- •POL6014 is a new orally inhaled potent and selective neutrophil elastase inhibitor.
- •POL6014 is well tolerated up to 480 mg in HVs and up to 320 mg in CF subjects.
- •POL6014 shows a low systemic burden in comparison to orally administered drugs.
- •Ratio between POL6014 sputum and plasma concentrations is 1000-fold in CF subjects.
- •>1-log reduction of active NE in sputum is reached 3 h post dosing.
POL6014 is a novel, orally inhaled neutrophil elastase (NE) inhibitor in development for cystic fibrosis (CF).
Two studies, one in healthy volunteers (HVs, doses 20 to 960 mg) and one in subjects with CF (doses 80 to 320 mg) were conducted to evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending doses of inhaled POL6014 with a Pari eFlow® nebuliser. PK was evaluated over a period of 24 h. In addition, NE activity in CF sputum was measured.
After single doses, POL6014 was safe and well tolerated up to 480 mg in HVs and at all doses in subjects with CF. POL6014 showed a dose-linear PK profile in both populations with Cmax between 0.2 and 2.5 μM in HVs and between 0.2 and 0.5 μM in subjects with CF. Tmax was reached at approximately 2–3 h. Mean POL6014 levels in CF sputum rapidly reached 1000 μM and were still above 10 μM at 24 h. >1-log reduction of active NE was observed at 3 h after dosing.
Inhalation of POL6014 can safely lead to high concentrations within the lung and simultaneously low plasma concentrations, allowing for a clear inhibition of NE in the sputum of subjects with CF after single dosing.
Trial Registration: European Medicines Agency EudraCT-Nr. 2015-001618-83 and 2016-000493-38.
In chronic inflammatory conditions of the lung, such as Cystic Fibrosis (CF), neutrophils are abundantly present in the tissue and sputum. Excessive release of neutrophil derived proteolytic enzymes, like neutrophil elastase (NE), will accelerate lung tissue damage, leading to an incapacitating and progressive decline in lung function [
- Tetley T.D.
Macrophages and the pathogenesis of COPD.
Chest. 2002; 121: 156S-159Shttps://doi.org/10.1378/chest.121.5_suppl.156S
- Polverino E.
- Rosales-Mayor E.
- Dale G.E.
- Dembowsky K.
- Torres A.
The role of neutrophil elastase inhibitors in lung diseases.
Chest. 2017; 152: 249-262https://doi.org/10.1016/j.chest.2017.03.056
- Henriksen P.A.
The potential of neutrophil elastase inhibitors as anti-inflammatory therapies.
Curr Opin Hematol. 2014; 21: 23-28https://doi.org/10.1097/MOH.0000000000000001
- Von Nussbaum F.
- Li V.M.J.
Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: into clinical testing with pre-adaptive pharmacophores.
Bioorg. Med. Chem. Lett. 2015; : 4370-4381https://doi.org/10.1016/j.bmcl.2015.08.049
- Tsai Y.-F.
- Hwang T.-L.
Neutrophil elastase inhibitors: a patent review and potential applications for inflammatory lung diseases (2010–2014).
Expert Opin Ther Pat. 2015; 25: 1145-1158https://doi.org/10.1517/13543776.2015.1061998
POL6014 is a novel, potent and selective NE inhibitor. It is a macrocycle based on the Protein Epitope Mimetic technology (proprietary of Polyphor Ltd). POL6014 is an orally inhaled, investigational compound that can be administered as a nebulized drug via the Pari eFlow® system. Pre-clinical data provided evidence that POL6014 potently and selectively inhibits NE in enzymatic assays and reduces neutrophils as well as inflammatory markers in animal models of neutrophilic inflammation. Additionally, POL6014 inhibited NE in ex-vivo bronchoalveolar lavage and sputum specimens of patients with CF [
]. Toxicology studies performed in rats and non-human primates at micromolar exposures showed excellent safety and tolerability. Consequently, first-in-human studies with POL6014 were initiated as single ascending (inhalational) dose studies, first in healthy volunteers (HV) and then in subjects with CF.
- Lacey N.
- Lavelle G.
- Flinn K.
- Hawkins P.
- Gargoum F.
- Dunlea D.
- et al.
