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Upadacitinib may best biologics for clinical remission of ulcerative colitis

Reuters Health - 06/01/2022 - A new network meta-analysis suggests that the selective JAK inhibitor upadacitinib ranks first with respect to clinical remission and response among ulcerative colitis (UC) treatments, although more head-to-head trials are needed, researchers say.

"Two previous network meta-analyses both showed infliximab was ranked first for all endpoints (clinical remission, endoscopic improvement, and clinical response) in moderate-to-severe UC," Dr. Alexander Ford of the University of Leeds, UK told Reuters Health by email. "Given that drug has been around for >20 years, that would seem 'disappointing' in terms of its superiority to novel therapies."

"In this new network meta-analysis, upadacitinib came first across almost all endpoints," he said. "Infliximab was still top for endoscopic improvement, but not when trials were subgrouped according to whether they recruited TNF-naïve or -exposed patients; in those two subgroup analyses, again upadacitinib came out first."

However, he added, "It's important to point out that the upadacitinib data have not been fully published as yet." In the U.S. and Europe, the drug is currently approved only for rheumatoid arthritis and psoriatic arthritis.

As reported in Gut, Dr. Ford and colleagues searched the literature to October 2021 and identified 28 trials involving 12, 504 patients. With regard to clinical remission, upadacitinib 45 mg once daily ranked first versus placebo (RR, 0.73), with infliximab 5mg/kg second, and infliximab 10mg/kg third.

Upadacitinib ranked first for clinical remission both in patients naïve to anti-TNF-alpha drugs (RR, 0.69) and previously exposed (RR, 0.78).

However, for achieving endoscopic improvement, infliximab 10 mg/kg ranked first (RR, 0.61); upadacitinib 45mg was second, and infliximab 5mg/kg, third.

Upadacitinib was more likely to lead to adverse events; however, serious adverse events were no more frequent, and withdrawals due to adverse events were significantly lower than with placebo.

Other comparisons showed that infections were significantly more likely with tofacitinib than placebo (RR, 1.41).

Overall, most drugs were safe and well tolerated.

Dr. Ford added, "We will update this network meta-analysis as new trials and new drugs become available. Only five of the trials within it were head-to-head studies of one drug versus another. The rest were placebo-controlled. We need more head-to-head trials, preferably of small molecules like JAK inhibitors against biologic drugs."

"The other issue is pooled remission rates with active drugs in the treatment arms were only around 20%, suggesting we need other approaches in inflammatory bowel disease, perhaps combinations of drugs," he concluded.

Dr. Caren Heller, Chief Scientific Officer at the Crohn's and Colitis Foundation, commented on the study in an email to Reuters Health, "While the findings are very interesting and look promising, upadacitinib is not yet on the market in the U.S. for ulcerative colitis, and so it would be premature to draw conclusions from this study."

"Moreover," she said, "the authors evaluated comparative effectiveness at the time of induction, at a minimum of six weeks, and it isn't clear how well one can extrapolate from induction effectiveness to long-term maintenance effectiveness."

"It will be important to continue to assess these agents both through well-controlled clinical trials, especially maintenance studies, head-to-head comparisons, and through analysis of real-world data among patients being treated routinely (rather than in clinical trials), such as that being collected through the Foundation's IBD Plexus initiative."

Dr. Matilda Hagan, Medical Co-Director at the Center for Inflammatory Bowel and Colorectal Diseases at Mercy Medical Center in Baltimore, also commented by email. "The findings are consistent with what is currently available in literature, that JAK inhibitors offer a promising avenue for disease management with regards to UC and that infliximab continues to be a very effective therapy. Ustekinumab's and vedolizumab's favorable safety profiles are also highlighted."

"While network meta-analysis provides indirect comparison of our available treatments, there are limitations, most of which the authors extensively discuss with regard to the present study," she said. "We still need to choose therapy based on our specific patients and their needs."

"All available small molecules and biologics are effective when compared with placebo," she added. "Overall, they appear to have a good safety profile. It is critical to get patients on an appropriate regimen based on their preferences and access to achieve disease control and steroid-free remission."

SOURCE: https://bit.ly/3HIE3i6 Gut, online December 22, 2021.

By Marilynn Larkin

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