Upadacitinib for CD: remarkable efficacy in induction therapy

U-EXCEL is already the second induction trial that demonstrated efficacy of upadacitinib with a fast onset of action in patients with moderate-to-severe Crohn’s disease (CD) at week 12. Although patients were intensively pre-treated, half of them achieved clinical and 28.9% of them endoscopic remission as early as week 12.

There is still a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with CD. Previously, the JAK1 inhibitor upadacitinib has been shown to be effective in inducing clinical and endoscopic improvement, with an acceptable safety profile in the U-EXCEED study (NCT03345836). U-EXCEL (NCT03345849) is a second induction study in patients with moderately to severely active CD. All participants were required to have failed or be intolerant to conventional or biologic therapy. By week 12, 88.0% of the placebo group (n=155) and 93.7% of the upadacitinib group (n=328) completed the study. Almost half (45%) of the study population had already failed prior biologic therapy, in most cases a prior TNF blocker. The primary endpoints of U-EXCEL at week 12 were clinical remission measured by the Crohn’s Disease Activity Index (CDAI <150) and by the patient-reported symptoms of stool frequency/abdominal pain (SF/AP) and endoscopic response [1].

A significantly higher percentage of participants treated with upadacitinib achieved the co-primary endpoints compared with placebo: 49.5% of participants treated with upadacitinib achieved CDAI <150 compared with 29.1% in the placebo group (P<0.0001). The SF/AP clinical remission (average daily stool frequency ≤2.8 and average daily abdominal pain ≤1 and neither worse than at baseline) was 50.7% versus 22.2% (P<0.0001), for the upadacitinib and placebo group respectively. In addition, endoscopic response was significantly higher in upadacitinib-treated participants with a clinically relevant difference of 33% (P<0.0001). “I believe that the achievement of endoscopic response in CD in almost half of the participants is a unique achievement of efficacy in an induction trial,” said Prof. Julian Panés (Hospital Clínic Barcelona, Spain). A significant proportion of participants treated with upadacitinib achieved clinical response as early as week 2 and clinical remission at week 4. Among patients taking corticosteroids at baseline, a significantly higher proportion of participants receiving upadacitinib 45 mg achieved steroid-free clinical remission per CDAI and per SF/AP compared with placebo at week 12 (P<0.0001 vs placebo for each comparison). “Finally, as much as 28.9% of participants treated with upadacitinib achieved endoscopic remission at this early time point,” Prof. Panés pointed out.

Treatment-emergent adverse events were noted in 58.6% of participants on placebo compared with 62.8% in the upadacitinib arm, but there was no difference in serious adverse events between the groups, and no deaths occurred. A higher proportion of participants in the placebo arm reported worsening of UC (3.7% for upadacitinib vs 10.7% for placebo), whereas anaemia (6.3% for upadacitinib vs 4.5% for placebo) and acne (6.9% of the participants treated with upadacitinib vs 0.6% for placebo) were more frequent in the upadacitnib arm, a class-related effect as Prof. Panés pointed out. In addition, herpes zoster (2.9% for upadacitinib and 0% for placebo) was more frequent in the upadacitinib arm but there was no case of GI perforation.

1. Loftus EV, et al. Efficacy and safety of upadacitinib induction therapy in patients with moderately to severely active Crohn’s Disease: results from a randomized phase 3 U-EXCEL study. OP129, UEG Week 2022, 8–11 October, Vienna, Austria.

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Posted on 1 December, 20228 April, 2024