Upadacitinib (ABT-494) is an investigational oral treatment being developed by AbbVie to treat patients with rheumatoid arthritis (RA), atopic dermatitis (eczema), psoriatic arthritis, Crohn’s disease, and ulcerative colitis. It belongs to a class of drugs called JAK inhibitors, which dampen the autoimmune response by blocking the actions of the Janus kinase (JAK) family of signaling proteins.

How upadacitinib works

Cytokines are small proteins released by immune cells that play an active role in inflammation and autoimmune diseases. They exert their effects when they bind to receptors found on the surface of their target cells. JAKs are a specific family of proteins that transmit signals inside the cell when a cytokine binds to its receptor. Binding to a receptor activates the JAK proteins, which sets off a signaling cascade within the cell that leads to the proliferation and maturation of immune cells. That increases inflammation.

Upadacitinib and other JAK inhibitors fight inflammation by binding to JAK proteins to block the pro-inflammatory effects of cytokines on the target cells.

Upadacitinib in clinical trials for IBD

In May 2017, Abbvie announced positive results from a Phase 2 placebo-controlled trial (NCT02365649) called CELEST. The trial used varying doses of upadacitinib in adult patients with moderate to severe Crohn’s disease who had not been helped by other treatments. Most patients in the study had already been on at least two other immune-modulating therapies that had not brought about disease remission.

Participants were randomized to receive either placebo or one of five doses of upadacitinib (3 mg, 6 mg, 12 mg, or 24 mg two times a day, or 24 mg once a day) for 16 weeks. Of participants who took 24 mg twice a day, 22% achieved endoscopic remission, compared to none in the placebo group. Twenty-seven percent of patients in the 6 mg dose group achieved clinical remission, compared to 11% in the placebo group. The safety profile was similar to that observed in a previous study of upadacitinib in patients with RA.

A Phase 2 open-label extension study (NCT02782663) to evaluate the long-term safety and effectiveness of upadacitinib in the same group of patients with Crohn’s disease is underway. All participants in the extension study will receive the investigational therapy.

Upadacitinib’s positive results in patients with Crohn’s disease in the initial Phase 2 trial support its advancement to a Phase 3 trial. Upadacitinib is already being tested in Phase 3 trials in patients with RA and psoriatic arthritis.

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