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JAK1 inhibitor shows promise in refractory Crohn’s
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CHICAGO — Upadacitinib effectively induced remission on various levels in patients with Crohn’s disease who almost all previously failed anti-tumor necrosis factor medications, according to a presenter at Digestive Disease Week.
“Upadacitinib demonstrated efficacy and safety as an induction treatment in patients with long-standing and refractory Crohn’s disease,” William J. Sandborn, MD, professor of medicine, chief of the division of gastroenterology and director of the University of California San Diego Inflammatory Bowel Disease Center, said during his Late Breaker presentation. “Ninety-five percent of patients had failed TNF blockers and two-thirds of those had failed two or three TNF blockers and almost 40% of patients had failed vedolizumab. I think this is the most refractory patient population ever reported.”
William J. Sandborn
Sandborn and colleagues randomly assigned 220 patients with active Crohn’s disease to induction therapy with either placebo (n = 37) or upadacitinib (ABT-494, AbbVie) 3 mg (n = 39), 6 mg (n = 37), 12 mg (n = 36) or 24 mg twice daily (n = 36) or 24 mg once a day (n = 35) for 16 weeks with tapering of any corticosteroids from week 2. The study continued under a blinded extension therapy for 36 weeks.
The endpoints were set at clinical remission — defined as stool frequency 1.5 or less and abdominal pain score of one or less and neither worse than baseline — at week 16 and endoscopic remission, defined as Simplified Endoscopic Score for CD (SES-CD) at 4 or less and 2 or more points reduction, at week 12 and week 16. Sandborn noted that these are very tough endpoints and trials designed after this one had more relaxed standards of remission.
Looking at endoscopic remission at weeks 12 and 16, Sandborn showed that none of the placebo patients reached that endpoint while all but the 6 mg upadacitinib group had significant improvement, ranging from 8.3% in the 12-mg group (P < .01) to 22.2% in the 24 mg twice-daily group (P < .01).
In the analysis of clinical remission at week 16, only the 6-mg group showed a significant change (27%; P < .01), but all groups showed some response, including placebo, according to Sandborn.
“There was a significant dose–response relationship compared to placebo for secondary endpoints,” he said.
Looking at secondary endpoints, Crohn’s disease activity index (CDAI) remission at week 16 was more likely in all treatment groups, but only significantly different than placebo in the 12-mg group (38.9%; P < .05). Clinical response at week 16 was seen in more than 40% of all treated participants in each group, with the 6-mg group (56.8%; P < .05) and the 24-mg group (61.1%; P < .05) showing the greatest response.
Sandborn also showed that endoscopic response by 50% at weeks 12 and 16 was evident in all the treatment groups, reaching significance in the 6 mg (21.2%; P < .05), 12 mg (29.4%; P < .01), 24 mg twice-daily (33.3%; P < .01) and 24 mg once-daily (25%; P < .05) groups.
Modified clinical response at week 16 was only significantly different in the 6-mg group (30.3%; P < .01) and the 24-mg twice-daily group (36.7%; P < .05).
Combining steroid-free remission and CDAI remission at week 16, Sandborn showed that no placebo-treated participants met that secondary endpoint while it was seen in 20% of the 3-mg group (P < .01), 38,9% of the 12-mg group (P < .05) and 33.3% of the 24-mg twice-daily group (P < .05).
“We can see ... early and significant improvements in hsCRP and fecal calprotectin,” Sandborn added.
While he showed there were a few adverse events, some resulting in termination of the medication, “Everything is kind of consistent with Janus kinase inhibitors. No surprises from a safety perspective,” Sandborn said. “The safety and tolerability was consistent with ... studies with this agent in rheumatoid arthritis.” – by Katrina Altersitz
Reference: Sandborn WJ. Abstract 874h. Presented at: Digestive Disease Week; May 6-9, 2017; Chicago.
Disclosures: This project was supported by a grant from the Agency for Healthcare Research and Quality. Please see the abstract for full list of disclosures.