Development of a Topical Treatment for Psoriasis Targeting RORγ: From Bench to Skin

Abstract

BackgroundPsoriasis is a chronic inflammatory skin disorder involving marked immunological changes. IL-17-targeting biologics have been successful in reducing the disease burden of psoriasis patients with moderate-to-severe disease. Unfortunately, the stratum corneum prevents penetration of large molecule weight proteins, including monoclonal antibodies. Thus, for the majority of psoriasis patients ineligible for systemic treatments, a small molecule targeting RORγt, the master regulator of IL-17 family cytokines, may represent an alternative topical medicine with biologic-like efficacy.Methods and FindingsThe preclinical studies described in this manuscript bridge the gap from bench to bedside to provide the scientific foundation for a compound entering clinical trials for patients with mild to moderate psoriasis. In addition to several ex vivo reporter assays, primary T cell cultures, and the imiquimod mouse model, we demonstrate efficacy in a newly developed human ex vivo skin assay, where Th17-skewed cytokine expression is induced from skin-resident immune cells. Importantly, the skin barrier remains intact allowing for the demonstration of topical drug delivery. With the development of this novel assay, we demonstrate potent compound activity in the target tissue: human skin. Finally, target engagement by this small molecule was confirmed in ex vivo lesional psoriatic skin.ConclusionsOur work describes a progressive series of assays to demonstrate the potential clinical value of a novel RORγ inverse agonist small molecule with high potency and selectivity, which will enter clinical trials in late 2015 for psoriasis patients.

Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

“…Evidence has accumulated demonstrating that RORs act as ligand-dependent transcription factors [74, 76–78]. Cholesterol and cholesterol sulfate and small molecules can interact with the LBD of RORs to modulate their transcriptional activities [79].…”

A phase I randomized controlled trial to evaluate safety and clinical effect of topically applied GSK2981278 ointment in a psoriasis plaque test

“…However, drug delivery to the target site is unconfirmed. Although preclinical biological effects were observed within the time frame studied, a longer treatment period and/or a more frequent application may be needed to induce detectable clinical/biological effects in patients.…”

“…GSK2981278 is a highly potent and selective inverse agonist of RORγ under development for the topical treatment of psoriasis. Preclinical data showed that GSK2981278 significantly inhibited production of the Th17 signature cytokines in multiple in vitro and human tissue‐based systems . GSK2981278 may block the transcriptional activity of RORγt, leading to local suppression of cytokine expression and ultimately, improvement in psoriasis.…”

Metadichol, A Novel ROR Gamma Inverse Agonist and Its Applications in Psoriasis

“…A small molecule like Metadichol as alternative topical medicine with biologic like efficacy targets RORγt, the master regulator of IL-17 family cytokines, thus leads to improved clinical outcomes desired in Psoriasis patients. Recent data suggest that topical treatment limits Th17-type cytokine expression with clinical candidates like GSK2981278 could lead to improved health outcomes for patients [35].…”