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Upadacitinib May Best Biologic for Clinical Remission of Ulcerative Colitis

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Upadacitinib May Best Biologic for Clinical Remission of Ulcerative Colitis
By Marilynn Larkin
January 07, 2022

NEW YORK (Reuters Health) - 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.

Reuters Health Information © 2022


Well-known member
Yeah we have discussed it with her GI. If Tofa can hold her until it is approved she will likely switch to it given the theoretical better safety profile. Jury is still out about her TI though.

Upadacitinib (RINVOQ®) Achieved Primary and Key Secondary Endpoints in First Phase 3 Induction Study in Patients with Crohn's Disease

- In U-EXCEED, a significantly higher proportion of patients with moderate to severe Crohn's disease treated with upadacitinib (45 mg once daily for induction) achieved both primary endpoints of clinical remission[a,b] and endoscopic response[c] compared to placebo at week 12[1]
- The study showed that a significantly higher proportion of upadacitinib-treated patients achieved steroid-free clinical remission[d] at week 12 compared to placebo[1]
- The safety results in this study were consistent with the known profile of upadacitinib, with no new safety risks observed[1-6]
- Upadacitinib, a selective and reversible JAK inhibitor discovered and developed by AbbVie, is being studied as an oral therapy for moderate to severe Crohn's disease and several other immune-mediated inflammatory diseases[1,6-14]

NORTH CHICAGO, Ill., Dec. 6, 2021 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced positive top-line results from U-EXCEED, a Phase 3 induction study, showing upadacitinib (45 mg once daily) achieved both primary endpoints of clinical remissiona,b and endoscopic responsec at week 12.1 The U-EXCEED study enrolled patients with moderate to severe Crohn's disease who had an inadequate response or were intolerant to biologic therapy, with over 60 percent having previously failed two or more biologics.1 U-EXCEED is the first of two Phase 3 induction studies to evaluate the safety and efficacy of upadacitinib in adults with moderate to severe Crohn's disease.1

"The data from this first Phase 3 induction study in Crohn's disease suggest upadacitinib may help address the needs of patients suffering from this disease, as demonstrated in stringent endpoints such as endoscopic response," said Michael Severino, M.D., vice chairman and president, AbbVie. "We continue to leverage our expertise in IBD by driving research and development that help shape the IBD landscape and elevate standards of care for patients."

In U-EXCEED, clinical remission was measured by the Crohn's Disease Activity Index (CDAI) and by the patient-reported symptoms of stool frequency/abdominal pain (SF/AP).1 A significantly greater proportion of patients treated with a 12-week induction regimen of upadacitinib 45 mg daily achieved clinical remission per CDAI at week 12 compared to placebo (39 percent, versus 21 percent; p<0.0001).1 Similar results were seen with clinical remission per SF/AP (40 percent in upadacitinib-treated patients versus 14 percent in placebo-treated patients; p<0.0001).1 In this study, all patients were also evaluated for improvement in the intestinal mucosa by endoscopy.1 At week 12, a significantly greater proportion of patients treated with upadacitinib 45 mg achieved endoscopic response compared to the placebo group (35 percent versus 4 percent; p<0.0001).1

Among patients taking corticosteroids at baseline, a significantly higher proportion of patients receiving upadacitinib 45 mg achieved steroid-free clinical remissiond per CDAI and per SF/AP compared to placebo at week 12.1 A significantly higher proportion of patients receiving upadacitinib compared to placebo also achieved early symptom improvement measured by CR-100 (defined as reduction of CDAI ≥100 points from baseline) at week 2 as well as clinical remission at week 4.1

"I am thrilled to see the results of this first Phase 3 induction study of upadacitinib, particularly in this difficult-to-treat refractory patient population," said Jean-Frederic Colombel, M.D., professor of medicine and director of Inflammatory Bowel Disease Center, Icahn School of Medicine, Mount Sinai, and U-EXCEED study investigator. "These results demonstrate upadacitinib's potential to achieve endoscopic response and clinical remission, including steroid-free clinical remission, at 12 weeks in patients living with Crohn's disease."

Efficacy Results at Week 121
Upadacitinib 45 mg
(n = 324)
Clinical Remission (per CDAI)a21%39%*
Clinical Remission (per SF/AP)b14%40%*
Endoscopic Responsec4%35%*
* Co-primary endpoints were clinical remission (per CDAI for the U.S. FDA and per SF/AP for the EU EMA) and endoscopic response at week 12. All primary endpoints achieved statistical significance with p-values of <0.0001 versus placebo.
a Clinical remission (per CDAI) is defined as CDAI <150.
b Clinical remission per SF (stool frequency)/AP (abdominal pain) (also referred to as PRO-2) is defined as average daily very soft or liquid stool frequency ≤2.8 AND average daily abdominal pain score ≤1.0, and both not greater than baseline.
c Endoscopic response is defined as a decrease in simple endoscopic score for Crohn's disease (SES-CD) of >50 percent from baseline (or at least a 2-point reduction from baseline for subjects with a baseline SES-CD of 4), as scored by central reviewer.
During the 12-week, double-blind, placebo-controlled period, the safety profile of upadacitinib 45 mg was consistent with the safety profile observed in previous studies across indications, with no new safety risks observed.1 The most common adverse event was nasopharyngitis for upadacitinib and exacerbation of Crohn's disease for placebo.1 Serious adverse events occurred in 9.3 percent of patients in the upadacitinib 45 mg group compared to 9.9 percent of patients in the placebo group.1 Rates of serious infections were 2.8 percent in those treated with upadacitinib 45 mg and 1.8 percent in patients who received placebo.1 All events of herpes zoster (1.5 percent of patients) were nonserious and reported in the upadacitinib group only.1 There was one case of adjudicated gastrointestinal perforation in the upadacitinib group.1

An additional 207 patients at week 12 received an upadacitinib 45 mg daily induction regimen (including non-responders to placebo or from an open label arm).1 Among these patients, there were two additional cases of adjudicated gastrointestinal perforation reported.1 Overall, the safety results in these patients were consistent with what was observed in the upadacitinib 45 mg group during the placebo-controlled period.1

In the study, no treatment-emergent cases of adjudicated cardiovascular event, malignancy, thromboembolic event or death were reported across treatment groups.1

Full results from the U-EXCEED study will be presented at upcoming medical conferences and published in a peer-reviewed medical journal. Use of upadacitinib in Crohn's disease is not approved and its safety and efficacy have not been evaluated by regulatory authorities.
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