In moderate-to-severe Crohn disease, upadacitinib increased clinical remission at 12 and 52 wk

Two phase 3 induction trials, U-EXCEL and U-EXCEED, randomly assigned patients with moderate to severe Crohn's disease to receive 45 mg of upadacitinib or placebo once daily for 12 weeks. Those who responded clinically were randomly assigned to receive 15 mg of upadacitinib, 30 mg of upadacitinib, or placebo once daily for 52 weeks in the U-ENDURE maintenance trial. At 12 and 52 weeks, clinical remission and endoscopic response were higher in those who received upadacitinib versus those on placebo, with no increase in adverse events compared with placebo.

The results were published May 25 by The New England Journal of Medicine. The following commentary by Catherine Rowan, MB BCH BAO, MD, was published in the ACP Journal Club section of the September Annals of Internal Medicine.

Janus kinase (JAK) inhibitors are oral small molecules that affect the phosphorylation of JAK molecules, thereby inhibiting the transcription of pro-inflammatory cytokines. Upadacitinib, a selective JAK-1 inhibitor, has recently been shown to be effective for moderately-to-severely active ulcerative colitis.

The trials by Loftus and colleagues showed the efficacy of upadacitinib in Crohn disease using a responder re-randomization design. 75% of patients in the maintenance trial had previous biologic failure, many of whom failed ≥3 biologic therapies and a third of whom were receiving steroids at induction. This reflects a more treatment-refractory cohort.

The stringent end points included centrally read endoscopic activity and clinical end points indicative of the patient's own experience. Upadacitinib at a maintenance dose of 30 mg/d produced robust endoscopic response rates compared with placebo and achieved steroid-free clinical remission in 45% of patients at week 52. Furthermore, fatigue, quality of life, and extra-intestinal manifestations improved at this dose.

Concerns about the safety profile of JAK inhibitors led the U.S. Food and Drug Administration to include a warning about the risk for major adverse cardiovascular events, infection, thrombosis, and malignancy. The safety data presented by Loftus and colleagues are reassuring in this regard. The rate of serious infections with upadacitinib was similar to that with placebo, and ≤1% had venous thromboembolism.

Upadacitinib's position in treatment algorithms will depend on the individual patient. It is approved for use in patients who have failed anti–tumor necrosis factor therapy and is highly effective for Crohn disease and its extra-intestinal manifestations. As a small molecule, it is a convenient oral therapy sidestepping the risk for immunogenicity with a rapid onset. These benefits must be weighed against an individual patient's risk profile. Overall, upadacitinib is an important step forward in treating Crohn disease.