Dr Brian Feagan
COPENHAGEN, Denmark — The reversible oral Janus kinase (JAK) inhibitor upadacitinib (Rinvoq, provera faz mal ao feto AbbVie) was associated with superior endoscopic outcomes at 12 weeks and 1 year compared with placebo among people with moderately to severely active Crohn’s disease.
The findings of this subanalysis come from two phase 3 induction trials (U-EXCEL and U-EXCEED) and one maintenance study (U-ENDURE) of upadacitinib in this patient population.
“Upadacitinib shows large differences relative to placebo in endoscopic response and remission…in a difficult-to-treat population of patients, the majority of whom had failed an advanced therapy,” lead investigator Brian Feagan, MD, senior scientific director of the GI contract research firm Alimentiv in London, Ontario, Canada, told Medscape Medical News.
“The absolute magnitude of the finding was unanticipated — a greater treatment effect than might be anticipated for these outcomes compared with other advanced treatments for Crohn’s disease in these higher-risk patients,” he said.
Feagan presented the research live and virtually at the European Crohn’s and Colitis Organisation (ECCO) 2023 Congress in Copenhagen, Denmark.
At baseline, participants had an average daily stool frequency of 4 or more and/or an abdominal pain score of 2 or greater. They also had a Simple Endoscopic Score for Crohn’s disease of 6 or more, excluding a narrowing component, or a score of 4 or more for isolated ileal Crohn’s disease.
In the treatment induction phase, patients were randomly assigned 2:1, with 674 people receiving 45 mg upadacitinib and 347 taking a placebo once daily for 12 weeks.
Participants who experienced at least a 30% decrease in stool frequency and/or daily abdominal pain scores were enrolled in the maintenance phase of the study. For this phase, patients were randomly assigned again, with 168 receiving 30 mg upadactinib,169 receiving 15 mg upadacitinib, and 165 taking a placebo once daily for 52 weeks.
In each induction and maintenance cohort, more than 70% of patients had failed one prior biologic therapy, with failure defined as inadequate response or intolerance. Among those who failed a previous biologic in induction, 96% had also failed prior treatment with an anti-tumor necrosis factor (anti-TNF) inhibitor.
Participants’ mean age was 38-40 years, and 52%-55% were men. Patients who had not failed previous therapy had Crohn’s disease for a median of 6-7 years. In contrast, the prior-failure group had Crohn’s disease for a median of 9-10 years.
At 12 weeks, endoscopic response among patients who had not failed a prior biologic was 52% in the treatment group versus 16% of the placebo group. In the prior-failure group, endoscopic response was observed in 36% and 5%, respectively.
Endoscopic remission at 12 weeks among patients who had not failed a prior biologic was 36% in the treatment group versus 10% in the placebo group. In the prior-failure group, endoscopic remission was 20% in the treatment group versus 3% in those who took placebo.
Participants in the treatment groups of the 52-week maintenance phase of the study experienced higher endoscopic response and endoscopic remission rates compared with those who received placebo.
Endoscopic response in the group without prior biologic failure was 44% in the 30-mg upadacitinib group, 40% in the 15-mg group, and 18% in the placebo group. Among those with prior biologic failure, endoscopic response was seen in 39% of the 30-mg upadacitinib group, 23% of the 15-mg group, and 4% of the placebo group.
There is a “very striking difference in endoscopic response rates between the high dose and placebo,” Feagan said. “That difference here is in the response rate. You see dose separation.”
Endoscopic remission among those without prior biologic failure was observed in 34% of the 30-mg upadacitinib group, 27% of the 15-mg group, and 16% of the placebo group. Among those with prior biologic failure, endoscopic remission was seen in 27% of the 30-mg upadacitinib group, 16% of the 15-mg group, and 2% of the placebo group.
The results show “a clear advantage for the 30-mg dose versus the 15 mg in the maintenance component, especially in patients who had failed an advanced therapy,” Feagan said.
Upadacitinib was well-tolerated in the induction and maintenance phases, and no new safety risks were observed compared with the known safety profile of the drug, the researchers note.
For example, during the induction studies, the rate of any adverse event among patients without prior biologic failure was 60% in the 45-mg upadacitinib group and 53% in the placebo group. Among those who failed a prior biologic, the rates were 67% in the 45-mg upadacitinib group and 66% in the placebo group.
The adverse events were “issues that have already been identified with JAK inhibitors, the biochemical abnormalities with CPK [creatine phosphokinase] elevations and transaminase elevations,” Feagan said.
There were no cases of herpes zoster among patients who received placebo compared with five cases in the 45-mg upadacitinib group without prior biologic failure and 10 cases in the prior biologic failure group.
“The zoster signal is there even at induction with the 45-mg dose versus placebo,” Feagan said.
The study indicates that upadacitinib is effective in improving endoscopic outcomes for patients with Crohn’s disease, regardless of their prior biologic treatments, Robin L. Dalal, MD, assistant professor of medicine at Vanderbilt University in Nashville, Tennessee, said when asked to comment on the study.
“This is important because, as the treatment landscape for Crohn’s disease has expanded, sequencing of therapies has become more complex,” added Dalal, who was not involved in the research. “For upadacitinib in Crohn’s disease, prior biologic use may not be a factor in endoscopic response rates.”
The findings are “very encouraging for physicians and practitioners who treat IBD [inflammatory bowel disease] patients,” Maithili Chitnavis, MD, of the Inflammatory Bowel Disease Section at Atrium Health Gastroenterology in Charlotte, North Carolina, told Medscape Medical News when asked for comment.
“We clearly care about how patients feel overall, but endoscopic and histologic outcomes are important to investigate because we want to ensure there is internal healing to prevent a lot of the longstanding complications of Crohn’s disease, such as malignancy, strictures, fistulizing/penetrating disease, and need for surgery,” said Chitnavis, who was not involved with the study.
Upadacitinib is an oral agent, which distinguishes it from the injectable or infusion-based biologic therapies for Crohn’s disease, Chitnavis noted.
The finding that the medication works in patients with or without prior biologic failure is important, she said.
“With its anticipated…approval for Crohn’s disease [by the US Food and Drug Administration], it is expected that patients will have had to have demonstrated a lack of or loss of response to another biologic, specifically in the anti-TNF category (for example, infliximab, adalimumab, certolizumab) prior to starting upadacitinib due to concerns of potential side effects associated with the class of medications to which it belongs,” Chitnavis said. “Therefore, it makes it even more relevant to know how patients who have failed a prior biologic respond to this therapy.”
Feagan has reported serving as a consultant and speaker for AbbVie. Dalal has reported being a consultant for AbbVie in 2021. Chitnavis has reported no relevant financial relationships.
European Crohn’s and Colitis Organisation (ECCO) 2023 Congress: Abstract OP17. Presented March 3, 2023.
Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology, and critical care. Follow Damian on Twitter: @MedReporter.
For more news, follow Medscape on Facebook, Twitter, Instagram, YouTube, and LinkedIn.
Source: Read Full Article