A novel neutrophil elastase inhibitor, POL6014, for therapeutic potential in cystic fibrosis and airways disease characterised by neutrophil-dominated inflammation.
in: 30th annu. North Am. cyst. fibros. conf. 2016: S95https://doi.org/10.1002/ppul.23576
Here we present the safety and pharmacokinetic data of both Single Ascending Dose (SAD) studies.
2. Materials and methods
POL6014 was manufactured by Solid Phase Peptide Synthesis by Bachem (Bubendorf, Switzerland). Before administration, POL6014 stock solution (80 mg/mL) was diluted with 0.5% saline solution, the same diluent as placebo. The administered volume was 4 mL for doses up to 320 mg, 6 mL for the 480 mg dose, and 12 mL for the 960 mg dose. Study medication was inhaled using an eFlow® nebuliser handset (Pari Pharma GmbH, Gräfelfing, Germany). In vivo, three major metabolites designated M9, M18, and M20 are produced from POL6014. To quantify metabolite content in clinical samples, reference peptides as well as their deuterated isoforms were synthesized by Polyphor Ltd. (Allschwil, Switzerland).
2.2.1 Study design
Both HV and CF SAD studies were single centre, randomised, double-blind, placebo-controlled, parallel-group studies with 8 subjects per dose randomly allocated to POL6014 or placebo in a 3:1 fashion. In the HV study, the following doses were investigated: 20, 60, 120, 240, 480 and 960 mg; in the CF study, patients received single ascending doses of 80, 160 and 320 mg.
2.2.2 Safety measurements, blood and urine collection
Safety measurements, as well as plasma and urine sample collections were performed at different time points during the 24 h following inhalation for pharmacokinetic (PK) assessment. Escalation to the next dose was executed after evaluation of all safety and PK data of the preceding dose level by a dedicated safety evaluation team.
2.2.3 Sputum collection and processing
In subjects with CF, spontaneous sputum collection was performed pre-dose, within the first hour, 3 h and 24 h after inhalation of POL6014 or placebo. Sputum was collected after the subjects had rinsed their mouths to remove saliva and solid particles. Sputum was collected in Petri dishes and put on ice immediately. For further processing details, see Appendix 1, Online Supplementary Material.
2.2.4 Pharmacokinetic and pharmacodynamic measurements
POL6014 and its metabolites (M9, M18, M20) present in plasma and urine were analysed by high-resolution LC-MS by Pharmacelsus GmbH (Saarbrücken, Germany).
Active elastase was measured by an enzymatic assay using the Fluorescence Resonance Energy Transfer (FRET) based substrate Abz-APEEIMRRQ-YNO2 as described by Korkmaz et al. [
- Korkmaz B.
- Attucci S.
- Epinette C.
- Pitois E.
- Jourdan M.L.
- Juliano L.
- et al.
Measurement of neutrophil elastase, proteinase 3, and cathepsin G activities using intramolecularly quenched fluorogenic substrates.
Methods Mol Biol. 2012; 844: 125-138https://doi.org/10.1007/978-1-61779-527-5_9
Pharmacodynamic results that were below the Lower Level of Quantification (LLOQ) were imputed with half the lowest quantifiable value when taking into account sample dilution.
2.3 Statistical analysis
The statistical analysis of the PK parameters consisted of descriptive statistics, including arithmetic mean, median, standard deviation (SD), min and max. Values below the LLOQ, i.e. 1 ng/mL in plasma and 112 ng/mL in urine for POL6014 and its three metabolites, 50.4 ng/mL for POL6014 in sputum, were excluded from calculations. The following pharmacokinetic characteristics were calculated using non-compartmental procedures: Cmax, AUC0-∞, CL, Vd, tmax, t1/2, λz, AUC0-tlast (see Appendix 2, Online Supplementary Material).
Healthy male subjects (n = 48), aged 19–46 years, with a Body Mass Index (BMI) in the range of 18.6 to 28.2 kg.m−2 and a Forced Expiratory Volume in one second (FEV1) > 80% of predicted value were enrolled into the HV study (see Table 1).
