**4.1 RORγ antagonists**

RORγt is a master transcription factor of TH17 cells, which activates the transcription of IL-23 receptor gene as well as pro-inflammatory cytokines such as IL-17A, IL-17F, IL-21, and IL-22, and enhances the inflammatory process. Clinical success of biologics in the IL23/IL17 axis suggests that inhibiting RORγ could be an effective alternative therapy for psoriasis.

Vitae Pharmaceuticals (acquired by Allergan, later by Abbvie) developed an orally active RORγt antagonist VTP-43742 for the treatment of autoimmune diseases, including psoriasis through suppression of IL-17A production and down-regulation of the IL-23 receptor [73]. VTP-43742 with high systemic exposure demonstrated a clear signal of efficacy over a short four-week period from a Phase 2a clinical trial


*DNMT = DNA methyltransferase; PDE4 = phosphodiesterase-4; AhR = aryl hydrocarbon receptor.*

#### **Table 2.**

*New targeted therapeutics under clinical trials for topical treatment of plaque psoriasis.*

in psoriatic patients [74]. It provides a proof of concept of RORγ antagonists for the treatment of psoriasis, consistent with the clinical success of biologics in the IL23/ IL17 axis.

#### *Developing Novel Molecular Targeted Therapeutics for Topical Treatment of Psoriasis DOI: http://dx.doi.org/10.5772/intechopen.102725*

Nevertheless, two drug candidates terminated their clinical trials due to potential safety liability. Four patients in the 700 mg VTP-43742 dose group showed reversible transaminase elevations, which led the company to terminate the development of VTP-43742. In addition, Takeda Pharmaceutical Company terminated a phase 1 trial of oral RORγ antagonist TAK828 for evaluation of the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating multiple doses in healthy volunteers in the United states (NCT02817516). The decision was based on critical non-monitorable toxicology findings in both monkeys and rats, combined with the potential for teratogenicity in humans [75].

RORγ has two isoforms, RORγ1 and RORγ2 (most commonly referred to as RORγt) [76]. RORγt is a differentially spliced isoform of RORγ1, 19 amino acids shorter at N-terminus. The biochemical assay for evaluation of the compounds using LBD of the receptor will result in pan-RORγ antagonists. RORγt is exclusively expressed in a few distinct cell types of the immune system, including Th17, Tc17, γδ T cells and regulatory T cells [43, 77–80] whereas, RORγ1 exhibits oscillatory expression in liver, brown adipose tissue, and kidney [76, 81]. Systemic exposure of the Pan-RORγ antagonists may have off-target effects against the not-intended target, RORγ1, during the treatment of the diseases. In addition, a mouse genetics study indicated that 50% of embryonic RORγ deficient mice developed T-cell lymphoma [82]. Lymphoma was also observed in adult RORγ knockout mice with immune systems intact [83]. The phenotypes of RORγ knockout mice cause concerns of the consequences of systemic treatment of RORγ antagonists in the patients with psoriasis.

Developing RORγ antagonists with the skin-restricted exposure may alleviate the safety risk of systemic exposure while still maintaining similar efficacy as biologics in the IL-23/IL17 pathway, and may provide a new option as topical targeted therapeutics for psoriasis patients. Phase 1 trial of topical RORγ antagonist GSK2981278 for the treatment of psoriasis was not advanced further (**Table 2**) [84]. 0.03%, 0.1%, 0.8% and 4% GSK2981278 ointments were used in the tria, respectively. Across all doses, infiltrate thickness was not altered. Biomarker results did not support that the target was engaged. Although GSK2981278 was shown *in vitro* as a highly potent and selective antagonist of RORγ, the limited *in vivo* efficacy in reduction of epithermal thickness (23% reduction vs. placebo with imiquimod (IMQ ) control at 1% GSK2981278 ointment) was observed in IMQ-induced mouse psoriasis-like inflammation model [85]. The skin exposure of GSK2981278 was not disclosed while its systemic exposure in mouse serum was relatively low [85]. It is speculated that insufficient drug exposure at the target site might be one of the reasons for its lacking efficacy in phase 1 trial [84].

More effort was then focused on developing RORγ antagonists in restricted exposure and prolonged action at the skin while being rapidly eliminated from the systemic circulation for topical therapy in psoriasis. ESR114 topical gel is a selective, potent inhibitor of RORγ designed to have its pharmacological activity targeted to the skin with minimal systemic absorption [86]. In 2019, Escalier Biosciences completed a phase I/II trial evaluating ESR-114 topical gel in patients with mild-to-moderate psoriasis in USA and Canada (NCT03630939, **Table 2**). Nevertheless, no trial results were disclosed yet. In addition, it was reported that a novel series of benzimidazole with RORγ antagonistic activity, SHR168442, was developed with desirable skinrestricted PK properties for a topical drug [87]. SHR168442 suppressed the IL-17 gene transcription, and reduced IL-17 cytokine secretion, and, more importantly, achieved skin-restricted exposure suitable for topical delivery. In the IMQ-induced and IL-23 induced psoriasis-like skin inflammation mouse models, SHR168442 ointment

exhibited excellent efficacy, which correlated with the reduction of Th17 pathway cytokines, IL-17A, IL-6 and TNFα. This novel RORγ antagonist may represent a new option as topical targeted therapeutics for mild to moderate psoriasis patients. Results from further clinical evaluation of this specific mechanism for the treatment of mild to moderate psoriasis are highly anticipated.
