piperidines and ponesimod

Psoriasis is chronic inflammatory skin condition that imposes a significant physical and psychosocial burden on patients. Moderate to severe psoriasis often requires systemic treatments, including oral systemic therapies and biologics. An addition to the treatment repository for psoriasis is oral small molecules, which include apremilast, tofacitinib, and ponesimod. Of these 3 medications, only apremilast is currently approved for the treatment of psoriasis. Long-term safety data for apremilast suggest that it has a tolerable safety profile and leads to significant improvement in patients with psoriasis; however, there are few head-to-head comparisons with other oral systemic medications. Tofacitinib and ponesimod have demonstrated clinical efficacy in treating psoriasis; however, further studies are required to understand the benefit-risk profile of these medications in psoriasis patients.

Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Humans; Patient Selection; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Thalidomide; Thiazoles

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