Table 1Subject demographic and baseline characteristics for HV and CF studies.
|Subject demographic and baseline characteristics for the HV study|
|20 mg||60 mg||120 mg||240 mg||480 mg||960 mg|
|Age yrs||32.7 ± 7.4||27.3 ± 8.2||30.0 ± 5.2||30.5 ± 5.9||29.5 ± 6.8||31.8 ± 11.5||31.8 ± 6.0|
|BMI kg.m−2||20.5 ± 2.4||22.2 ± 2.2||24.4 ± 1.5||24.0 ± 1.3||24.4 ± 2.6||23.4 ± 3.1||24.3 ± 1.7|
|FEV1% pred median (min-max)||108.5 (89.8–122.7)||105.3 (88.1–121.2)||100.8 (91.1–121.1)||103.6 (91.7–124.8)||101.2 (93.9–111.8)||100.4 (89.2–114.0)||108.5 (89.8–122.7)|
|Subject demographic and baseline characteristics for the CF study|
|80 mg||160 mg||320 mg|
|Age yrs||30.7 ± 7.0||33.2 ± 7.4||30.2 ± 6.8||29.8 ± 5.5|
|BMI kg.m−2||20.5 ± 2.4||23.5 ± 3.5||23.1 ± 2.4||22.0 ± 1.8|
|FEV1% pred median (min-max)||68.6 (59.6–97.0)||70.7 (52.0–91.9)||67.0 (62.2–105.3)||70.0 (60.2–89.0)|
Data are presented as mean ± SD or n unless otherwise stated. BMI: body mass index; FEV1: forced expiratory volume in 1 s; % pred: % predicted.
In the CF study (see Table 1), 26 male and female (of non-child bearing potential) patients were screened, and 24 were randomised. Patients aged 18–41 years, with a confirmed diagnosis of CF, a BMI between 17.7 and 27.4 kg.m−2, and a FEV1 ≥ 60% of predicted value participated in the study. All subjects with CF had stable disease when they entered the study and remained stable until the end of the study. Patients were allowed to maintain their daily routine CF medication during the study. Pulmozyme® and hypertonic saline were administered ≥12 h prior to dosing.
3.2 Safety and tolerability
3.2.1 Safety in healthy volunteers
Inhalation time in HVs increased with doses up to 30 min for the dose group 480 mg; for the highest dose group (960 mg) an inhalation time between 55 and 68 min was observed due to the administered volume of 12 mL.
No serious adverse event (SAE) occurred during the HV study. In total, 27 AEs, 24 of which treatment-emergent AEs (TEAEs), were recorded in 13 subjects (27.1%). All of these subjects had received POL6014. No AE was reported for subjects having inhaled placebo solution. The most frequently recorded AE was ‘cough’ (5 events). In 18 of the 24 TEAEs, a relationship to the investigational product could not be ruled out. 1 TEAE was rated as severe (‘vomiting’ in a subject from dose group 120 mg). 26 AEs resolved without sequelae. 1 AE was recorded as ongoing at the End-of-Study Visit (‘nasopharyngitis’, in a subject from dose group 240 mg). Regarding the number of AEs as well as their intensity and causal relationship to the study medication, a large proportion of AEs and related AEs was reported in the dose group 960 mg. The majority of AEs and symptoms reported was related to the respiratory system (Appendices 3 and 5, Online Supplementary material). Doses of up to 480 mg POL6014 were assessed as safe and well tolerated. The administration of the 960 mg dose of POL6014 triggered inhalation related AEs (i.e. short transient decline in FEV1, cough, respiratory tract irritation) in 3 out of 6 subjects. These AEs were considered unacceptable for routine clinical use of POL6014, hence this dose should not be used in further clinical studies. Clinical laboratory investigations, electrocardiogram and blood pressure measurements showed no clinically significant adverse findings. The overall tolerability was not recorded as per protocol but most HVs (97.9%) judged it as good or very good.
3.2.2 Safety in subjects with CF
In the CF study, an inhalation time shorter than 15 min was aimed to prevent treatment compliance deviations during chronic use. Based on the safety data obtained in HVs and the dose packaging a dose range from 80 to 320 mg POL6014 was selected for the subjects with CF. The mean inhalation time was approximately 10 min.
