Induction therapy with Janus kinase inhibitor upadacitinib is superior to placebo for patients with moderately to severely active ulcerative colitis (UC), regardless of prior biologic treatments, based on results of the phase 3 U-ACHIEVE trial.
Clinical responses in the upadacitinib group occurred as soon as 2 weeks and were sustained through the 8-week study period, reported lead author Silvio Danese, MD, PhD, of Humanitas Clinical and Research Center IRCCS and Hunimed, Milan.
“Despite availability of multiple treatment options, many patients with ulcerative colitis do not achieve disease remission with current therapies and unmet therapeutic need remains, especially in patients with moderate to severe disease,” said coauthor Peter Higgins, MD, PhD, of the University of Michigan, Ann Arbor, who presented findings at the annual meeting of the American College of Gastroenterology.
The U-ACHIEVE trial involved 474 patients with moderate to severe UC randomized to receive either upadacitinib induction therapy (45 mg once daily; n = 319) or placebo (n = 155). The primary endpoint was clinical remission at week 8. Secondary endpoints included endoscopic improvement at week 8, endoscopic remission at week 8, clinical response at week 8, clinical response at week 2, histologic-endoscopic mucosal improvement at week 8, and adverse events.
The study population was “very sick” and “very experienced,” Dr. Higgins said, noting that approximately half of the patients had inadequate responses to prior biologics, and within this subgroup of inadequate responders, approximately two-thirds of the patients had received more than one prior biologic. According to Dr. Higgins, this helps explain why 12.3% of the patients in the placebo group discontinued therapy, compared with just 3.8% in the upadacitinib group – because most patients involved were “quite ill.”
At week 8, 26.1% of the patients in the upadacitinib group had achieved clinical remission, versus 4.8% of the patients given placebo (26.1% vs. 4.8%; P < .0001). Clinical response at week 2 followed a similar pattern (60.1% vs. 27.3%; P < .001), as did clinical response at week 8 (72.6% vs. 27.3%; P < .0001).
All other 8-week secondary endpoints also significantly favored upadacitinib, including endoscopic improvement (36.3% vs 7.4%), endoscopic remission (13.7% vs 1.3%), and histologic-endoscopic mucosal improvement (29.9% vs. 6.5%).
Serious and severe adverse events were more common in the placebo group, and patients in the placebo group more frequently discontinued therapy because of treatment-related adverse events. While rates of serious infection were similar between groups, patients taking upadacitinib had higher rates of neutropenia and lymphopenia.
Based on these findings, the investigators concluded that upadacitinib induction therapy is superior to placebo for clinical remission and clinical response regardless of previous treatment failure.
According to, of New York University Langone Health, the findings reflect a real-world setting and clinicians should take note of the rapid response observed with upadacitinib.
“This was a relatively sick group, so you know this reflects what we’re seeing in clinical practice,” Dr. Axelrad said in an interview. “Clinical response was detected as early week 2, and that’s extremely important to highlight, because a lot of our drugs that we have on the market – some of these biologics – may take a little time to work. Having a drug that can work fast and is effective is critical.”
Dr. Axelrad suggested that second-line JAK inhibitors like upadacitinib, which target JAK proteins more selectively than first-generation agents, may alleviate some lingering concerns about JAK inhibitor safety; still, optimal treatment sequencing remains unclear.
“With more selective inhibition, you’re getting less of that side-effect profile,” Dr. Axelrad said, noting that long-term data is needed to confirm this likelihood. “The real question moving forward is: Will upadacitinib replace first-generation JAK inhibitors as a category, or, because of the broader safety profile, will it come earlier in the positioning of where we put our drugs for colitis?”
Dr. Axelrad suggested that the answer may ultimately come from regulators, although patients could also guide decision-making.
“Oral drugs are a really important mode of administration that we’re missing for the moderate to severe group,” he said. “Should [further clinical trials] demonstrate superior safety to nonselective JAK inhibitors, upadacitinib could be a first-line option for patients who don’t want to be taking an infusion or injection, more especially so for those that are already biologically experienced, or need something fast.”
Siddharth Singh, MD, director of the IBD Center at the University of California, San Diego, called U-ACHIEVE a “pivotal trial” that demonstrated the “remarkable efficacy” of upadacitinib for moderate to severe ulcerative colitis; still, he noted that drug sequencing remains undetermined.
“It’s unclear whether or not it’ll be the best in class for JAK inhibitors right now,” Dr. Singh said in an interview. “A lot of that hinges on the safety of this drug. In terms of positioning, it depends on whether the [Food and Drug Administration] requires patients to have failed anti–[tumor necrosis factor] therapy before using this drug, like tofacitinib.”
That may depend on long-term data, he suggested.
“Right now, it is hard to comment on the relative safety of upadacitinib versus tofacitinib,” Dr. Singh said. “While the JAK1 selectivity may contribute to efficacy by allowing us to use a higher dose, it’s unclear whether the higher dose of this medication is any safer than tofacitinib. Longer term, 5- to 7-year registry studies of real-world data are warranted to examine risk of cardiovascular disease, thromboembolism, malignancy, and mortality with upadacitinib.
“How to sequence and position these therapies in real-world practice is a key question,” he concluded.
The study was supported by AbbVie. The investigators disclosed additional affiliations with Genentech, Ferring, AstraZeneca, and others. Dr. Axelrad has previously consulted for AbbVie. Dr. Singh has received research funding from AbbVie, Pfizer, and Janssen in the last 24 months, as well as personal fees from Pfizer for an ad hoc grant review.