A Close Look at the Data Backing Upadacitinib’s Approval in Crohn’s

The selective Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) improved clinical remission and endoscopic response rates compared with placebo in patients with moderate-to-severe Crohn’s disease, according to two induction trials and one maintenance trial.

In the phase III induction trials — U-EXCEL and U-EXCEED — a significantly higher proportion of patients who received 45-mg oral upadacitinib once-daily for 12 weeks experienced clinical remission and an endoscopic response compared with those who received placebo (P<0.001 for all comparisons), reported Jean-Frederic Colombel, MD, of the Icahn School of Medicine at Mount Sinai in New York City, and colleagues:

• U-EXCEL: clinical remission 49.5% vs 29.1%, endoscopic response 45.5% vs 13.1%
• U-EXCEED: 38.9% vs 21.1% and 34.6% vs 3.5%, respectively

Patients who had a clinical response to upadacitinib induction therapy were then randomly assigned in the U-ENDURE maintenance trial to receive 15-mg upadacitinib, 30-mg upadacitinib, or placebo once daily for 52 weeks, Colombel and team noted in the New England Journal of Medicine.

At week 52, a higher proportion of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) compared with placebo (15.1%), and the same was true for endoscopic response: 27.6% and 40.1% versus 7.3%, respectively (P<0.001 for all comparisons).

These results “align with the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) clinical practice recommendations, which include short-term and intermediate-term treatment goals of early symptomatic response, remission, and normalization of high-sensitivity CRP [C-reactive protein] and fecal calprotectin levels, along with long-term goals of endoscopic healing and quality-of-life improvements,” Colombel and team wrote.

Combined, the findings from the three trials led to the JAK inhibitor’s FDA approval earlier this month for adults with moderately to severely active Crohn’s disease who have failed or are intolerant to one or more tumor necrosis factor (TNF) inhibitors. Upadacitinib is also approved for the treatment of ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, and ankylosing spondylitis.

In an editorial accompanying the publication of the trial data, Maria T. Abreu, MD, of the University of Miami Miller School of Medicine in Florida, noted that “the incidences of clinical remission [seen in the current studies] were greater than those observed in most studies of biologic drugs to treat Crohn’s disease. Moreover, upadacitinib was more likely than placebo to resolve extraintestinal manifestations.”

Furthermore, “patients and their physicians are generally concerned about injectable biologics and tend to be less intimidated by oral drugs, which can be stopped and started without potential consequences of immunogenicity,” she added.

Due to safety concerns observed in prior trials, the FDA has limited the use of JAK inhibitors in inflammatory conditions, such as Crohn’s disease, to patients who fail on or cannot tolerate TNF blockers.

Adverse events that occurred or worsened during treatment were similar among all trial groups during the 12 weeks of induction and 52 weeks of maintenance, Colombel’s group reported. These included acne, anemia, nasopharyngitis, headache, and upper respiratory infections.

Herpes zoster infections occurred more frequently in the groups receiving the 45-mg and 30-mg doses of upadacitinib compared with placebo. Liver disorders and neutropenia were more frequent in the 30-mg upadacitinib group than in the other maintenance groups. Four patients who received 45-mg upadacitinib and one patient each who received 30-mg or 15-mg upadacitinib developed gastrointestinal perforations.

A total of 526 patients were included in U-EXCEL, while U-EXCEED included 495 patients; they were randomized in a 2:1 ratio to upadacitinib or placebo. Patients enrolled in these trials had an inadequate response or unacceptable side effects with one or more conventional or biologic therapies. Use of biologic therapies and immunosuppressants other than methotrexate or glucocorticoids was not allowed during the trials.

All patients had moderate-to-severe Crohn’s disease, defined as an average of four or more instances of very soft or liquid stools daily or an abdominal pain score of 2 or more, plus a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of 6 or more (≥4 for patients with isolated ileal disease), excluding the part of the scale on the presence of narrowing. Mean age across these trials was 38-40, and 52-56% were men.

Clinical remission was defined as a Crohn’s Disease Activity Index score of <150, and endoscopic response was defined as a decrease in the SES-CD of >50% from baseline of the induction trial (or for patients with an SES-CD of 4 at baseline, a decrease of ≥2 points from baseline).

U-ENDURE included 502 patients, and patients were randomized in a 1:1:1 ratio to 15-mg upadacitinib, 30-mg upadacitinib, or placebo. Mean age was 37-38, and 53-60% were men.

Colombel and team were unable to identify rare, low-incidence, or long-latency adverse events, including in high-risk patients, which was the main limitation of the trials. The extension trial of U-ENDURE is evaluating these patients for up to 5 years, they said.