No SAE occurred during the course of the CF study. There were no inhalation related, local AEs. In total, 6 AEs, all of them TEAEs, were recorded in 6 subjects. 5 of these subjects (83.3%) were on active compound: 1 subject on 80 mg POL6014 and 2 subjects each on 160 mg and 320 mg POL6014. The most frequently reported AEs were ‘dizziness’ and ‘headache’ with 2 events each. All 6 TEAEs were regarded as being not related to POL6014. None of the TEAEs were rated as severe. AE duration was transient. All 6 AEs resolved without sequelae. Regarding the number of AEs as well as their intensity and causal relationship to the study medication, no difference between the dose levels was apparent. The majority of results from lung function tests were as expected of patients with CF. In most subjects (including some placebo treated subjects), an asymptomatic, small and clinically not significant decline in FEV1 was observed at 0.5 h after dosing (Appendix 5, Online Supplementary material). In the majority of these subjects, the FEV1 values recovered to predose or even above within 24 h after dosing. The changes in FEV1 [range between maximum % decrease and maximum % increase] from baseline to 24 h post dose were [−6.5/+6.4] at 80 mg, [−9.3/+3.6] at 160 mg, [−6.1/+4.2] at 320 mg, and [−4.2/+9.4] in the placebo group. None of the patients reported dyspnoea, wheezing or any other respiratory symptom; clinical parameters, especially oxygen saturation, remained stable throughout the study in all subjects. All dose levels including the 320 mg dose level were assessed as safe and well tolerated.
All subjects with CF in the POL6014 groups rated the overall tolerability as “good” (3 of 18) or “very good” (15 of 18) after study end.
3.3.1 PK after SAD of POL6014 in HVs and in subjects with CF
Mean plasma levels of POL6014 in HVs are depicted in Fig. 1. Similar absorption and elimination patterns were observed in subjects with CF when administered doses between 80 mg and 320 mg (Fig. 2).
Mean PK parameters of POL6014 are shown in Table 2.
Table 2PK parameters (mean (SD)) after inhalation of single ascending doses of POL6014 ranging from 20 to 960 mg, in HVs and subjects with CF.
|Dose||Healthy Volunteers||Subjects with CF|
|Cmax (ng/mL)||AUC0-∞ (ng*h/mL)||t1/2 (h)||Cmax (ng/mL)||AUC0-∞ (ng*h/mL)||t1/2 (h)|
|20 mg||70.0 (39.2)||405 (235)||2.9 (0.5)|
|60 mg||276.5 (69.5)||1529 (412)||3.3 (0.4)|
|80 mg||314.8 (321.1)||1743 (1710)||4.1 (1.3)|
|120 mg||418.0 (192.0)||2212 (823)||3.1 (0.3)|
|160 mg||441.0 (180.2)||2776 (1164)||3.5 (0.4)|
|240 mg||743.6 (124.9)||5775 (1594)||3.5 (0.6)|
|320 mg||694.1 (291.9)||5199 (2193)||3.8 (0.5)|
|480 mg||1977.6 (676.3)||13698 (3987)||3.4 (0.4)|
|960 mg||3603.1 (2055.2)||26845 (13727)||6.0 (0.9)|
Abbreviations: AUC0-∞ = Area under curve (total drug exposure over time), Cmax = maximal concentration, t1/2 = half-life.
Mean changes of sputum and plasma levels of POL6014 over a period of 24 h following inhalation of single ascending doses ranging from 80 mg to 320 mg by CF patients are shown in Fig. 2.
No comparison with PK results obtained by intravenous administration of POL6014 were available to make a proper bioavalability assessment for the inhalation administration. However, overall it appears that the transit of POL6014 through the lung epithelium is slow. It can be approximated that only small amounts (<5–10%) of the administered dose become systemically available.
3.3.2 Degradation and elimination of POL6014
In the systemic compartment, POL6014 is proteolytically degraded with three major POL6014 metabolites M9, M18 and M20 observed in plasma and urine of HVs and subjects with CF. Metabolites were not detected in sputum. None of these metabolites inhibits human NE in vitro. Mean Cmax (± SD) values of these metabolites after inhalation of a single dose of POL6014 in HVs and in subjects with CF are shown in Appendix 4, Online Supplementary Material.
