AP301: Development of inhalation medicine from scientific discovery to clinical proof-of-concept for treatment of life-threatening pulmonary oedema

Bernhard Fischer, Susan Tzotzos, Hendrik Fischer, Helmut Pietschmann, Waheed Shabbir, Rosa Lemmens-Gruber, Rudolf Lucas

Pulmonary oedema is a life-threatening complication in patients with a variety of underlying critical diseases. Today, no medicinal product has been authorised directly activating alveolar liquid clearance.
Based on the TNF loop structure as determined by x-ray crystallography, a family of AP301 peptides has been designed. Assessment of human epithelial cells A549 and H441 as well as primary isolates from mouse, rat, pig and dog demonstrated that AP301 binds to and activates the amiloride-sensitive epithelial sodium ion channel (“ENaC”) of pulmonary cells. The interaction of AP301 and ENaC leads to enhanced Na+ ion transport, a Na+ ion gradient and a directed osmotic force across the pulmonary epithelial cell layer. Water molecules follow this osmotic gradient – thus clearing oedema fluid from the lung. The oedema clearing potential of AP301 has been studied in great detail in various animal models of non-cardiogenic and cardiogenic pulmonary oedema, including models of hydrostatic and permeability oedema, Acute Lung Injury / ARDS, pneumonia, sepsis and lung transplantation. In addition to non-clinical pharmacodynamics studies, the complete battery of safety and toxicity studies has been conducted in mice, rats, pigs and dogs prior clinical assessment. To target the AP301 peptide into the pulmonary air space, AP301 peptide has been specifically formulated. Liquid preparation of AP301 is converted into an aerosol of fine particles by a mesh-type nebuliser. The AP301 aerosol is dispensed directly in the circuit of mechanically ventilated ICU-patients thus delivering a constant stream of AP301 droplets into the lung.
Safety and tolerability of orally inhaled AP301 has been demonstrated in a Phase I clinical study in 48 volunteers in 2011. From 2012 to 2014, an interventional, randomized, double-blind, placebo-controlled, phase IIa study has been conducted. The clinical study demonstrated that oral inhalation of AP301 by mechanically ventilated ICU-patients with lung oedema led to an earlier onset and more effective oedema clearance, improvement of Murray Lung Injury Score and increase in ventilator free days in comparison to placebo treatment, respectively.

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