Upadacitinib (ABT-494) is a Janus kinase 1 (JAK1) inhibitor currently being developed by AbbVie for the treatment of rheumatoid arthritis (RA), Crohn’s disease, ulcerative colitis, atopic dermatitis, and psoriatic arthritis. It is also being investigated as a potential treatment for people with active ankylosing spondylitis (AS).

AS is an inflammatory, progressive autoimmune disease that affects the joints of the spine. As the disease progresses, calcium deposits form where ligaments attach to the bones that form the spine, leading to reduced flexibility of the back.

How upadacitinib works

Janus kinase inhibitors (also known as Jakinibs) are disease-modifying drugs that target the JAK enzymes, which are found inside cells and play important roles in cytokine-mediated cell signaling.

Many immune system diseases are related to an abnormal production of cytokines, a group of proteins that help communication between cells. For example, a cytokine called interleukin-2 (IL-2) stimulates the production of T-cells, a specialized type of immune cell. After a cytokine binds to its receptor, JAKs contribute to the processes within the cell to produce an immune or inflammatory response. JAK inhibitors may have an important role in autoimmune diseases such as AS, as they suppress immune responses.

Upadacitinib in clinical trials

The pharmacokinetics, safety, and tolerability of upadacitinib have been evaluated in a Phase 1 clinical trial (NCT01741493) in healthy volunteers and in people with RA.

The positive results from this study supported further evaluations of the potential therapy in Phase 2 trials in RA (NCT02720523 and NCT02049138), Crohn’s disease (NCT02782663 and NCT02365649), ulcerative colitis (NCT02819635), and atopic dermatitis (NCT02925117).

The compound is also being tested in a number of Phase 3 trials in RA, ulcerative colitis, and psoriatic arthritis. In June 2017, Abbvie announced positive top-line results from their Phase 3 SELECT-NEXT clinical trial (NCT02675426) evaluating upadacitinib in patients with moderate to severe rheumatoid arthritis (RA).

A phase 2b/3 study (NCT03178487) is now underway to evaluate upadacitinib’s safety and effectiveness in people with active AS. This multicenter, randomized, double-blind, placebo-controlled study aims to recruit about 228 participants with active AS and is estimated to be completed by 2020.

Other details

The most common adverse events associated with the use of upadacitinib were headache, nausea, and upper respiratory and urinary tract infections.

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