Sara Asimus1, Robert Palmér2, Muna Albayaty3, Henrik Forsman4, Christina Lundin4, Marita Olsson5, Rikard Pehrson6, John Mo7, Muir Russell8, Sara Carlert9, David Close10, David Keeling6. 1. Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gaithersburg, MD, USA. 2. Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gothenburg, Sweden. 3. Early Phase Clinical Unit, Parexel, London, UK. 4. Clinical Development, Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 5. Early Biostats and Statistical Innovation, Data Science and AI, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 6. Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 7. Patient Safety, Respiratory, Inflammation and Autoimmunity, Chief Medical Office, R&D, AstraZeneca, Gothenburg, Sweden. 8. Study Delivery, Early Oncology Clinical, Oncology R&D, AstraZeneca, Cambridge, UK. 9. Early Product Development, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden. 10. Clinical Development, Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Abstract
AIMS: Retinoic acid-related orphan receptor γ (RORγ), a master regulator of T-helper 17 (Th17) cell function and differentiation, is an attractive target for treatment of Th17-driven diseases. This first-in-human study aimed to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of the inverse RORγ agonist AZD0284. METHODS: We conducted a phase I, randomized, single-blind, placebo-controlled, two-part, first-in-human study with healthy subjects receiving single (4-238 mg) or multiple (12-100 mg) oral doses of AZD0284 or placebo after overnight fasting. Subjects in the one single dose cohort additionally received a single dose of AZD0284 after a high-calorie meal. AZD0284 plasma concentrations, as well as inhibition of ex vivo-stimulated interleukin (IL)-17A release in whole blood, were frequently measured after both single and multiple dosing. RESULTS: Eighty-three men participated in the study. AZD0284 was absorbed rapidly into plasma after oral dosing and exhibited a terminal half-life of 13-16 hours. Both the area under the concentration-time curve (AUC) and maximum concentration (Cmax ) increased subproportionally with increasing dose (95% confidence intervals of slope parameter were 0.71-0.84 and 0.72-0.88 for AUC and Cmax , respectively). Food intake delayed the absorption of AZD0284 but did not affect the overall exposure or half-life. AZD0284 showed dose-dependent reduction of ex vivo-stimulated IL-17A release after both single and multiple doses. No significant safety concerns were identified in the study. CONCLUSIONS: AZD0284 was well tolerated, rapidly and dose-dependently absorbed, and reduced stimulated IL-17A release after single and multiple dosing. The results of this study support further clinical development of AZD0284.
AIMS: Retinoic acid-related orphan receptor γ (RORγ), a master regulator of T-helper 17 (Th17) cell function and differentiation, is an attractive target for treatment of Th17-driven diseases. This first-in-human study aimed to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of the inverse RORγ agonist AZD0284. METHODS: We conducted a phase I, randomized, single-blind, placebo-controlled, two-part, first-in-human study with healthy subjects receiving single (4-238 mg) or multiple (12-100 mg) oral doses of AZD0284 or placebo after overnight fasting. Subjects in the one single dose cohort additionally received a single dose of AZD0284 after a high-calorie meal. AZD0284 plasma concentrations, as well as inhibition of ex vivo-stimulated interleukin (IL)-17A release in whole blood, were frequently measured after both single and multiple dosing. RESULTS: Eighty-three men participated in the study. AZD0284 was absorbed rapidly into plasma after oral dosing and exhibited a terminal half-life of 13-16 hours. Both the area under the concentration-time curve (AUC) and maximum concentration (Cmax ) increased subproportionally with increasing dose (95% confidence intervals of slope parameter were 0.71-0.84 and 0.72-0.88 for AUC and Cmax , respectively). Food intake delayed the absorption of AZD0284 but did not affect the overall exposure or half-life. AZD0284 showed dose-dependent reduction of ex vivo-stimulated IL-17A release after both single and multiple doses. No significant safety concerns were identified in the study. CONCLUSIONS: AZD0284 was well tolerated, rapidly and dose-dependently absorbed, and reduced stimulated IL-17A release after single and multiple dosing. The results of this study support further clinical development of AZD0284.
Authors: Frank Narjes; Yafeng Xue; Stefan von Berg; Jesper Malmberg; Antonio Llinas; Roine I Olsson; Johan Jirholt; Hanna Grindebacke; Agnes Leffler; Nafizal Hossain; Matti Lepistö; Linda Thunberg; Hanna Leek; Anna Aagaard; Jane McPheat; Eva L Hansson; Elisabeth Bäck; Stefan Tångefjord; Rongfeng Chen; Yao Xiong; Ge Hongbin; Thomas G Hansson Journal: J Med Chem Date: 2018-08-27 Impact factor: 7.446
Authors: Roine I Olsson; Yafeng Xue; Stefan von Berg; Anna Aagaard; Jane McPheat; Eva L Hansson; Jenny Bernström; Pia Hansson; Johan Jirholt; Hanna Grindebacke; Agnes Leffler; Rongfeng Chen; Yao Xiong; Hongbin Ge; Thomas G Hansson; Frank Narjes Journal: ChemMedChem Date: 2015-11-10 Impact factor: 3.466
Authors: Sara Asimus; Robert Palmér; Muna Albayaty; Henrik Forsman; Christina Lundin; Marita Olsson; Rikard Pehrson; John Mo; Muir Russell; Sara Carlert; David Close; David Keeling Journal: Br J Clin Pharmacol Date: 2020-03-03 Impact factor: 4.335
Authors: Stephen P H Alexander; Eamonn Kelly; Alistair Mathie; John A Peters; Emma L Veale; Jane F Armstrong; Elena Faccenda; Simon D Harding; Adam J Pawson; Joanna L Sharman; Christopher Southan; O Peter Buneman; John A Cidlowski; Arthur Christopoulos; Anthony P Davenport; Doriano Fabbro; Michael Spedding; Jörg Striessnig; Jamie A Davies Journal: Br J Pharmacol Date: 2019-12 Impact factor: 8.739
Authors: Sara Asimus; Robert Palmér; Muna Albayaty; Henrik Forsman; Christina Lundin; Marita Olsson; Rikard Pehrson; John Mo; Muir Russell; Sara Carlert; David Close; David Keeling Journal: Br J Clin Pharmacol Date: 2020-03-03 Impact factor: 4.335