220.127.116.11 In plasma
At all doses of POL6014, Cmax for the metabolites M9 and M18 was reached around 4 h after dosing. Cmax values showed dose linearity. M20 was barely detectable. POL6014 metabolites were eliminated at a slightly slower rate compared to the test drug POL6014 - ranging from 3.9 to 9.7 h (960 mg dose). On a molar basis, throughout all tested doses, Cmax of M9 was on average 2.2% of the Cmax of POL6014. For M18 the Cmax ratio with POL6014 was 12.0%, thus at very low levels as compared to the precursor molecule.
18.104.22.168 In urine
Across all dose groups in HVs and subjects with CF, M9 and M18 already appeared in the first urine fraction (0–4 h sampling interval) in the majority of dose groups. M20 was not detected in urine. The amount of metabolites excreted in urine remained constant in the urine fractions 0–4 h and 4–8 h and in terms of relation of amounts excreted, consistent to the relations seen in plasma, i.e. high amounts of POL6014, small amounts of M18, and lesser amounts of M9.
Thus, although proteolytic degradation takes place, the majority of POL6014 related material excreted is the precursor molecule itself.
Absolute individual and mean values of active NE levels in sputum pre- and post-inhalation of 80, 160 and 320 mg of POL6014 or placebo are depicted in Fig. 3.
The mean (SD) predose active NE levels were 0.638 (0.078) μM, 0.324 (0.210) μM and 0.356 (0.356) μM respectively for the dose groups 80, 160 and 320 mg. Shortly after inhalation of POL6014, reduction of active NE in sputum was observed at all doses tested in subjects with CF. Mean (SD) log10 reduction of active NE concentrations from predose to 3 h after inhalation was 1.42 (0.94) for the dose group 80 mg, 1.65 (0.26) for the dose group 160 mg and 1.30 (0.77) for the dose group 320 mg. There was no clear dose-effect relationship as illustrated in Fig. 3A, B and C. At 24 h there was still inhibition of active NE in some individuals, although to a lesser extent than at 3 h. The concentration of active NE in patients inhaling placebo remained approximately at predose levels with a mean (SD) log10 reduction from predose to 3 h after inhalation of 0.06 (0.28).
In the SAD studies, inhaled POL6014 was well tolerated in both HVs (doses ranging between 20 and 480 mg) and in clinically stable subjects with CF (doses from 80 to 320 mg). In HVs at the POL6014 dose of 960 mg, 9 out of 11 TEAEs were related to the respiratory system, such as ‘cough’, ‘respiratory tract irritation’ or a transient decrease in FEV1. The inhalation time in this dose group was approximatively 1 h and the onset time of all these respiratory AEs was 30 min and more after start of inhalation. TEAEs were drug related and were considered not acceptable. The dose of 480 mg was therefore estimated as the maximum tolerated dose because the 4 observed TEAEs in this dose group were not considered drug related. Based on these observations and the volume of the dose packaging, a dose range between 80 and 320 mg was tested in subjects with CF. Except headache no TEAEs were reported by the patients on placebo or POL6014. Doses from 80 to 320 mg were administered in an acceptable time frame for the patient, i.e. below 15 min. After single administration of POL6014 FEV1 values remained fairly stable over 24 h. Nevertheless a transient decline in FEV1 was observed in two HVs and most subjects with CF just after inhalation. This was considered non clinically meaningful and has often been observed with other inhaled protease inhibitors [
] and approved treatments in CF [
- Gaggar A.
- Chen J.
- Chmiel J.F.
- Dorkin H.L.
- Flume P.A.
- Griffin R.
- et al.
Inhaled alpha1-proteinase inhibitor therapy in patients with cystic fibrosis.
J Cyst Fibros. 2016; https://doi.org/10.1016/j.jcf.2015.07.009
]. The transient FEV1 decrease is most likely due to hyperresponsiveness of the airways [
- Eyns H.
Bronchial hyperreactivity related to inhalation therapy in cystic fibrosis patients.
J Pulm Respir Med. 2014; 04: 1-10https://doi.org/10.4172/2161-105X.1000211
]. Although not even mentioned by the subjects themselves FEV1 changes will be monitored carefully in forthcoming studies.
- Tobin M.
- Maguire O.
- Reen D.
- Tempany E.
- Fitzgerald M.
