The results of a preliminary study published in The Journal of the European Academy of Dermatology & Venereology supported further clinical development of orismilast as a novel therapeutic intervention for chronic inflammatory skin diseases (CISDs).
Orismilast, a potent, selective inhibitor of phosphodiesterase 4 (PDEA4) which is highly expressed in keratinocytes and has been identified as a predominant driver of inflammation, is overexpressed in CISDs.
In this study, the effects of orismilast were evaluated using in vitro, ex vivo, and in vivo experiments in human whole blood and peripheral blood mononuclear cell (PBMC) tissues and a murine model.
The selectivity and potency of orismilast was tested against phosphodiesterase (PDE) 1-11. Orismilast demonstrated near full inhibition of PDE4 and less inhibition of other PDE subfamily members. In addition, orismilast was a potent inhibitor of all PDE4B (half-maximal inhibitory concentration [IC50] range, 3-10 nM) and PDE4D (IC50 range, 3-9 nM) splice variants but had reduced potency for PDE4C2 (IC50, 104 nM) and PDE4A10 (IC50, 52 nM).
In whole blood and PBMC tissues, orismilast better inhibited lipopolysaccharide-induced (IC50, 10 vs 52 nM) and aCD3/aCD28-induced (IC50, 30 vs 432 nM) tumor necrosis factor (TNF)-α release compared with apremilast, respectively. In T-helper cell sublineages, orismilast best inhibited release of TNF-α (Emax, 95%), followed by interferon (IFN)-ϒ (Emax, 91%), and interleukin (IL)-23 (Emax, 80%).
In a chronic oxazolone mouse model, both a 10 and 30 mg/kg dose of oral orismilast significantly reduced ear thickness over time (both P <.0001) without affecting bodyweight. Both doses were associated with a greater reduction in IL-β, IL-4, IL-5, TNF-α, mouse keratinocyte-derived chemokine, and IFN-g levels compared with 2 mg/kg dexamethasone.
Compared with 2 mg/kg dexamethasone, 30 mg/kg oxazolone is associated with a similar reduction in ear thickness (area under the curve [AUC], 3.4 vs 2.7 day x mm), respectively.
Mean serum concentrations of oxazolone were 1009 ng/mL for 30 mg/kg and 423 ng/mL for 10 mg/kg oxazolone doses.
The findings suggest to investigators that orismilast, a selective oral PDE4 inhibitor, may have efficacy in the setting of CISDs. “The results of the study support clinical development of oral orismilast as a novel treatment option for CISD including psoriasis, atopic dermatitis, and hidradenitis suppurativa,” they elaborated.
Disclosure: Several authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.
Silverberg JI, French LE, Warren RB, et al. Pharmacology of orismilast, a potent and selective PDE4 inhibitor. J Eur Acad Dermatol Venereol. Published online December 17, 2022. doi:10.1111/jdv.18818