICO conducted a Phase I clinical study for safety and tolerability of orally inhaled AP301. From mid-2012 to February 2014 APEPTICO assessed the effect of orally inhaled AP301 on alveolar liquid clearance in ICU patients in an interventional, randomized, double-blind, placebo-controlled, parallel-group, Phase IIa clinical study in collaboration with the Medical University Vienna. This proof-of-concept study delivered top-line results for AP301 treatment associated changes of extra-vascular lung water (EVLW) within 7 days of treatment of mechanically ventilated patients with various forms acute lung injury.
Dr. Bernhard Fischer, CEO of APEPTICO, commented: “Together with the researchers from the Department of Pharmacology and Toxicology of the University Vienna we are very happy to have our scientific results highlighted as key scientific contribution in the biomedical research. These cell-based results confirm was we have discovered very recently in our Phase IIa “proof-of-concept” clinical study in mechanically ventilated patients: AP301 activates pulmonary oedema clearance in patients with life-threatening respiratory failure.” “AP301 will be the one-and-only orally inhaled drug compound that activates oedema clearance making use of the sodium-ion transport mechanism in pulmonary tissue” Dr. Fischer added.
About APEPTICO GmbHwww.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 family
AP301 and derived peptides are synthetic molecules whose structures are based on the lectin-like domain of human Tumour Necrosis Factor alpha. AP301 peptides are 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. AP301 and derived peptides are designed for activation of the pulmonary epithelial sodium channel (ENaC). Activation of ENaC by AP301 results an accelerated lung oedema clearance in the airspace. Comprehensive research and development conducted by APEPTICO has demonstrated that AP301 peptides are effective in animal models of various forms of pulmonary oedema, including high altitude pulmonary oedema, acute lung injury / acute respiratory distress syndrome, pneumonia, influenza virus lung infection, and lung transplantation. In addition to the use of AP301 for the treatment of patients suffering from life-threatening oedematous respiratory failure, the compound is assessed for the treatment of primary graft dysfunction following lung transplantation, respectively.
About oedematous respiratory failure
Respiratory failure occurs when the respiratory system fails in oxygenation and/or carbon dioxide elimination. Oedematous Respiratory Failure is caused by a massive and life-threatening 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); lung infections (pneumonia); cerebral damage or trauma to other parts of the body. 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 30% to 60% within two to four weeks. Currently, no specific drug treatment exists for patients suffering from hyper-permeability-caused lung oedema.
About Primary Graft Dysfunction
Primary Graft Dysfunction (PGD) (Ischemia Reperfusion Injury, IRI) is characterized by poor oxygenation as the main criterion for the condition and is also characterized by low pulmonary compliance, interstitial/alveolar oedema, pulmonary infiltrates on chest radiographs, increased pulmonary vascular resistance, intrapulmonary shunt and acute alveolar injury, as revealed by diffuse alveolar damage (DAD) on pathology. PGD occurs in approximately 20% of lung transplant recipients and patients face prolonged ventilation, prolonged stays in the ICU and the hospital overall, increased medical costs, and increased risk of morbidity and mortality. Currently, no specific drug treatment exists for patients suffering primary graft dysfunction following lung transplantation.