Atopy and bronchial reactivity in older patients with cystic fibrosis.
Thorax. 1980; 35: 807-813https://doi.org/10.1136/thx.35.11.807
Systemic exposures (Cmax and AUC0-∞) of POL6014 showed a linear correlation with the administered dose over the tested range. Cmax is reached at approximately 2–3 h post inhalation and t1/2 is between 3 and 4 h. In subjects with CF, POL6014 levels in sputum appeared to be up to 1000-fold higher compared to plasma levels at 3 and 24 h post dosing; this indicates a concentration gradient where, with this route of administration, systemic exposure to POL6014 is small, compared with the much higher exposure in the lung.
Several NE inhibitors have failed to show significant clinical disease control or modification in chronic neutrophilic inflammation of the lungs. One such example, AZD9668, was administered orally in doses of 60 mg twice daily. Plasma and sputum data published for AZD9668 [
- Stevens T.
- Ekholm K.
- Granse M.
- Lindahl M.
- Kozma V.
- Jungar C.
- et al.
AZD9668: pharmacological characterization of a novel oral inhibitor of neutrophil elastase.
J Pharmacol Exp Ther. 2011; 339: 313-320https://doi.org/10.1124/jpet.111.182139
- Stockley R.
- De Soyza A.
- Gunawardena K.
- Perrett J.
- Forsman-Semb K.
- Entwistle N.
- et al.
Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis.
Respir Med. 2013; 107: 524-533https://doi.org/10.1016/j.rmed.2012.12.009
- Gunawardena K.A.
- Gullstrand H.
- Perrett J.
Pharmacokinetics and safety of AZD9668, an oral neutrophil elastase inhibitor, in healthy volunteers and patients with COPD.
Int J Clin Pharmacol Ther. 2013; 51: 288-304https://doi.org/10.5414/CP201674
14], showed maximal plasma levels in the range of 1–2 μM at around 3–4 h after administration, whereas the highest concentration achieved in sputum was not higher than 0.2 to 1 μM. Whereas these doses may have been chosen due to safety limitations, the achieved concentrations might have been too low to effectively and constantly inhibit NE in the target tissues. In contrast to an orally delivered compound, high sputum concentrations of POL6014 can be reached with inhaled POL6014, in the presence of rather low plasma concentrations.
- Elborn J.S.
- Perrett J.
- Forsman-Semb K.
- Marks-Konczalik J.
- Gunawardena K.
- Entwistle N.
Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis.
Eur Respir J. 2012; 40: 969-976https://doi.org/10.1183/09031936.00194611
In our CF study, a clear inhibition of active NE in sputum, already established at 80 mg, was shown with all three doses of POL6014 at 3 h after single administration. The concentration-effect relationship of POL6014 needs further exploration with an increased number of CF subjects. In addition, the levels of active NE in sputum before dosing were in the lower range compared to literature data as these subjects with CF were clinically stable and not suffering from acute exacerbations [
]. Thus, future studies need to evaluate whether higher sputum NE levels (e.g., above 20 μM) can be sufficiently inhibited by the POL6014 doses applied here, and that clinically relevant effects are associated with reduction of active NE in subjects with CF. Unfortunately NE activity has not been measured between 3 and 24 h. Repeated dosing as planned in forthcoming studies should lead to steady state drug concentrations in sputum, sustained reduction of active NE and hopefully also to improved lung function as reported [
- Sagel S.
- Wagner B.
- Anthony M.
- Emmett P.
- Zemanick E.
Sputum biomarkers of inflammation and lung function decline in children with cystic fibrosis.
Am J Respir Crit Care Med. 2012; 186: 857-865https://doi.org/10.1164/rccm.201203-0507OC
]. Since NE can already be detected in infant airways, anti-proteases as POL6014 may prevent lung damage in early life.
- Mayer-Hamblett N.
- Aitken M.
- Accurso F.
- Kronmal R.
- Konstan M.
- Burns J.
- et al.
Association between pulmonary function and sputum biomarkers in cystic fibrosis.
