Deucravacitinib, a selective tyrosine kinase 2 inhibitor, for the treatment of moderate-to-severe plaque psoriasis

ABSTRACTABSTRACTIntroduction Protein kinases play a crucial role in intracellular signaling pathways that lead to inflammation and cell proliferation. New understandings of the involvement of these metabolic pathways in the pathogenesis of psoriasis allowed the development of a new class of drugs. Unlike biologics, these compounds work by blocking intracellular targets involved in the immune response.Areas covered Deucravacitinib is an oral small-molecule inhibitor of TYK2 that binds the pseudokinase domain and locks the kinase in an inactive state by an allosteric mechanism, arresting TYK2-mediated signaling cascades and disabling the upregulation of proinflammatory genes implicated in psoriasis. The authors present the results of phase I–III clinical trials of deucravacitinib for the treatment of psoriasis.Expert opinion At week 16 about 56% of the patients treated with deucravacitinib achieved PASI75. No serious infections were reported, nor were thromboembolic events or laboratory abnormalities. Efficacy was reported to be persistent and safety profiles were shown to be consistent for up to 2 years. Deucravacitinib can potentially become a safe, effective, well-tolerated treatment for patients suffering from moderate-to-severe disease. Future studies and real-life experiences will be important to determine the exact role of this drug in the treatment of psoriasis.KEYWORDS: DeucravacitinibpsoriasisTYK2BMS-986165small molecule Article highlights The great advantage of biological drugs in the treatment of psoriasis is that they target a precise object involved in a pathological process, yielding a high effectiveness/side effects ratio. Despite this, some patients do not respond or respond only partially, or the treatment loses its effectiveness over time. New evidences in pathogenesis, identification of several psoriasis-susceptibility genes and advances in the understanding of intracellular metabolic pathways, have generated new perspectives on psoriasis treatment and led to the development of a new class of drugs with the ability to inhibit certain intracellular proteins involved in the immune response.Deucravacitinib is an oral small-molecule inhibitor of TYK2 that binds the pseudokinase domain and locks the kinase in an inactive state by an allosteric mechanism, arresting TYK2-mediated signaling cascades.TYK2 mediates immune and inflammatory signaling pathways by regulating key inflammatory cytokines, including IL-12, IL-23, and Type I IFNs.Molecules that selectively inhibit TYK2-mediated pathways without involving other JAKs can lead to a broad range of therapy for psoriasis pathogenesis with a reduction in off-target effects, for example, serious infections, malignancies, thrombosis, and MACE.Moreover, deucravacitinib has no impact on the so-called ‘IL-6 inhibition signatures’ obtained with known inhibitors of the IL-6 pathway, such as JAK1 inhibitors, that can increase cholesterol levels and decrease neutrophil counts.Declaration of interestThe authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.Reviewer disclosuresA reviewer on this manuscript has disclosed they have received research, speaking and/or consulting support from Eli Lilly and Company, GlaxoSmithKline/Stiefel, AbbVie, Janssen, Alovtech, vTv Therapeutics, Bristol-Myers Squibb, Samsung, Pfizer, Boehringer Ingelheim, Amgen, Dermavant, Arcutis, Novartis, Novan, UCB, Helsinn, Sun Pharma, Almirall, Galderma, Leo Pharma, Mylan, Celgene, Ortho Dermatology, Menlo, Merck & Co, Qurient, Forte, Arena, Biocon, Accordant, Argenx, Sanofi, Regeneron, the National Biological Corporation, Caremark, Teladoc, BMS, Ono, Micreos, Eurofins, Informa, UpToDate and the National Psoriasis Foundation. They are also the founder and part owner of Causa Research and holds stock in Sensal Health.Another peer reviewer on this manuscript has disclosed that they conduct research for Amgen, Argenx, Bristol Myer Squibb, Pfizer, and Regeneron.Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.Additional informationFundingThis paper was not funded.