AbbVie's Risankizumab and Upadacitinib Show Promise in Phase 3 IBD Trials Published in The Lancet
核心洞察
AbbVie (搜索) announced The Lancet published results from three pivotal Phase 3 trials evaluating risankizumab (SKYRIZI) in moderately to severely active Crohn's disease (搜索) patients who had inadequate response to conventional or biologic therapy.
The ADVANCE and MOTIVATE induction studies and FORTIFY maintenance study evaluated clinical remission and endoscopic response with risankizumab versus placebo over 12 weeks and 52 weeks respectively.
Simultaneously, The Lancet published results from three Phase 3 trials of upadacitinib (RINVOQ) in ulcerative colitis (搜索), including U-ACHIEVE induction, U-ACCOMPLISH, and U-ACHIEVE maintenance studies.
AbbVie (搜索) announced that The Lancet has published results from six pivotal Phase 3 clinical trials evaluating two of its investigational therapies for inflammatory bowel diseases. The publications include data on risankizumab (SKYRIZI) for Crohn's disease (搜索) and upadacitinib (RINVOQ) for ulcerative colitis (搜索), representing significant developments in the treatment landscape for these chronic inflammatory conditions.
Risankizumab Phase 3 Program in Crohn's Disease
The Lancet published results from three Phase 3 studies—ADVANCE, MOTIVATE (induction studies) and FORTIFY (maintenance study)—evaluating risankizumab in patients with moderately to severely active Crohn's disease (搜索) who had inadequate response, lost response or were intolerant to conventional or biologic therapy.
The ADVANCE and MOTIVATE studies are multicenter, randomized, double-blind, placebo-controlled induction studies designed to evaluate the efficacy and safety of two doses of risankizumab, 600 mg and 1200 mg, compared to placebo over 12 weeks. The primary endpoints were achievement of clinical remission and endoscopic response at week 12. Clinical remission was measured by PRO-2 for the outside U.S. protocol (daily stool frequency and abdominal pain score) and by CDAI for the U.S. protocol (CDAI score less than 150). Endoscopic response was defined as a decrease in SES-CD of greater than 50 percent from baseline.
The ADVANCE study included a mixed population of patients who had responded inadequately or were intolerant to conventional and/or biologic therapy, while the MOTIVATE study specifically evaluated patients who had responded inadequately or were intolerant to biologic therapy.
The FORTIFY maintenance study evaluated risankizumab 180 mg and 360 mg as maintenance therapy versus withdrawal over 52 weeks in patients who responded to risankizumab induction treatment. The co-primary endpoints were achievement of endoscopic response and clinical remission at week 52.
Upadacitinib Phase 3 Program in Ulcerative Colitis
The Lancet also published results from three Phase 3 studies—U-ACHIEVE (induction), U-ACCOMPLISH and U-ACHIEVE (maintenance)—evaluating upadacitinib in patients with moderately to severely active ulcerative colitis (搜索) who had inadequate response, lost response or were intolerant to conventional or biologic therapy.
The studies evaluated the efficacy and safety of upadacitinib 45 mg once daily as induction therapy, and upadacitinib 15 mg and 30 mg once daily as maintenance therapy. The trials assessed clinical remission and endoscopic improvement with oral upadacitinib versus placebo over 8 weeks and 52 weeks, respectively.
Disease Burden and Unmet Medical Need
Crohn's disease (搜索) is a chronic, systemic disease that manifests as inflammation within the gastrointestinal tract, causing persistent diarrhea and abdominal pain. It is a progressive disease, meaning it gets worse over time in a substantial proportion of patients. The unpredictable signs and symptoms cause significant burden on patients—physically, emotionally and economically.
Ulcerative colitis (搜索) is a chronic, idiopathic, immune-mediated inflammatory bowel disease (搜索) of the large intestine that causes continuous mucosal inflammation extending from the rectum to the more proximal colon. The hallmark symptoms include rectal bleeding, abdominal pain, bloody diarrhea, tenesmus, urgency and fecal incontinence. The severity of symptoms and unpredictability of disease course can lead to substantial burden and often disability among those living with the disease.
Mechanisms of Action
Risankizumab is an interleukin-23 (IL-23 (搜索)) inhibitor that selectively blocks IL-23 by binding to its p19 subunit (搜索). IL-23, a cytokine involved in inflammatory processes, is thought to be linked to a number of chronic immune-mediated diseases, including Crohn's disease (搜索).
Upadacitinib is a selective and reversible JAK inhibitor discovered and developed by AbbVie (搜索) scientists. Based on enzymatic and cellular assays, upadacitinib demonstrated greater inhibitory potency for JAK-1 (搜索) versus JAK-2, JAK-3, and TYK-2, though the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known.
Regulatory Status
The use of risankizumab for Crohn's disease (搜索) is not approved and its safety and efficacy remain under regulatory review. Similarly, the use of upadacitinib for ulcerative colitis (搜索) is not approved in the European Union and its safety and efficacy remain under review by global health authorities.
Data from these three studies formed the basis of AbbVie (搜索)'s applications for approval by global health authorities for both indications. The company previously announced topline results from these trials between December 2020 and June 2021.