Julia Larsson1, Magnus Nilsson2, Annemarie Hasselberg3, Eylem Gürcan3, Rod Hughes4, Ulf Hedström3, Camille Riff1
1Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden 2Medicinal Chemistry, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden 3Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden 4Early Respiratory & Immunology Clinical Development, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
Background: AZD4604 is a small molecule selective JAK1 inhibitor, in development for the treatment of asthma [1,2]. Janus kinase inhibitors (JAKis) are highly effective therapies for various inflammatory diseases. First-generation JAKis block multiple JAKs (i.e., JAK1, JAK2, JAK3, and TYK2), resulting in adverse effects, likely due to their lack of selectivity. Non-selective JAK inhibitors block a wide variety of cytokines mediated by JAK-~STAT pathways, and have been associated with systemic adverse effects such as thrombosis, atherosclerosis and infection. Inhaled administration can achieve high lung exposure and a therapeutic effect through local JAK1 inhibition coupled with insignificant systemic exposure minimizing potential risks of systemic effects.
Objectives: To compare plasma exposure of AZD4604 and marketed JAK inhibitors with their respective half-maximal inhibitory concentrations (IC50s) in four JAK-dependent pathways to predict systemic activity of AZD4604 and marketed JAK inhibitors on JAK signaling pathways at therapeutic doses.
Methods: A non-linear mixed effect model has been developed using plasma PK concentrations collected after multiple dose administrations of AZD4604 in a 3-part phase 1 study (NCT04769869). Healthy participants and patients received twice daily administration of AZD4604 from 0.4 to 3 mg for 7 and 10 days, respectively.
The developed AZD4604 model was used to simulate steady state PK profiles at the predicted therapeutic dose. PK models for abrocitinib [3], upadacitinib [4] (JAK1 selective inhibitors) and deucravacitinib [5] (an allosteric and selective TYK2 inhibitor) were used to simulate steady state exposures at their respective therapeutic dose. IC50s of AZD4604, abrocitinib, upadacitinib and deucravacitinib in vitro in four JAK-dependent pathways (IFN-α, GM-CSF, IL-12, EPO) in human whole blood were determined and plotted against simulated pharmacokinetic profiles.
Model development was performed with NONMEM 7.4.4 using PsN 4.9.0 and the PK profiles were simulated in R 4.4.1.
Results: For the population PK analysis of AZD4604, approximately 700 observations from 18 healthy participants and 450 observations from 13 patients were included. A 2-compartment linear model captured the PK plasma profile of AZD4604 after multiple inhalations well. After inhalation, absorption occurred very quickly (Cmax occurred at the first post-dose observation of 5 min) and was modeled as an IV bolus input. Inter-individual variability (IIV) was assigned to the clearance parameters and the central volume using a log-normal distribution, and the residual error was captured using an additive error on log scale. The population typical values (IIV as ω) of CL/F, Vc/F, Q/F, and Vp/F were estimated to 21.4 L/hr (0.24), 106.1 L (0.54), 1230 L/hr (0.29), and 1000 (-) L, respectively. Residual error (σ) was 0.15. No covariate was included in the model.
At therapeutic doses, abrocitinib, upadacitinib, and deucravacitinib systemic exposure was, as expected, above their respective IFN-α (JAK1/TYK2) potency. Abrocitinib and upadacitinib systemic exposure was within 10-fold of their GM-CSF (JAK2/JAK2), EPO (JAK2/JAK2) and IL-12 (JAK2/TYK2) IC50s, while deucravacitinib systemic exposure was close to 1-fold of its IL-12 (JAK2/TYK2) IC50. In contrast, AZD4604 systemic exposure remained below the IC50s for all four pathways, having an approximate 9-, 290-, 590- and 1200-fold margin between Cmax at anticipated maximal therapeutic exposure and the IFN-α (JAK1/TYK2), GM-CSF (JAK2/JAK2), EPO (JAK2/JAK2) and IL-12 (JAK2/TYK2) IC50s, respectively.
Conclusions: A PK modeling approach was used to simulate plasma PK profiles at therapeutic doses and compare selectivity profiles of AZD4604 with marketed JAK inhibitors. Currently marketed oral JAKis showed broad systemic activity on JAK pathways at therapeutic dose. In contrast, at anticipated therapeutic exposure, inhaled AZD4604 leads to minimal systemic target engagement across the investigated JAK signaling pathways, reducing the risk of potential systemic side effects experienced with oral JAKis. The efficacy and risks of this approach will be further evaluated in clinical trials.
References:
[1] Nilsson, M.; Rhedin, M.; Hendrickx, R.; Berglund, S.; Piras, A.; Blomgran, P.; Cavallin, A.; Collins, M.; Dahl, G.; Dekkak, B.; Ericsson, T.; Hagberg, N.; Holmberg, A. A.; Leffler, A.; Lundqvist, A. J.; Markou, T.; Pinkerton, J.; Rönnblom, L.; Siu, S.; Taylor, V.; Wennberg, T.; Zervas, D.; Laurence, A. D. J.; Mitra, S.; Belvisi, M. G.; Birrell, M.; Borde, A. Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma. Drug Des. Develivery Ther. 2022, Volume 16, 2901−2917.. doi: 10.2147/DDDT.S354291
[2] Nilsson, M.; Berggren, K.; Berglund, S.; Cerboni, S.; Collins, M.; Dahl, G.; Elmqvist, D.; Grimster, N. P.; Hendrickx R.; Johansson, J. R.; Kettle, J. G.; Lepistö, M.; Rhedin, M.; Smailagic, A.; Su, Q.; Wennberg, T.; Wu, A.; Österlund, T.; Naessens, T.; Mitra, S. Discovery of the potent and selective inhaled Janus Kinase 1 inhibitor AZD4604 and its preclinical characterization. Journal of Medicinal Chemistry 2023 66 (19), 13400-13415 DOI:10.1021/acs.jmedchem.3c00554
[3] Multi-discipline Review and Evaluation, NDA 213871 Abrocitinib tablets, October 12, 2018
[4] Clinical Pharmacology and Biopharmaceutics Review(S), NDA 211675 Upadacitinib, 17 May 2019
[5] Multi-discipline Review and Evaluation, NDA 214958 Sotyktu (Deucravacitinib) tablets, 6 mg, September 9, 2022
Reference: PAGE 32 (2024) Abstr 11032 [www.page-meeting.org/?abstract=11032]
Poster: Clinical Applications