Final U-ACHIEVE analysis: Upadacitinib is well tolerated and maintains clinical remission in ulcerative colitis

In two identical double-blind randomized clinical trials (U-ACHIEVE induction and U-complete), patients with moderately to severely active ulcerative colitis (UC) and an inadequate response, loss of response, or intolerance to conventional or biologic treatments were studied. An 8-week double-blind induction treatment was performed with upadacitinib (Upadacitinib) 45 mg once daily. Compared with placebo, the proportion of patients achieving clinical remission at week 8 was significantly higher and was well tolerated.

In thePhase 3 U-ACHIEVE maintenance study, patients from U-ACHIEVE induction (n=319), U-ACHIEVE (n=341) and 2 681 patients in the phase b induction (n = 21) trial who had a clinical response to once-daily upadacitinib 45 mg were randomly assigned to once-daily placebo (n = 223), upadacitinib 15 mg (n = 225), or upapatinib 30 mg mg group (n=233), for 52 weeks. Participants who received at least one dose of study drug were included in the 8-week intention-to-treat efficacy population. In addition, 746 patients (552.9 patient-year exposure) achieved clinical remission after 8 weeks of treatment with upadatinib 45 mg once daily and were included in the 8-week induction remission safety population. The primary outcome was clinical remission according to the adapted Mayo score, defined as a stool frequency score of no more than 1 and no increase above baseline; a rectal bleeding score of zero; and an endoscopic score of no more than 1 and no friability.

Researchers reported that a significantly higher proportion of patients achieved clinical remission at week 52 in the 15 mg (40.4%) and 30 mg (53.6%) groups compared with the placebo group (10.8%). Similarly, 15 mg and 30 mg upadatinib group achieved endoscopic improvement (48.5% and 63.3% vs. 14.1%, respectively) and histological-endoscopic improvement (40.5% and 56% vs. 12.3%). Across all efficacy endpoints analyzed, results for upapatinib 30 mg once daily were numerically superior to upadacitinib 15 mg once daily.

According to the safety analysis, 9 patients who took placebo experienced worsening of ulcerative colitis.Two patients taking upadatinib 30 mg developed COVID-19 pneumonia and cryptococcal pneumonia. Patients in the treatment group experienced higher rates of exposure-adjusted events including herpes zoster, liver disease, elevated creatine phosphokinase, and neutropenia compared with placebo. Less than 1% of patients in the placebo group and the upatinib 30 mg group experienced a adjudicated major cardiovascular adverse event, and 1% of patients in both upatinib dose groups experienced a venous thromboembolic event. All of these events occurred in patients with known risk factors.

Both upadatinib maintenance doses were significantly more effective than placebo in achieving important clinical, endoscopic and histological outcomes while maintaining an acceptable safety profile in the entire trial population over 52 weeks with no new safety risks. In this analysis, the favorable benefit-risk profile for both maintenance doses was consistent with that observed in the preliminary analysis in a smaller patient population. According to the study results, key clinical, endoscopic and histological outcomes were achieved at maintenance doses of patinib compared with placebo in patients with moderate to severe ulcerative colitis, with no new safety risks reported.