A Review of Upadacitinib in Crohn’s Disease: A Promising JAK1 Inhibitor

Ravi Shah, MD

Therapies with novel mechanisms of action are required to treat patients suffering from moderate to severe Crohn’s disease. Given that Janus kinase (JAK)-mediated activation of signal transducers and activators of transcription (STATs) in T cells contribute to the pathogenesis of Crohn’s disease, JAK inhibition is hypothesized to be a potential therapeutic target.

Upadacitinib, a selective JAK1 inhibitor, has previously been approved for the treatment of moderate-severe ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, and ankylosing spondylitis. Loftus et al. conducted a multicenter, randomized, double-blinded, placebo-controlled trial including a pair of phase 3 induction trials (U-EXCEL and U-EXCEED) and a maintenance trial (U-ENDURE) assessing the efficacy—including clinical remission defined as a Crohn’s disease activity index (CDAI) <150 and endoscopic response defined as a decrease in the SES-CD score of >50% from baseline—as well as the safety of upadacitinib for patients with moderate to severe Crohn’s disease who have previously failed biologic or conventional therapy.

The 2 induction studies randomized the study population to upadacitinib 45 mg orally versus placebo (n = 350 vs n = 176; and n = 324 vs n = 171). The upadacitinib group achieved the primary endpoints, clinical remission (49.5% vs 29.1%; 38.8% vs 21.1%; P <.001) and endoscopic response (45.5% vs 13.1%; 34.6% vs 3.5%; P <.001), at 12 weeks significantly more than the placebo group. Those induced with upadacitinib also achieved significantly higher rates of secondary endpoints: stool frequency and abdominal pain scores; endoscopic remission; corticosteroid-free clinical remission; fatigue scores; quality of life scores; clinical remission at 4 weeks and response at 2 and 12 weeks, but not Crohn’s related hospitalizations or resolution of extraintestinal manifestations.

The maintenance study randomized patients who achieved the primary endpoint from the two induction studies to receive upadacitinib 30 mg (n = 160), 15 mg (n = 169), or placebo (n = 165) for 52 weeks. The upadacitinib 30 mg and 15 mg groups had significantly higher rates of clinical remission (30 mg, 47.6%; 15 mg, 37.3%; placebo, 15.1%; P <.001) and endoscopic response (30 mg, 40.1%; 15 mg, 27.6%; placebo, 7.3%; P <.001) than the placebo group. There were also higher rates of achieving secondary outcomes, including bowel frequency and abdominal pain scores, clinical response and remission, glucocorticoid-free clinical remission, endoscopic and deep remission, and quality of life scores in the upadacitinib groups. The 30 mg upadacitinib group also reported higher rates of improved fatigue scores and resolution of extraintestinal manifestations.

The most common adverse events in the induction trial of upadacitinib 45 mg were acne (6.9%); anemia (6.3%); nasopharyngitis (7.1%); headache (6.2%); worsening of Crohn’s disease (5.9%); and upper respiratory tract infection (5.2%). Serious infections occurred in 1.1% and 2.8% as compared to 1.7% and 1.8% in the induction group compared to the placebo group, and the most common serious infection was gastrointestinal (e.g. anal abscess). Herpes zoster infection was reported in the induction group but not the placebo group (2.9%, 1.5% vs 0%).

Other non-infectious adverse events included higher rates of neutropenia and creatine kinase elevation in the upadacitinib group. In the maintenance group, exacerbation of Crohn’s disease was the most frequently reported adverse event. Rates of serious infections were similar across the three groups. Herpes zoster was higher in the 30 mg group than the 15 mg group or placebo group (7.2 events per 100 person-years vs 4.0 or 4.7 events per 100 person-years). One gastrointestinal perforation was reported in each of the upadacitinib-treated groups; however this adverse event is thought to be a byproduct of the degree of inflammation rather than one of the medication. Although thrombus formation is a feared complication of JAK inhibitors, there was only one case of thrombus in the upadacitinib group, and this was associated with concurrent Crohn’s disease exacerbation rather than the medication.

Upadacitinib, a selective JAK1 inhibitor, is an essential tool to add to current pharmacologic therapies against Crohn’s disease and especially in those who have previously failed conventional or biologic therapies. Although there are potential adverse events to the medication, preventative care (i.e, vaccination) and careful monitoring (i.e, laboratory monitoring) may be efficient methods to curb these.

Long-term five-year data on the efficacy and safety of this therapy as an extension of the U-ENDURE trial are eagerly awaited. Future studies on positioning upadacitinib and characterizing patient profiles that may benefit the most from this therapy are required.