Upadacitinib Effective in Moderately to Severely Active Crohn's Disease

David Rubin, MD, FACG

Image credit: University of Chicago Medicine

The oral JAK1 inhibitor upadacitinib (Rinvoq) as induction and maintenance therapy demonstrated consistent activity in patients with baseline moderately to severely active Crohn's disease (CD), as defined as CD activity index (CDAI) of 220 or greater, according to a poster presentation at the American College of Gastroenterology (ACG) 2023 Annual Scientific Meeting in Vancouver, Canada. Findings for the poster came from a post-hoc analysis of the 2 phase 3 induction trials U-EXCEED and U-EXCEL and the phase 3 U-ENDURE maintenance study.¹

“Patients with baseline CDAI that was in the range of eligibility had higher rates of CDAI clinical remission, endoscopic response, and key secondary end points at week 12 with upadacitinib 45 mg compared with placebo,” said lead investigator David Rubin, MD, FACG, from the University of Chicago Medicine, Inflammatory Bowel Disease Center. “The efficacy of upadacitinib in the induction studies U-EXCEL and U-EXCEED and the maintenance study U-ENDURE in patients meeting CDAI criteria for disease activity and CDAI response criteria of 100 points to induction remain consistent with previous results. No new safety signals occurred.”

In May 2023, the FDA approved upadacitinib as a treatment for patients with moderately to severely active CD, following an inadequate response or intolerance to TNF blockers. This approval was based on findings from the U-EXCEED, U-EXCEL, and U-ENDURE trials, and made upadacitinib the first oral therapy available to patients with moderately to severely active CD.² “These [ACG] findings are important in considerations for regularly approval in the United States and our use of the therapy in our patients,” said Rubin.

The FDA's label for the indication advises to start upadacitinib at a dose of 45 mg once daily for 12 weeks followed by a maintenance dose of 15 mg once daily. In some cases, the FDA advises for a 30 mg once daily maintenance dose, based on severity of the disease. This dosing schema mirrors the approach taken in the trials that were the basis for the approval.

Across the studies, the baseline characteristics were balanced between the investigational and the placebo arms. The mean age of patents ranged from 36.1 years to 39.8 years. The ileal-colonic region was the most common site of disease, with approximately half of patients across the studies having CD in this location. The mean CDAI at baseline ranged from 314.1 to 339.8 and the mean very soft or liquid stool frequency per day was between 5.4 times per day and 6.4. Most patients had received a prior advanced therapy, including a TNF blocker (90.8% to 98.5%), vedolizumab (Entyvio) or natalizumab (Tysabri; 29.4% to 37.1%), and ustekinumab (Stelara; 34.4% to 48.4%).

In the U-EXCEL trial, specifically in patients with a CDAI of 220 or more, a CDAI clinical remission at 12 weeks was experienced by 46.2% of patients treated with upadacitinib compared with 22.5% of those in the placebo group (delta, 23.8%; P <.0001). By endoscopic response, the 12-week response rate was 45.5% with upadacitinib compared with 12.6% for placebo (delta, 33.2%; P <.0001). Similar results were seen across other key secondary end points.

In the U-EXCEED trial, upadacitinib demonstrated similar findings for patients with CDAI of 220 or more at baseline. A CDAI clinical remission was experienced by 35.9% of patients treated with upadacitinib compared with 17.8% of those in the placebo group (delta, 17.3%; P <.0001). By endoscopic response, these rates were 34.1% and 3.4%, respectively (delta, 29.9%; P <.0001). Secondary end points were also substantially improved in this study.

The analysis explored patients treated with maintenance upadacitinib who had a CDAI of 220 at baseline for induction therapy and who had achieved a score of 100 or more by week 0 of maintenance (a 100-point improvement). In this group, the larger 30 mg dose of upadacitinib was superior to the 15 mg dose for the co-primary end points of CDAI remission and endoscopic response. CDAI remission was seen in 54.6% of those treated with the 30 mg dose compared with 41.6% at the 15 mg dose and for 14.4% of those with placebo. Similarly, for endoscopic response, 41.2% experienced a response with the 30 mg dose compared with 27.8% for the 15-mg dose of upadacitinib and for 7.2% of those treated with placebo.

“The 100-point responders at week 12 had higher rates of CDAI clinical remission and endoscopic response with the upadacitinib vs the placebo at week 52,” said Rubin. “This was true for both doses of upadacitinib. A higher proportion of patients also met key secondary end points at week 52 with both doses compared with placebo.”

In the U-EXCEED and the U-EXCEL trials, an adverse event (AE) of any grade was experienced by a similar number of patients in each group. For those treated with placebo, an AE of any grade occurred for 62.2% of patients compared with 65.1% of those treated with upadacitinib. Serious AEs were experienced by 8.4% of those in the placebo group compared with 8.0% of those in the upadacitinib arm. A similar number of events were seen with the 15 mg and 30 mg doses in the maintenance phase.

References

1. ^{Rubin DT, Loftus EV, Regueiro M, et al. Efficacy of Upadacitinib in Patients With Crohn’s Disease Activity Index-Based Eligibility Criteria: Post Hoc Analysis of U-EXCEL, U-EXCEED, and U-ENDURE Phase 3 Trials. Presented at: ACG 2023 Annual Meeting; October 20-25, 2023. Abstract P0732.}
2. ^{FDA approves first oral treatment for moderately to severely active Crohn’s disease. News release. FDA. May 18, 2023. Accessed October 22, 2023.} https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-oral-treatment-moderately-severely-active-crohns-disease