Upadacitinib tartrate, a small-molecule selective inhibitor of JAK1, was recently approved in the U.S. as a treatment for adults with moderately to severely active rheumatoid arthritis (RA) and an inadequate response or intolerance to methotrexate. In addition to being under regulatory review in the E.U. and Japan for this indication, Upadacitinib is also in the advanced stage of clinical development for several other indications, including atopic dermatitis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, giant cell arteritis and ankylosing spondylitis.
Introduction of Upadacitinib
Upadacitinib tartrate is a selective JAK1 inhibitor being developed for the treatment of inflammatory diseases. It was engineered to enhance selectivity of JAK1 by exploiting interactions outside the ATP-binding site. In vitro, upadacitinib demonstrated higher inhibition for JAK1 over JAK2 and JAK3, suggesting a potentially improved therapeutic profile in treating patients with inflammatory diseases compared to nonselective JAK inhibitors. In cellular assays, upadacitinib demonstrated to be approximately 74-fold more selective for JAK1 over JAK2, and approximately 58-fold more selective for JAK1 over JAK3, with IC50 values of 0.043, 0.2, 2.3 and 4.7 muM for JAK1, JAK2, JAK3 and TYK2, respectively.
Introduction of JAK
The JAK enzymes are tyrosine kinases that play important roles in the signaling pathways of various cytokines, growth factors, and hormones, and are implicated in the pathogenesis of RA and other autoimmune inflammatory diseases. This enzyme family consists of four members: JAK1, JAK2, JAK3 and TYK2. It has been hypothesized that selectively inhibiting JAK1 can intercept the pathogenic cytokine signaling involved in RA while sparing other signaling pathways required for normal physiological functions. To this date, Tofacitinib and Baricitinib are the only approved Jakinibs and may be used as a second-line treatment for RA in combination or as monotherapy. Nonetheless, expectations may be reduced due to dose-limiting tolerability and safety concerns. Therefore, JAK1 inhibitors have been structurally designed for a greater selectivity for JAK1, with the aim of reducing potential JAK2 and JAK3 associated side effects without loss of efficacy.
The approval of Rinvoq is based on data from the global SELECT III phase of the RA project, which is one of the largest registered III phase projects in the RA field, including five III phase studies involving about 4400 RA patients. These studies assessed the efficacy, safety, and tolerance of Rinvoq in patients with various types of RA, including patients with failed or intolerant biologic disease modification antirheumatic drugs, patients who have not received methotrexate (MTX), or patients with insufficient response to MTX. In all studies, Rinvoq reached the primary and secondary endpoints of the study. The market estimate for Rinvoq is very optimistic. Evaluate Pharma, a pharmaceutical market research firm, previously released a report predicting that Rinvoq will reach global sales of $2.57 billion in 2024, making it the fifth best-selling anti-rheumatic drug in the world.
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2. Beck, L. A., Silverberg, J. I., Grebe, K., Feng, H., Parmentier, J., Teixeira, H., & Guttman-Yassky, E. (2019). Eosinophil Count and Serum Immunoglobulin E Levels in Atopic Dermatitis: Analysis of Upadacitinib Phase 2 Study Findings. Journal of Allergy and Clinical Immunology, 143(2), AB125.