Chief of the Digestive Disease Institute
Cleveland Clinic, Ohio
This month in The Regueiro Report, I discuss two studies, the first of which—the report of the phase 3 VIVID-1 trial—I am the lead author. In the trial, we found that mirikizumab (Omvoh, Lilly) was more effective than placebo in reducing fatigue in people with moderate to severe Crohn’s disease.
This is important because fatigue is a common symptom for individuals with inflammatory bowel disease that significantly affects their quality of life. We focused on CD in this study, but fatigue also is common in ulcerative colitis. This was a large prospective trial in which fatigue was an important secondary end point that was prospectively measured. This is unique in that many other IBD studies have evaluated fatigue in a post hoc fashion.
There’s often not a good explanation for fatigue in IBD. While it can be associated with depression, anemia and IBD activity, even people in remission who are not depressed or anemic report fatigue. We hypothesize that there may be a cytokine-mediated aspect to fatigue, that is, immune chemicals in the body are causing people with IBD to experience fatigue. This has not been proved, was not part of the study and remains an important, open question.
Compared with blood-based biomarkers or objective outcomes to assess clinical or endoscopic remission, measuring fatigue is inherently subjective. In this study, we used a validated self-reported fatigue outcome called FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue). This is a Likert scale in which people quantify their fatigue, from “not at all” to “very much,” with higher scores indicating less fatigue.
We prospectively compared mirikizumab with placebo to assess which strategy was better at reducing fatigue over time, and mirikizumab outperformed placebo in this respect. Prior data from VIVID-1 showed that mirikizumab resulted in and maintained symptom improvement as well as clinical and endoscopic remission in people with CD.
Although we found that mirikizumab was better at lowering fatigue, we cannot say that only mirikizumab can produce this result or that this medication’s mechanism of action is somehow specific to improving symptoms of fatigue, as other advanced IBD therapy studies also have reported improved fatigue.
This month’s other study assesses the long-term efficacy of upadacitinib (Rinvoq, AbbVie) in individuals with moderate to severe UC by assessing clinical and endoscopic remission rates up to three years after treatment initiation. This is an interim analysis of U-ACTIVATE, an ongoing long-term extension study of upadacitinib use in UC.
The investigators found strong, sustained clinical and endoscopic remission rates at three years, with no new safety signals.
Three years of clinical trial follow-up is hard to achieve; study participants may move, for example, or simply opt out of continued participation. The longitudinal data from U-ACTIVATE are impressive in the efficacy, safety and durability end points. And clinically, the study demonstrates that most patients with UC who are in remission after the first year on upadacitinib will remain in remission.
Historically, IBD has a long history of therapies that work well for the first year, after which there is a precipitous drop-off in remission rates. Given that history, it is great to see evidence that one of our advanced therapies provides sustained benefit through three years.
Impact of Mirikizumab on Fatigue in CD
J Crohns Colitis 2025;19(7):jjaf100
Of the 778 adults with moderate to severe CD included in VIVID-1, 579 received mirikizumab and 199 received placebo. All had tried at least one biologic agent or conventional therapy without success. Baseline enrollment showed a strong association between depressive symptoms and greater feelings of fatigue.
By week 12, patients in the placebo group had a FACIT-Fatigue score improvement of 2.64, compared with 5.86 in the mirikizumab arm (P=0.000005). At week 52, scores were 3.08 for placebo and 7.47 for mirikizumab (P<0.000001).
Long-Term Efficacy and Safety of Upadacitinib in UC
Lancet Gastroenterol Hepatol 2025;10(6):507-519
Of 369 adults with UC who received upadacitinib in the long-term extension phase of the U-ACTIVATE trial, 142 started with 15 mg of upadacitinib and 227 began with 30 mg of upadacitinib. All participants in the study had achieved clinical remission by week 52 in the initial study, U-ACHIEVE. Over the next 96 weeks, most participants remained in U-ACTIVATE, but there was some attrition.
By week 96 of continued use of upadacitinib, 69 of 91 people (76%) who took 15 mg of upadacitinib were in clinical remission, as were 104 of 141 (74%) taking 30 mg of upadacitinib.
Most people who began U-ACTIVATE in endoscopic remission maintained it by week 96, which includes 20 of the 31 patients (65%) who took 15 mg of upadacitinib and 37 of the 51 (73%) who took 30 mg.
This article is from the September 2025 print issue.