Patients with ulcerative colitis who were treated with upadacitinib showed significant improvement in symptoms compared to placebo within days of starting treatment, according to results of a new study.
Immunosuppressants and biologics used to treat moderate to severe disease can vary in their response times from weeks to months, and some ambulatory patients fail to respond to these treatments, wrote Edward V. Loftus Jr., MD, of the Mayo Clinic, Rochester, Minn., and colleagues.
:The lack of effective, quick-acting therapies may lead patients to experience prolonged relapses, reduced quality of life, and a significant burden of illness," the researchers said.
Upadacitinib, an oral, once-daily reversible JAK inhibitor, is approved by the Food and Drug Administration for patients with moderate to severe ulcerative colitis (UC) who have not responded to at least one tumor necrosis factor (TNF) blocker, but the time frame for response to upadacitinib has not been well studied, they said.
In a study published online in Clinical Gastroenterology and Hepatology, the researchers reviewed data from two phase 3 randomized, placebo-controlled induction trials, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026), that assessed the safety and efficacy of a 45-mg daily dose of upadacitinib for managing symptoms of moderate to severe UC over an 8-week period.
The intent-to-treat analysis included 660 patients who had been randomized to received upadacitinib and 328 in the placebo group. Demographics were similar between the groups. Symptom improvement was based on changes in inflammatory markers high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP) measured at week 2. Quality of life was assessed at 2 and 8 weeks.
Between 1 and 3 days after starting treatment, significantly greater percentages of patients in the treatment arm achieved a reduction of at least 50% from baseline in hs-CRP (75.7% vs. 21.9%) and FCP (48.2% vs. 20.2%).
The significant differences in symptom improvement persisted for 14 days from the first dose.
Patients in the upadacitinib group also showed increased rates of clinical remission/response (26.9%/59.4%) based on Partial Mayo scores at week 2 compared with placebo patients (4.3%/22.3%). Treated patients showed significant improvements in quality of life at weeks 2 and 8.
In addition, patient-reported UC symptoms of stool frequency, rectal bleeding, abdominal pain, and bowel urgency improved significantly compared with placebo by day 3, the researchers noted. :In this study, upadacitinib led to absence of rectal bleeding by day 1 and absence of abdominal pain and bowel urgency by day 3 in a significant proportion of patients vs. placebo (all P < .05)," they said.
The findings were limited by the post hoc design, but reflect results of other studies, including those of the JAK inhibitor tofacitinib, the researchers noted. The results of the current study demonstrate the ability of upadacitinib to alleviate key UC symptoms as early as 1 day after the first dose, they concluded.
Need for Rapid Onset Treatment
A majority of biologics used to treat IBD take weeks to months to exert an effect, :so it is crucial that a drug with more rapid onset of action become available," Atsushi Sakuraba, MD, director of clinical trial/IBD research at the University of Chicago, said in an interview.
Sakuraba, who was not involved in the study, said he was surprised by the findings.
:It is amazing that upadacitinib started to show response in 1-3 days and showed superior rates of remission/response versus placebo by week 2," he said.
:Clinicians treating IBD patients should take the time to response into consideration, because it leads to rapid improvement in quality of life and reduced need for steroids," Sakuraba said. The current study findings need to be confirmed in real life studies, he cautioned.
Expanding Clinical Options
Jeffrey Berinstein, MD, of the University of Michigan, Ann Arbor, who was not involved with the study, said in an interview that he was not surprised by upadacitinib's quick action, which supports what he has seen in clinical practice. :We now have post hoc data from the phase 3, multicenter induction trials ... to provide us with hard evidence to support our observations," he noted.
The current study is important because many patients with UC can be very symptomatic, with rectal bleeding, diarrhea, urgency, and abdominal pain, he said in an interview.
:It is often critical to have a fast-acting medication to avoid worsening symptoms, hospitalization, and severe complications. This study shows that upadacitinib, a new oral small molecule that selectively inhibits JAK-1, works within 1 day to improve symptoms and within 2 weeks to improve CRP and fecal calprotectin," he said.
The takeaway message to clinicians is that upadacitinib is effective, relatively safe, and fast-acting option for patients with UC who have previously failed an anti-TNF agent, he said.
Challenges remain, however.
:Despite this exciting new therapeutic, there is still significant research needed to break our current therapeutic efficacy ceiling and get more IBD patients into a stable and durable remission," Berinstein said. :Additional research is needed to develop personalized treatment strategies to address the unique needs of individual patients and to guide optimal medical management."
Berinstein and his team are exploring the use of upadacitinib on the sickest IBD patients, :those admitted to the hospital with acute severe ulcerative colitis," he said. Emerging data from multiple academic centers suggest that :upadacitinib induction may be a viable treatment strategy for these very high-risk patients. Of course, large prospective trials will be needed to confirm this," he added.
The study was funded by AbbVie, which markets upadacitinib (Rinvoq). Lead author Loftus and several study authors disclosed financial relationships with AbbVie and other companies. Sakuraba and Berinstein reported having no relevant financial conflicts.
This article originally appeared in GI and Hepatology News.
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Cite this: Upadacitinib Curbs UC Symptoms From Day 1: Study - Medscape - Dec 19, 2022.