The preclinical discovery and development of deucravacitinib for the treatment of psoriasis

ABSTRACTIntroduction Psoriasis is a chronic inflammatory skin disease that most commonly presents as plaque psoriasis. The understanding of the pivotal pathogenetic role of the IL-23/IL-17 axis has dramatically changed the therapeutic approach to the disease. The identification of intracellular signaling pathways mediating IL-23 activity provided the rationale for targeting TYK2.Areas covered This review assesses the underlying rationale that led to development of deucravacitinib, a novel oral TYK2 inhibitor, as a therapeutic option for the treatment of moderate-to-severe psoriasis, primarily focusing on pre-clinical and early phase clinical studies.Expert opinion Innovative therapies used in patients with moderate-to-severe psoriasis include biologic agents and small molecules, which are associated with less adverse events than traditional systemic agents. Deucravacitinib, which selectively targets TYK2, has demonstrated to be effective in treating psoriasis, preserving a more favorable safety profile compared to other JAK inhibitors approved for the treatment of other immune diseases that block the ATP-binding site. Because of its oral administration, deucravacitinib represents an intriguing option in the therapeutic armamentarium of psoriasis, though the evaluation of long-term efficacy and safety is necessary to establish its place-in-therapy.KEYWORDS: PsoriasispathogenesisIL-23/IL-17 axisJAK inhibitorsTYK2 inhibitorsdeucravacitinibsystemic treatmentssafety Article highlights Psoriasis is a chronic inflammatory skin disease whose pathogenesis is mainly driven by the IL-23/IL-17 axis.TYK2 plays an essential role in transducing the IL-23 mediated signal, thus representing a valid therapeutic target for moderate-to-severe psoriasis.By selectively blocking TYK2, deucravacitinib ameliorates the clinical manifestations of psoriasis.Deucravacitinib has demonstrated high selectivity for the TYK2 pseudokinase domain, thus blocking IL-23- and IL-12-mediated signaling and, in turn, IL-17 action.Deucravacitinib represents a valid therapeutic option due to its great manageability and its low rate of serious adverse events or off-target effects.Declaration of interestK Peris has served on the advisory board of, received honoraria for lectures from and/or research grants from AbbVie, Almirall, Eli Lilly and Company, Galderma, Leo Pharma, Pierre Fabre, Novartis, Sanofi, Sun Pharma and Janssen Pharmaceuticals. C De Simone has acted as a speaker and consultant for Almirall, AbbVie, Janssen Pharmaceuticals, Celgene, Leo Pharma, Novartis, Eli Lilly and Company, and UCB Pharma. A Chiricozzi has served as advisory board member and consultant and has received fees and speaker's honoraria and/or has participated in clinical trials for AbbVie, Almirall, Bristol Myers Squibb, Leo Pharma, Eli Lilly and Company, Janssen Pharmaceuticals, Novartis, Pfizer and Sanofi Genzyme. G Caldarola has received honoraria as a speaker and served as a consultant for AbbVie, Almirall, Biogen, Eli Lilly and Company, Leo Pharma, Novartis, Janssen, Sanofi, Pfizer, and UCB Pharma outside of this submitted work. G Girolomoni has served as a consultant and/or speaker for AbbVie, Abiogen, Almirall, Amgen, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Leo Pharma, Merck Serono, Novartis, Pfizer, Samsung Bioepis, Sanofi and UCB Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThis manuscript has not been funded.