Neutrophil elastase inhibitor POL6014
POL6014 is a novel, highly potent, selective and reversible inhibitor of human neutrophil elastase (hNE), a key target for the treatment of respiratory diseases like chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) and alpha-1-antitrypsin deficiency (AATD).
The key elements in the assessment of POL6014 are:
- Very potent on free and membrane bound hNE
- Highly efficacious in animal models of respiratory diseases
- Long and high exposure in lungs after inhalation while systemic exposure remains low
- Excellent tolerability and safety
- POL6014 can be formulated as an aerosol or dry powder formulation
- Excellent IP protection
- Significant market opportunities in orphan as well as non-orphan diseases
Cystic fibrosis (CF) is a lethal hereditary disease characterized by abnormal transport of Cl- and Na+ across the epithelium, leading to viscous secretions and neutrophil-dominated lung inflammation sustained by bacterial infections. Activated or necrotic neutrophils liberate proteases that cause damage to structural, cellular and soluble components of the pulmonary microenvironment. The progressive lung disease determines the morbidity and mortality of patients. Neutrophil elastase is the major protease released in the lung of CF patients and plays a major role in the disease process. POL6014 now offers the opportunity for a well controlled clinical study with a highly active and selective elastase inhibitor which can lead to an improved lung function.
Alpha-1-antitrypsin deficiency (AATD) is an hereditary disease characterized by low serum levels of alpha-1-antitrypsin inhibitor (AAT), the main protease inhibitor in human serum. The disease has a prevalence of 1:1'600 – 1:5'000 in the USA and Europe, predominantly among Scandinavian descendants. AATD leads to serious respiratory symptoms similar to COPD and often to chronic liver disease. At present, treatment options are very limited and AAT-infusions, although controversial, are often used. Highly active elastase inhibitors would offer an attractive alternative or complementary treatment option.
COPD is a complex disease with chronic bronchitis and inflammation resulting in destruction of the lung tissue which is essential for uptake of oxygen in the lung (emphysema). Characteristic of COPD is the chronic narrowing of the airways (bronchi) due to inflammatory and remodeling processes. This leads to a limitation of the airflow to and from the lungs causing shortness of breath and insufficient uptake of oxygen. In contrast to asthma, the limitation of airflow is poorly reversible and progressively worsens the destruction of lung tissue and thus the symptoms of COPD over time. In 1997 the World Health Organization (WHO) and the National Institutes of Health (NIH) have initiated the initiative called GOLD (Global Initiative for Chronic Obstructive Lung Disease) for an optimized worldwide approach of diagnosis and treatment of COPD. A study published in 2007 in Salzburg (Austria) showed that approximately a quarter of the examined people above forty years of age suffer from COPD. In the USA, COPD is the fourth largest cause of death and affects 24 million people, half of them undiagnosed. COPD is one of the few life threatening chronic diseases with increasing incidence and prevalence.
Preclinical pharmacological studies have shown that POL6014 inhibits the aggressive, tissue degrading enzyme neutrophil elastase in a highly potent, selective and reversible manner. After local application to the lungs by inhalation POL6014 reaches high concentrations in the lung while the systemic exposure remains low, thus reducing the risk of side-effects. Exploratory toxicology studies suggest that POL6014 is well tolerated when chronically inhaled as an aerosol. POL6014 is ready to enter preclinical development.