incb039110 and tofacitinib

Several classes of new oral therapy are in use or in development for the treatment of psoriasis. Despite the high efficacy of biologics, new oral therapies remain important as patients generally prefer this mode of administration and they offer an alternative risk-benefit profile. In this review, we discuss the novel modes of action of these drugs, including modulation of cellular pathways involving diverse targets such as Janus kinase, phosphodiesterase 4, sphingosine 1-phosphate, A3 adenosine receptor and rho-associated kinase 2. We review the available evidence around licensed drugs (apremilast) and drugs that are advanced (tofacitinib) or early (ponesimod, baricitinib, peficitinib, INCB039110, CF101, KD025) in the development pipeline. The key limitations of these oral therapies are their modest efficacy profile (apremilast, ponesimod) and the limitations of their safety profile (tofacitinib, ponesimod), while the evidence for the early pipeline drugs are at phase II level only. Potential niches of current unmet needs include apremilast for patients with concomitant psoriatic arthritis, as combination treatments with biologic therapies, and/or for patients in whom multiple biologic therapies have failed due to immunogenicity and secondary inefficacy. The present knowledge gap regarding these novel drugs includes the need for longer clinical trials or observational studies to evaluate safety, and randomised phase III trials for the early pipeline drugs. We conclude that further research and data are necessary to conclusively establish the role of these agents in the current psoriasis treatment paradigm.

Topics: Adamantane; Adenosine; Adenosine A3 Receptor Antagonists; Administration, Oral; Arthritis, Psoriatic; Azetidines; Biological Factors; Biological Therapy; Clinical Trials as Topic; Humans; Isonicotinic Acids; Janus Kinases; Niacinamide; Phosphodiesterase 4 Inhibitors; Piperidines; Protein Kinase Inhibitors; Psoriasis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Receptors, Lysosphingolipid; rho-Associated Kinases; Sulfonamides; Thalidomide; Thiazoles

The Janus kinase/signal transducers and activators of transcription (JAK/STAT) are key intracellular mediators in the signal transduction of many cytokines and growth factors. Common γ chain cytokines and interferon-γ that use the JAK/STAT pathway to induce biological responses have been implicated in the pathogenesis of alopecia areata (AA), a T cell-mediated autoimmune disease of the hair follicle. We previously showed that therapeutic targeting of JAK/STAT pathways using the first-generation JAK1/2 inhibitor, ruxolitinib, and the pan-JAK inhibitor, tofacitinib, was highly effective in the treatment of human AA, as well as prevention and reversal of AA in the C3H/HeJ mouse model. To better define the role of individual JAKs in the pathogenesis of AA, in this study, we tested and compared the efficacy of several next-generation JAK-selective inhibitors in the C3H/HeJ mouse model of AA, using both systemic and topical delivery. We found that JAK1-selective inhibitors as well as JAK3-selective inhibitors robustly induced hair regrowth and decreased AA-associated inflammation, whereas several JAK2-selective inhibitors failed to restore hair growth in treated C3H/HeJ mice with AA. Unlike JAK1, which is broadly expressed in many tissues, JAK3 expression is largely restricted to hematopoietic cells. Our study demonstrates inhibiting JAK3 signaling is sufficient to prevent and reverse disease in the preclinical model of AA.

Topics: Administration, Topical; Alopecia Areata; Animals; Azetidines; CD8-Positive T-Lymphocytes; Cytokines; Isonicotinic Acids; Janus Kinase 1; Janus Kinase 2; Janus Kinase 3; Macrophages; Mice, Inbred C3H; Nitriles; NK Cell Lectin-Like Receptor Subfamily K; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Triazoles