Abstract
The retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) is a master regulator of Th17 cell differentiation and production of IL17A, IL17F and IL22. Recent evidences in animal models and COPD patients suggest a strong role of RORγt-IL17 axis in COPD inflammation and exacerbation. An inhaled RORγt inverse agonist is expected to provide efficacy without potential systemic side effects.
We synthesized various novel, potent, selective RORγt inverse agonists for inhaled delivery. The lead compound, GRC39815, was evaluated in various in vitro and in vivo COPD models followed by toxicological assessment in preclinical species.
GRC39815 is a highly selective and potent inverse agonist of RORγt with physicochemical properties suitable for inhalation. In RORγt binding and functional assays, GRC39815 displayed a potent IC50 of 3-7 nM and is >390 fold selective over Th1 and Th2 cytokines. It demonstrated excellent selectivity over a panel of receptors, ion channels, transporters and enzymes. In animal models of sub-acute and chronic cigarette smoke induced COPD, intranasal delivery of GRC39815 demonstrated a dose dependent inhibition of lung inflammation, emphysema and IL17 immunoreactivity with very low systemic concentrations. In COPD patient BAL cells stimulated with anti CD3/28, GRC 39815 showed potent IL17 inhibition. GRC 39815 had no meaningful effect on hERG, action potential duration in canine Purkinje fibers and was non-genotoxic.
Conclusion: GRC39815 is a novel, selective and safe inhaled RORγt inverse agonist for potential antiinflammatory treatment of COPD and currently in Phase-1 clinical trial to evaluate safety, tolerability and pharmacokinetics in healthy adults.
Footnotes
Cite this article as: European Respiratory Journal 2021; 58: Suppl. 65, PA2128.
This abstract was presented at the 2021 ERS International Congress, in session “Prediction of exacerbations in patients with COPD”.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2021