Upadacitinib Showing Promise in Refractory Crohn's Disease

Damian McNamara

May 12, 2017

CHICAGO — Patients with Crohn's disease who are intolerant or respond incompletely to a tumor necrosis factor inhibitor could benefit from subsequent upadacitinib induction therapy, results from the double-blind, dose-ranging CELEST trial suggest.

"Upadacitinib demonstrated safety and efficacy as an induction treatment in subjects with long-standing and refractory Crohn's disease," said lead investigator William Sandborn, MD, from the University of California, San Diego in La Jolla.

At 16 weeks, clinical and endoscopic remission rates were significantly better with certain doses of the JAK-1 inhibitor upadacitinib, which is under development by AbbVie, than with placebo.

At baseline, the study participants had moderate to severe active disease, a mean Crohn's Disease Activity Index (CDAI) score of 302, and a mean disease duration of 13 years. Patients had a mean of at least 2.5 liquid or soft stools a day and a mean abdominal pain score of at least 2.0.

Overall, the endoscopist-rated Simplified Endoscopic Score for Crohn's disease (SES-CD) was at least 6; for patients with isolated ileal disease, it was at least 4.

I think this is the most refractory population ever treated in a Crohn's disease trial.

"I think this is the most refractory population ever treated in a Crohn's disease trial," Dr Sanborn pointed out.

He presented results on the 220 patients — who made up 82% of the cohort — who completed the 16-week induction phase of the trial during a packed late-breaking abstract session here at Digestive Disease Week 2017.

The primary end points were clinical remission, defined as 1.5 or fewer liquid or soft stools per day and an abdominal pain score of 1 or below, and endoscopic remission, defined as a decrease in SES-CD score of at least 2 points at either 12 or 16 weeks.

Table 1: Remission Rates After Induction Therapy at 16 Weeks

Dose n Clinical Remission, % Endoscopic Remission, %
Placebo 37 11 0
   3 mg twice daily 39 13 10*
   6 mg twice daily 37 27* 8
   12 mg twice daily 36 11 8*
   24 mg twice daily 36 22 22‡
   24 mg once daily 35 14 14†

*P = .1
P = .05
P = .01


Concomitant medications permitted at baseline included corticosteroids and stable doses of aminosalicylates or methotrexate. However, a rapid tapering of steroids started at week 2, which is "unique to this study," Dr Sandborn reported.

Clinical response and endoscopic response — secondary end points — were significantly better with upadacitinib at certain doses than with placebo.

Table 2: Response Rates After Induction Therapy at 16 Weeks

Dose n Clinical Response, % Endoscopic Response, %
Placebo 37 32 14
   3 mg twice daily 39 44 23
   6 mg twice daily 37 57† 43‡
   12 mg twice daily 36 47† 39‡
   24 mg twice daily 36 61† 50‡
   24 mg once daily 35 49 49‡

P = .05
P = .01


"There was a significant dose–response relation, compared with placebo, for secondary end points," Dr Sandborn said. A linear dose–response relation was also seen with C-reactive protein, calprotectin biomarker response, and the "tough end point" of steroid-free and CDAI remission at week 16, which was achieved in the two highest-dose groups, he reported.

No Surprises From a Safety Perspective

There was one case of herpes zoster infection in the 24 mg once-daily group, which is a potential risk "well described with a JAK-1 inhibitor," he pointed out. One case of nonmelanoma skin cancer was reported in the same group, but it was "probably unappreciated before the study," he added. There were two myocardial infarctions in the 12 mg twice-daily group, but the study was too small "to determine why that might be."

The rate of any adverse event ranged from 76% to 86% in the treatment groups and was 73% in the placebo group. "The safety and tolerability were consistent with observations in the phase 2 studies in rheumatoid arthritis," said Dr Sanborn.

The other traditional steroid medications have adverse effects, said session moderator Curtis Wray, MD, from the University of Texas in Houston. "So being able to take a medication with a potentially lower side-effect profile is attractive."

After the presentation, Dr Wray asked why 20% of participants did not complete the induction phase of the study.

"Median CDAI scores were pushing 300. It was a very refractory population; almost half were taking steroids and we withdrew them," Dr Sandborn explained. In addition, "our study at 16 weeks was longer than many previous studies, at 10 weeks. It was probably a combination of all those factors."

"It appears this drug is doing what the investigators hoped to demonstrate in their study," Dr Wray told Medscape Medical News.

"It's a very promising study. Crohn's disease is a very serious, chronic medical condition," he said. "When you look at some of these health-related quality-of-life outcomes — missed days of work, emergency room visits, hospital admissions, and visits to providers, the economic impact — it adds up quickly."

"We probably underestimate the direct and indirect costs," Dr Wray added. "So a drug to ameliorate those symptoms in this vulnerable population would be a big advancement."

Dr Sandborn is a consultant for AbbVie. Dr Wray has disclosed no relevant financial relationships.

Digestive Disease Week (DDW) 2017: Abstract 874h. Presented May 9, 2017.

Follow Medscape Gastroenterology on Twitter @MedscapeGastro and Damian McNamara @MedReporter


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