Pharmacokinetics and safety of AZD9668, an oral neutrophil elastase inhibitor, in healthy volunteers and patients with COPD

Gunawardena, K A; Gullstrand, Helena; Perrett, John

doi:10.5414/cp201674

Cited by 20 publications

(20 citation statements)

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“…Instead, AZD7986's mechanism of action can be considered beneficial, since NSP activity, both systemically and in tissues, is expected to stay low even if multiple doses of AZD7986 are missed. This is a clear advantage compared to direct NSP inhibitors, which are required in high local concentrations to continuously block NSP activity, 24,25 and may help overcome compliance challenges during chronic treatment.…”

Section: Discussionmentioning

confidence: 99%

Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Palmer

Mäenpää

Jauhiainen

et al. 2018

Clin Pharma and Therapeutics

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Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. High NSP levels can be detrimental, particularly in lung tissue, and inhibition of NSPs is therefore an interesting therapeutic opportunity in multiple lung diseases, including chronic obstructive pulmonary disease (COPD) and bronchiectasis. We conducted a randomized, placebo‐controlled, first‐in‐human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of the DPP1 inhibitor AZD7986 in healthy subjects. Pharmacokinetic and pharmacodynamic data were analyzed using nonlinear mixed effects modeling and showed that AZD7986 inhibits whole blood NE activity in an exposure‐dependent, indirect manner—consistent with in vitro and preclinical predictions. Several dose‐dependent, possibly DPP1‐related, nonserious skin findings were observed, but these were not considered to prevent further clinical development. Overall, the study results provided confidence to progress AZD7986 to phase II and supported selection of a clinically relevant dose.

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Section: Discussionmentioning

confidence: 99%

Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Palmer

Mäenpää

Jauhiainen

et al. 2018

Clin Pharma and Therapeutics

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“…or matching placebo. The dose selected was close to the maximum used in prior healthy volunteer studies with AZD9668 [14]. Standard CF therapies were continued; oral corticosteroids and nonprophylactic antibiotics were not allowed during the study and for 8 and 4 weeks, respectively, prior to randomisation.…”

Section: Treatmentsmentioning

confidence: 99%

Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis

et al. 2012

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The aim of this study was to evaluate the safety and effect on clinical outcomes and biomarkers of inflammation and tissue damage of the neutrophil elastase inhibitor AZD9668 (60 mg twice daily orally for 4 weeks) in cystic fibrosis.This was a randomised, double-blind, placebo-controlled study. Primary outcome measures were sputum neutrophil count, lung function, 24-h sputum weight, BronkoTest1 diary card data and health-related quality-of-life (revised cystic fibrosis quality-of-life questionnaire). Secondary end-points included sputum neutrophil elastase activity, inflammatory biomarkers in sputum and blood, urine and plasma desmosine (an elastin degradation marker), AZD9668 levels and safety parameters (adverse events, routine haematology, biochemistry, electrocardiogram and sputum bacteriology).56 patients were randomised, of which 27 received AZD9668. There was no effect for AZD9668 on sputum neutrophil counts, neutrophil elastase activity, lung function or clinical outcomes, including quality of life. In the AZD9668 group, there was a trend towards reduction in sputum inflammatory biomarkers with statistically significant changes in interleukin-6, RANTES and urinary desmosine. The pattern of adverse events was similar between groups.Consistent reductions in sputum inflammatory biomarkers were seen in the AZD9668 group, and reduction in urinary desmosine suggests that AZD9668 impacts elastin cleavage by neutrophil elastase.

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“…The IC 50 value of 12 nM is identical to that recently reported for AZD-9668 in the first disclosure of the activity of AZD-9668 at the September 2010 European Respiratory Society meeting [17]. Details of pharmacokinetic and initial efficacy studies were also presented at the same meeting [18,19].…”

Section: Expert Opinionmentioning

confidence: 69%

Crystalline form of a neutrophil elastase inhibitor, 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide p-toluene sulfonate – is it AZD-9668?: WO-2010094964

Norman¹

2011

Expert Opinion on Therapeutic Patents

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This patent application claims a novel crystalline form (Form A) of a tosylate salt of a previously disclosed neutrophil elastase inhibitor. It also claims oral compositions of the salt and a process for the preparation of the crystalline form. The novel form is indicated to show improved physical properties relative to the free base. The claimed compound is evidently one of the elastase inhibitors currently being developed by AstraZeneca.

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Pharmacokinetics and safety of AZD9668, an oral neutrophil elastase inhibitor, in healthy volunteers and patients with COPD

Abstract: The PK profile of AZD9668 was established in Caucasian and Japanese healthy volunteers and in patients with COPD. It was well tolerated at doses expected to produce a pharmacodynamic effect.

Cited by 20 publications

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Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis

Crystalline form of a neutrophil elastase inhibitor, 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide p-toluene sulfonate – is it AZD-9668?: WO-2010094964

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