Approach

The current therapy for Cystic Fibrosis (CF) has no effect on the persistent neutrophil lung inflammation that leads to airway obstruction, respiratory failure & premature death. Therefore, novel and effective anti-inflammatory therapies are urgently needed to improve clinical outcomes for patients with CF.

The Neuprozyme lead candidate drug XPZ-35 is an oral once-daily inhibitor of dipeptidyl peptidase I (DPPI; also known as cathepsin C) for treatment of inflammation in CF.

Due to overlapping phenotypes and similar underpinning molecular mechanism for a number of respiratory diseases, a positive effect of DPPI inhibition in CF will translate directly to potential treatment of other neutrophil mediated inflammatory lung diseases such as Non-CF Bronchiectasis (Brx), COPD and Alpha-1 Antitrypsin Deficiency (AATD).

Cystic fibrosis

CF is an inherited chronic inflammatory lung disease affecting approximately 75.000 people in North America, Europe, Australia and New Zealand of which 2.500 new cases of CF are diagnosed worldwide each year.

Although life expectancy of people with CF has significantly improved during the last 20 - 30 years, chronic progressive lung function decline remains the major contributor to CF morbidity and mortality. The average expected lifespan for a CF patient is about 40 years of age.

CF is caused by the mutation of the CF transmembrane conductance regulator (CFTR) gene, causing the lung to produce unusually thick mucus that clogs small airways leading to persistent lung inflammation and increasing risk of lung infections. The consequence of lung inflammation is development of bronchiectasis (i.e. irreversible enlargement of parts of the airways of the lung) and thus permanent reduction of lung function over time. Lung disease remains the major cause of hospitalizations and premature death in CF.

Neutrophil inflammation in cystic fibrosis

The inflammatory response in CF lung disease begins early in life and is characterized by excessive neutrophil influx into the airways which leads to lung destruction and loss of pulmonary function. Neutrophil Elastase (NE) released from neutrophil cells in the CF airways is the key component of the CF lung inflammation. NE acts synergistically with two other neutrophil elastase-like proteases – Cathepsin G (CatG) and Proteinase 3 (PR3) – as drivers of the inflammation.

Excess NE degrades healthy lung tissue by breaking down the collagen matrix that provides the flexibility that allows the lungs to expand and contract and over time, the lung becomes too weak to pull in air. Also, excess NE and CatG erodes the ability of neutrophils to find and kill bacteria, the very thing neutrophils are called to do in the first place. There are several other deleterious effects of excess NE, CatG and PR3 in the lung including inactivation of CFTR, and induction and activation of neutrophil chemoattractants.

Unmet need for anti-inflammatory therapies in cystic fibrosis

The current therapy for CF has no effect on the persistent neutrophil lung inflammation that leads to airway obstruction, respiratory failure & premature death. Therefore, novel and effective anti-inflammatory therapies are urgently needed to improve clinical outcomes for patients with CF.

The existing pulmonary treatment of CF patients focuses on improving lung function by loosening and removal of mucous using mucolytics and on avoiding or delaying lung infection and chronic bacterial colonisation using antibiotics, mainly by inhalation.

Furthermore, a new type of medicine - CFTR modulators - are designed to correct the function of the defective CFTR protein. These therapeutics aim to enhance the CFTR function by either restoring wild-type CFTR protein expression (CFTR correctors) or potentiating the function of mutant CFTR proteins in cells (CFTR potentiators). CFTR modulators has some impact on lung function measured by ppFEV1.

Neither mucolytics, antibiotics or CFTR modulators have any proven effect on the CF inflammation.

Treatment of inflammation in cystic fibrosis with DPPI inhibitors

The lysosomal cysteine protease dipeptidyl peptidase I (DPPI; also known as cathepsin C) is the only activator of NE, CatG and PR3 and activation takes place during neutrophil maturation in the bone marrow. Transitory and/or partial inhibition of DPPI in the neutrophil precursor cells tune down the activation of NE, CatG and PR3. This leads to circulating neutrophils with a reduced cargo of active NE, CatG and PR3 throughout their entire lifespan and thereby also reduced levels of NE, CatG and PR3 in inflamed lung tissue. Targeting DPPI in the bone marrow makes the treatment independent of difficult accessibility and challenging kinetics created by very high local concentrations of NE, CatG and PR3 in lung tissue. Also, challenges with metabolic drug instability under patho-physiological conditions in the lung is eliminated. Finally, targeting DPPI in the bone marrow bypass the risk of redundancy posed by direct inhibition of individual proteases.

Thus, inhibition of DPPI in the bone marrow opens up for an effective oral treatment of lung inflammation and tissue degradation and represents an attractive and logical therapeutic strategy to modulate the activity of NE, CatG and PR3 in CF. A DPPI inhibitor ensures efficient, controlled and prolonged regulation of the protease activities, is independent of fluctuating high levels of NE, CatG and PR3 and is likely to have clinical effect in contrast to what has not been possible to achieve by targeting NE with DPPI inhibitors.