Am J Respir Crit Care Med. 2007; 175: 822-828https://doi.org/10.1164/rccm.200609-1354OC
In conclusion, POL6014 is a new, selective and potent NE inhibitor administered via inhalation, which represents a strong advantage over the oral route by delivering the largest portion of the compound directly to the lung with a low systemic burden. The good safety profile and tolerability coupled with clear inhibition of active NE in sputum at 3 h after dosing warrant further clinical studies with POL6014 to establish proof of concept in CF and other chronic neutrophilic lung conditions.
Declaration of Competing Interest
These studies were performed by Polyphor; since their completion, Polyphor has transferred the development rights for POL6014 to Santhera Pharmaceuticals. AWA and JZI are employees of Polyphor Ltd. PBR was a consultant of Polyphor Ltd. till March 2018. LHO, PBA, ECH and OSE were employees of Polyphor during the conduct of the study. OSE is now an employee of Santhera Pharmaceuticals. All other co-authors were employees of Inamed GmbH during the conduct of the study.
The authors are grateful to the Cystic Fibrosis Foundation Therapeutics, Inc., for their financial support and advice in the development of POL6014.
Appendix A. Supplementary data
- Macrophages and the pathogenesis of COPD.Chest. 2002; 121: 156S-159Shttps://doi.org/10.1378/chest.121.5_suppl.156S
- The role of neutrophil elastase inhibitors in lung diseases.Chest. 2017; 152: 249-262https://doi.org/10.1016/j.chest.2017.03.056
- The potential of neutrophil elastase inhibitors as anti-inflammatory therapies.Curr Opin Hematol. 2014; 21: 23-28https://doi.org/10.1097/MOH.0000000000000001
- Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: into clinical testing with pre-adaptive pharmacophores.Bioorg. Med. Chem. Lett. 2015; : 4370-4381https://doi.org/10.1016/j.bmcl.2015.08.049
- Neutrophil elastase inhibitors: a patent review and potential applications for inflammatory lung diseases (2010–2014).Expert Opin Ther Pat. 2015; 25: 1145-1158https://doi.org/10.1517/13543776.2015.1061998
- A novel neutrophil elastase inhibitor, POL6014, for therapeutic potential in cystic fibrosis and airways disease characterised by neutrophil-dominated inflammation.in: 30th annu. North Am. cyst. fibros. conf. 2016: S95https://doi.org/10.1002/ppul.23576
- Measurement of neutrophil elastase, proteinase 3, and cathepsin G activities using intramolecularly quenched fluorogenic substrates.Methods Mol Biol. 2012; 844: 125-138https://doi.org/10.1007/978-1-61779-527-5_9
- Inhaled alpha1-proteinase inhibitor therapy in patients with cystic fibrosis.J Cyst Fibros. 2016; https://doi.org/10.1016/j.jcf.2015.07.009
- Bronchial hyperreactivity related to inhalation therapy in cystic fibrosis patients.J Pulm Respir Med. 2014; 04: 1-10https://doi.org/10.4172/2161-105X.1000211
- Atopy and bronchial reactivity in older patients with cystic fibrosis.Thorax. 1980; 35: 807-813https://doi.org/10.1136/thx.35.11.807
- AZD9668: pharmacological characterization of a novel oral inhibitor of neutrophil elastase.J Pharmacol Exp Ther. 2011; 339: 313-320https://doi.org/10.1124/jpet.111.182139
- Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis.Respir Med. 2013; 107: 524-533https://doi.org/10.1016/j.rmed.2012.12.009
- Pharmacokinetics and safety of AZD9668, an oral neutrophil elastase inhibitor, in healthy volunteers and patients with COPD.Int J Clin Pharmacol Ther. 2013; 51: 288-304https://doi.org/10.5414/CP201674
- Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis.Eur Respir J. 2012; 40: 969-976https://doi.org/10.1183/09031936.00194611
- Sputum biomarkers of inflammation and lung function decline in children with cystic fibrosis.Am J Respir Crit Care Med. 2012; 186: 857-865https://doi.org/10.1164/rccm.201203-0507OC
- Association between pulmonary function and sputum biomarkers in cystic fibrosis.Am J Respir Crit Care Med. 2007; 175: 822-828https://doi.org/10.1164/rccm.200609-1354OC
Published online: September 06, 2019
Accepted: August 20, 2019
Received in revised form: August 20, 2019
Received: March 29, 2019
© 2019 Santhera Pharmaceuticals. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.
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