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

Abstract

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.

Figure 1

(a) An illustration of neutrophil maturation stages, time of NSP activation, and expected neutrophil maturation rates in healthy individuals.3, 22 (b) Outline of the final model used to describe AZD7986 PK and NE activity data. AZD7986 PK was modeled by a three‐compartment model (upper part) and whole blood NE activity by a transit compartment model (lower part). AZD7986 plasma concentrations were assumed to inhibit the amount of active NE entering the first transit bone marrow (bm) compartment.

Figure 2

Observed geometric mean AZD7986 plasma concentrations after single/first dose (a) and after once‐daily dosing for 21 or 28 days (b). Data shown in (a) come from both Parts I and II, while data shown in (b) come from Part II only. In Part I, plasma concentrations were measured for up to 96 hours following a single dose of AZD7986. In Part II, plasma concentrations were measured for up to 24 hours following the first dose and 96 hours following the last dose of AZD7986. (c,d) Visual predictive checks (VPCs) of the final PK model. VPCs were prediction‐corrected and stratified on day (c = first dose, d = Day 21/28). Black dots show the individual observations. Blue lines show the 5^th and 95^th percentiles of the observed data, and red lines show the median of the observed data. The blue and red shaded areas show the 95% CIs of the model‐predicted 5^th, median, and 95^th percentiles based on simulated data from 1,000 simulations.

Figure 3

Observed percent change from baseline in whole blood NE activity after 21 or 28 days of repeated dosing with 10, 25, or 40 mg AZD7986 (a–c) or placebo (d). Each line represents data from one subject. For each subject, baseline NE activity was defined as the median of all observations up to Day 7 after initiation of dosing. Follow‐up NE activity data were not collected in the 10 mg cohort. Placebo data (d) have been pooled from all three cohorts.

Figure 4

Visual predictive checks (VPCs) of the final NE activity model. VPCs were stratified on dose group (a = 10 mg, b = 25 mg, c = 40 mg, d = pooled placebo). Black dots show the individual observations of ANC‐normalized NE activity (see Supplementary Methods). Blue lines show the 5^th and 95^th percentiles of the observed data, and red lines show the median of the observed data. The blue and red shaded areas show the 95% CIs of the model‐predicted 5^th, median, and 95^th percentiles based on simulated data from 1,000 simulations.

Figure 5

Estimated mean and 95% CIs for the steady‐state dose (a) and exposure (b) response of whole blood NE activity after once‐daily dosing with AZD7986. The mean level of inhibition and confidence intervals were derived using population typical PK and PD parameters and their estimated variance‐covariance. Percentages shown in (a) indicate the estimated mean inhibition for the three once‐daily doses (10, 25, and 40 mg) of AZD7986 studied in Part II. (c,d) Simulations with the final model highlighting the response of the system at different doses (c) and after a period of 0‐14 days of missed doses (d). Red numbers in (d) indicate number of missed doses.

Figure 6

Skin findings after once‐daily repeated dosing with AZD7986. (a) Exfoliation in the right hand of Subject 2 after receiving 25 mg of AZD7986 for 23 days. (b) Scaling and erythema on the left sole and toe of Subject 3 after receiving 40 mg of AZD7986 for 23 days. (c) Spontaneous skin recovery and decreased scaling on the toe of Subject 3 after receiving 40 mg of AZD7986 for 26 days. Red arrows in (b,c) indicate area on the left toe to be compared between Day 23 and 26.