Inhaled inhibitor of neutrophil elastase, one of the major lung tissue degrading enzymes, for the treatment of Cystic Fibrosis and other neutrophilic lung diseases
Treatment of neutrophilic lung diseases
POL6014 is primarily developed to decrease inflammation associated with Cystic Fibrosis 1, 2. In addition, it may be further beneficial in a range of neutrophilic lung diseases with high medical need, such as Non-Cystic Fibrosis Bronchiectasis 3, or in rare diseases such as Alpha-1 Antitrypsin Deficiency 4. POL6014 is derived from Polyphor’s proprietary platform.
Cystic Fibrosis (CF) is a hereditary, life-threatening, progressive disease, mainly found in Europe and North America (1 in 20 heterozygotic Caucasians, 1 in 3000 live births), that is characterized by persistent lung infection and inflammation and limits the ability to breathe over time. A defective gene (CFTR) for an ion channel causes thick mucus formation, mucus plugging of the airways and other organs and the trapping of bacteria, leading to infection and sustained neutrophil-dominated lung inflammation.
Activated or necrotic neutrophils liberate proteases that cause damage to structural, cellular and soluble components of the pulmonary microenvironment 5. The progressive lung damage causes lung function deterioration, 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 1.
- Kelly, E. et al. Targeting neutrophil elastase in cystic fibrosis. Expert Opin. Ther. Targets. 2008; 12(2):145–157
- Griese, M. et al. Inhibition of airway proteases in cystic fibrosis lung disease. Eur Respire J. 2008;32(3):783–795
- Chalmers, J. D. and Hill, A.T. Mechanisms of immune dysfunction and bacterial persistence in non-cystic fibrosis bronchiectasis. Mol Immunol. 2013;55:27–34
- Fregonese, L. and Stolk, J. Hereditary alpha-I-antitrypsin deficiency and its clinical consequences. Orphanet Journal of Rare Diseases. 2008;3:16–25
- Downey, DG et al. Neutrophils in cystic fibrosis. Thorax. 2009;64:81–88
A highly potent elastase inhibitor
Human neutrophil elastase (hNE), a key target for the treatment of neutrophilic respiratory diseases like Cystic Fibrosis (CF)
POL6014 is a very potent and selective inhibitor of human Neurophil Elastase (hNE). hNE is a protease that is released by activated neutrophils in case of chronic inflammation like in CF. Excess production of hNE degrades elastin and collagen, leading to lung tissue damage, increased mucus hyper-secretion and upregulates pro-inflammatory cytokines (IL-8) maintaining chronic bronchitis and persistent neutrophilia 1, 5.
A central role in the pathophysiology of CF has been attributed to neutrophil elastase as high levels of hNE have been detected in CF sputa and these high levels of hNE correlate with disease severity as measured by FEV1%pred reduction 6, 7.
POL6014, administered by inhalation using Pari eFlow®, was shown to reach high concentrations in the lung, favoring local activity, while systemic exposure remains low, thus reducing the risk of side effects.
Based on its pharmacological profile, POL6014 offers an opportunity as an active and selective elastase inhibitor with the potential to treat chronic neutrophilic inflammation in CF.
1. Kelly, E. et al. (2008) Targeting neutrophil elastase in cystic fibrosis. Expert Opin. Ther. Targets 12 (2) 145–157
5. Downey, DG et al. (2007) Neutrophils in cystic fibrosis. Thorax 2009;64:81–88
6. Mayer-Hamblett, N et al. (2007). Association between Pulmonary Function and Sputum Biomarkers in Cystic Fibrosis. Am J Respir Crit Care Med Vol 175. pp 822–828, 2007
7. Griese, M. et al. (2007) a1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur Respir J 2007; 29: 240–250
POL6014 is a novel, highly potent, selective and reversible inhibitor of human neutrophil elastase.
POL6014’s key attributes:
- Very potent on free and membrane-bound hNE 8, 9
- Highly effective in animal models of respiratory injury and sputum from patients 8, 9
- Long and high exposure in lungs after inhalation while systemic exposure remains low 9
- Formulated as an aerosol delivered with Pari eFlow®
8. ATS, San Diego, May 2009 (poster)
9. ERS, Barcelona, September 2013 (oral communication)
In clinical studies performed so far with inhaled POL6014, no safety issues were noted and inhibition of sputum neutrophil elastase was observed after single dosing.
POL6014 has successfully completed the first-in-man Phase 1 study in healthy volunteers and a Single Ascending Dose (SAD) safety and tolerability Phase 1 study in CF patients, confirming the safety, favorable pharmacokinetic profile and strong elastase inhibition as previously shown in animal models 10.
- In these Phase 1 studies: POL6014 was administered in an aerosol formulation via the PARI eFlow® system.
- POL6014 appeared safe and well tolerated in both, healthy volunteers and CF patients. No serious adverse events were observed.
- In both studies the plasma pharmacokinetics were similar in HVs and CF patients and showed a linear dose relationship.
- In the CF patient study POL6014 strongly inhibited active sputum hNE as was previously shown in animals
- A Multiple Ascending Dose (MAD) study in the EU is planned to start in Q3 2017 to evaluate the safety and tolerability of POL6014 in patients with CF
- 3 million dollar have been awarded by the US Cystic Fibrosis Foundation
10. ECFS, Sevilla, June 2017 (poster & oral communication)