(W-035) Systems model to predict fractional exhaled nitric oxide response to inhaled JAK inhibitors in patients with mild to moderate asthma

Miaoran Ning, Ph.D. – Principal Scientist, Genentech, Inc.; Justin Feigelman, Ph.D. – N/A, Genentech, Inc.; Matthew Durk, Ph.D. – Senior Principal Scientist, Genentech, Inc.; Hart Rardin, Ph.D. – N/A, Genentech, Inc.; Fang Cai, M.D. – Medical Director, Genentech, Inc.; Rui Zhu, Ph.D. – Distinguished Scientist, Genentech, Inc.; Yixuan Zou, Ph.D. – Senior Data Scientist, Genentech, Inc.; Ryan Owen, Ph.D. – Senior Director, Genentech, Inc.; Matthew Wright, Ph.D. – Executive Director, Genentech, Inc.; Saroja Ramanujan, Ph.D. – Consultant, Genentech, Inc.; Kapil Gadkar, Ph.D. – Senior Director & Distinguished Scientist, Genentech, Inc.

Objectives: A physiologically based pharmacokinetic (PBPK) model of the lung was integrated with a quantitative systems pharmacology (QSP) model of asthma to predict fractional exhaled nitric oxide (FeNO) response to inhaled JAK inhibitors in patients with mild to moderate asthma.

Methods: A PBPK model for inhaled JAK inhibitors was developed describing regional particle deposition within the lung, followed by dissolution in the bronchial lining fluid, and drug permeation into the bronchial tissue, which is the site of action. The PBPK model was integrated with an asthma QSP model, which included FeNO response.[1] JAK inhibition was then implemented as a reduction in cell-specific cytokine signals mediated by JAK isoforms: IL-4/IL-13 for JAK1, and IL-5/TSLP for JAK2. Additionally, a reference virtual patient (VP) and virtual population (Vpop) were developed to represent mild to moderate asthma patients appropriate to inhaled JAK inhibitor clinical trials.

Results: The lung PBPK model captures the observed plasma pharmacokinetic profiles for inhaled JAK inhibitors.[2,3] Relevant clinical data for key cytokines and cells at baseline is well represented by the mild to moderate asthma reference VP within the QSP model. Additionally, the mild to moderate asthma Vpop captures clinical variability for FeNO and eosinophil levels, both at baseline and in response to lebrikizumab therapy.[4] Finally, utilizing the integrated PBPK/QSP model, the new Vpop appropriately describes clinical data for FeNO response to the inhaled JAK inhibitors GDC-0214 and GDC-4379.[3,5]

Conclusions: The PBPK/QSP model developed for inhaled JAK inhibitors captures relevant clinical data both at baseline and in response to therapy for patients with mild to moderate asthma. The model can thus be utilized to predict FeNO response to novel inhaled JAK inhibitors in this patient population. Applications of the model include informing candidate selection in a preclinical setting, as well as supporting dose selection for proof of concept clinical trials.

Citations: [1] Gadkar, K., et al. (2022). Integrated systems modeling of severe asthma: Exploration of IL‐33/ST2 antagonism. CPT: Pharmacomet Syst Pharmacol, 11(9), 1268–1277.

[2] Zhu, R., et al. (2022). Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC‐0214 in healthy volunteers. Clin Transl Sci, 15(5), 1225–1237.

[3] Chen, H., et al. (2022). Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation. Pulm Pharmacol Ther, 75, 102133.

[4] Noonan, M., et al. (2013). Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. J Allergy Clin Immunol, 132(3), 567-574.e12.

[5] Braithwaite, I. E., et al. (2021). Inhaled JAK inhibitor GDC-0214 reduces exhaled nitric oxide in patients with mild asthma: A randomized, controlled, proof-of-activity trial. J Allergy Clin Immunol, 148(3), 783–789.