Long-term upadacitinib treatment was linked to low rates of blood clots, major cardiovascular events, and cancer in patients with moderate to severe ulcerative colitis (UC) or Crohn’s disease (CD). However, shingles (herpes zoster) and some laboratory abnormalities occurred more often with upadacitinib than with placebo, according to an analysis of six clinical trials.
The safety analysis, published in Clinical Gastroenterology and Hepatology, combined data from three ulcerative colitis and three Crohn’s disease trials of the oral Janus kinase (JAK) inhibitor. During induction, 725 patients received placebo and 1,393 received upadacitinib 45 mg once daily. During maintenance and long-term follow-up, 468 received placebo, 471 received upadacitinib 15 mg, and 480 received 30 mg. Total exposure to the 15-mg and 30-mg doses reached 5,149 patient-years.
Senior author David T. Rubin, MD, of the University of Chicago Medicine Inflammatory Bowel Disease Center, and colleagues tracked side effects that occurred after patients received at least one study dose. Long-term event rates were reported per 100 patient-years. Safety outcomes included serious and opportunistic infections, shingles, gastrointestinal perforation, cancer, major cardiovascular events, blood clots, and laboratory abnormalities.
During induction, 61% of patients taking upadacitinib 45 mg experienced a side effect compared with 57% taking placebo. Serious side effects occurred in 6% of the upadacitinib group and 7% of the placebo group, and 4% vs. 6% stopped treatment because of side effects. No deaths occurred. Acne was more common with upadacitinib than placebo (6% vs. 1%), but most cases were mild.
Among patients who responded to induction and continued into maintenance or long-term follow-up, overall side effect rates were lower with upadacitinib than placebo. Serious side effects and side effects that led patients to stop treatment also occurred less often with both the 15-mg and 30-mg doses than with placebo.
Side effects of particular concern with JAK inhibitors remained uncommon. Blood clot rates were 0.3 and 0.4 events per 100 patient-years with upadacitinib 15 mg and 30 mg, respectively, with no events in the placebo group. Seven blood clots occurred with upadacitinib, mostly in patients with existing risk factors. Rates of major cardiovascular events and cancer were also low and generally similar across groups.
Shingles became more common as the upadacitinib dose increased. During maintenance and long-term follow-up, rates were 1.9 events per 100 patient-years with placebo, 3.9 with the 15-mg dose, and 6.6 with the 30-mg dose. Most cases were mild to moderate and occurred in patients who had not previously had shingles or been vaccinated against it. Rates were somewhat higher in patients with CD.
Upadacitinib was also associated with higher rates of neutropenia, lymphopenia, creatine phosphokinase elevation, and hepatic disorders. Most liver-related events were mild or moderate, were not serious, and did not lead patients to stop treatment. No cases of severe drug-related liver injury were identified.
Safety findings were generally similar in patients younger than 65 years and those aged 65 years or older, although few older patients were included. The study also included few patients with other health conditions, no patients older than 75 years, and shorter follow-up with placebo than with upadacitinib. The authors said these limitations may make the findings less applicable to broader patient populations and called for more long-term, real-world data.
“No new or unexpected safety risks were reported with [upadacitinib], suggesting an overall acceptable safety profile in patients with moderately to severely active UC and CD who are undergoing long-term therapy with [upadacitinib],” the authors concluded.
AbbVie funded and designed the trials, analyzed the data, and supported medical writing; investigators and the sponsor jointly collected and interpreted the data. Dr. Rubin and many co-authors reported financial relationships with AbbVie and other pharmaceutical companies; nine were AbbVie employees with potential stock or options, and one was employed by AbbVie during the analysis.
Expert Insight
GI & Hepatology News asked Jason Ken Hou, MD, MS, FACG, a gastroenterologist at Baylor College of Medicine, Houston, and medical director of IBD at the Michael E. DeBakey VA Medical Center, to weigh in on the study results.
Why do these findings matter?
Dr. Hou: This study is important as there have been potential safety concerns with the Janus kinase inhibitor class of medication due to prior data from tofacitinib regarding thrombosis and the upadacitinib regarding increased risk of shingles. Randomized trials are powered for efficacy and may miss subtle safety signals so combined safety analyses may uncover or highlight additional safety concerns. Randomized controlled trials are also helpful for safety analyses as there is a placebo group for comparison which is an advantage over observational studies.
How might the findings influence clinical practice?
Dr. Hou: The findings are encouraging that no new safety signals emerged with combined analyses.
Where are the knowledge gaps, and what still needs investigation?
Dr. Hou: Randomized controlled trials are too short and small to evaluate some risks, including risks of malignancy which require longer follow up and sample sizes.
Is there anything else you’d like to say about this work?
Dr. Hou: The study provides additional reassurance on the relative safety of upadacitinib for UC and CD. The risk of herpes zoster appears more pronounced at the 30 mg vs. 15 mg daily doses. Acne risk occurred across indications in induction, but the authors note the rate causing drug discontinuation were low. There were several lab abnormalities, including neutropenia and lymphopenia, and creatine kinase elevations that were noted to be higher than placebo, so lab monitoring is important for patients on upadacitinib. However, those abnormalities did not appear to be severe.
Dr. Hou was a site principal investigator for the phase 3 upadacitinib trials in UC and CD. He is also an associate editor for Clinical Gastroenterology and Hepatology.