乌帕替尼治疗克罗恩病可改善其临床和内镜下疗效

Introduction: Using upadacitinib to treat Crohn's disease can improve its clinical and endoscopic efficacy

On February 24, 2022, AbbVie Pharmaceuticals announced the main results of the U-EXCEL Phase 3 induction study, which showed that upadacitinib achieved the primary endpoints of clinical remission and endoscopic remission at week 12. The dosage was 45 mg once daily. U-EXCEL is a Phase 3 induction study designed to evaluate the safety and efficacy of upadatinib in adult patients with moderate to severe Crohn's disease who have had an inadequate response to or are intolerant to conventional or biologic therapies.

"The results of this study reaffirm the U-EXCEED data and demonstrate the potential impact upadatinib may have on clinical and endoscopic outcomes in patients with moderate to severe Crohn's disease," said Dr. Michael Severino, vice chairman and president of AbbVie. "Our decades-long collaboration with the Society of Gastroenterology demonstrates AbbVie's commitment to discovering and developing multiple treatment options for patients with inflammatory bowel disease."

U-EXCEL and U-EXCEED have the same primary endpoint and key secondary endpoints, with clinical response measured by the Crohn's Disease Activity Index (CDAI) and patient-reported stool frequency/abdominal pain symptoms (SF/AP). According to the Crohn's Disease Activity Index, a significantly higher proportion of patients who received upadatinib (45 mg daily) induction therapy achieved clinical remission at week 12 compared with placebo (49% vs 29%; p < 0.0001). The SF/AP report showed similar results (51% in the upadacitinib group vs. 22% in the placebo group; p < 0.0001). At Week 12, a significantly higher proportion of patients receiving upadatinib 45 mg achieved endoscopic response compared with placebo (46% vs. 13%; p < 0.0001).

Consistent with the results of the U-EXCEED induction study, the rate of steroid-free clinical remission at week 12 was significantly higher in the group receiving upadatinib (45 mg) compared with the placebo group. In addition, a higher proportion of patients achieved both early symptom improvement as measured by CR-100 (defined as a ≥100-point reduction in CDAI from baseline) and clinical remission at week four in the upadacitinib arm.

"This study is impressive in achieving meaningful results in patients with moderate to severe Crohn's disease who have had an inadequate response to immunosuppressants or biologics," said Edward V. Loftus Jr., MD, professor of medicine in the Department of Gastroenterology and Hepatology at the Mayo Clinic in Rochester. "Upadatinib may help treat patients who are unable to control their disease, including symptoms and intestinal inflammation, despite conventional or biologic treatment options."

During the 12-week double-blind, placebo-controlled period, the safety profile of upadatinib (dose 45 mg) was consistent with that observed in previous studies, and no new safety risks were observed. The most common adverse events in the upadacitinib group were acne and anemia. Serious adverse events occurred in 6.9% of patients in the upadacitinib group and 6.8% of patients in the placebo group. The rate of serious infection was 1.1% in the upadacitinib group and 1.7% in the placebo group. In the upadatinib group, the proportion of patients who developed herpes zoster was 2.9%, and all cases were non-severe. There were no confirmed cases of gastrointestinal perforation or death during the placebo-controlled period. One major adverse cardiovascular event (MACE) was reported in the placebo group.

Patients who received upadatinib (45 mg) but did not achieve clinical remission at week 12 were included in another treatment group with upadatinib (30 mg), which was also treated for 12 weeks. One patient in this group died of COVID-19. Patients who received placebo but did not achieve clinical response at week 12 were enrolled in a separate treatment group receiving upadatinib (45 mg). One case of gastrointestinal perforation occurred among all patients.

During the U-EXCEL trial, there were no treatment-emergent cases of major adverse cardiovascular events, malignancies, or venous thromboembolic events among patients treated with upadacitinib.

Full results from the U-EXCEL study will be presented at an upcoming medical meeting and published in a peer-reviewed medical journal. Key results from Phase 3 of the first induction study, U-EXCEED, were announced in December 2021, and maintenance studies for this study are ongoing. Upadatinib is not approved for the treatment of Crohn's disease, and its safety and effectiveness have not been evaluated by regulatory authorities.

On February 24, 2022, the China Food and Drug Administration approved the marketing of AbbVie’s upadatinib extended-release tablets for the treatment of moderate to severe atopic dermatitis in adults and adolescents aged 12 years and above who are suitable for systemic treatment. In August 2019, the drug was approved for the treatment of rheumatoid arthritis in the United States, and was subsequently approved in Europe and Japan. It is worth mentioning that in August 2021, upadatinib expanded its new indications for atopic dermatitis in Europe and became the first JAK inhibitor approved for the treatment of atopic dermatitis in the EU.