Phase 2b/3 QUASAR Program: Guselkumab for Induction and Maintenance Therapy in Moderate-to-Severe Ulcerative Colitis

Background: Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon’s mucosal surface, frequently accompanied by debilitating symptoms such as bloody diarrhea, urgency, and abdominal discomfort. Despite the availability of corticosteroids, immunosuppressants, and advanced biologic or small-molecule therapies, many patients still experience suboptimal outcomes. Targeting interleukin (IL)-23, a critical cytokine in the inflammatory cascade, has gained increasing attention. Guselkumab, a human IgG1 monoclonal antibody against the IL-23p19 subunit, has shown clinical promise in psoriasis, psoriatic arthritis, and Crohn’s disease. This article reports findings from the phase 2b/3 QUASAR clinical development program evaluating guselkumab in UC.

Objective: To assess the efficacy and safety of intravenous (IV) guselkumab induction therapy (200 mg every 4 weeks) compared to placebo, followed by subcutaneous (SC) maintenance regimens (200 mg every 4 weeks or 100 mg every 8 weeks) compared to placebo (withdrawal) in adults with moderately to severely active UC who had inadequate responses or intolerance to at least one conventional or advanced therapy.

Methods: In these double-blind, randomized, placebo-controlled studies within the QUASAR program, adults with a baseline modified Mayo (mMayo) score of 5–9 (which excludes the physician’s global assessment) and evidence of active UC underwent IV induction with either guselkumab or placebo at Weeks 0, 4, and 8. The primary endpoint of the induction trial was clinical remission at Week 12 in the primary analysis population (patients with mMayo score 5-9), defined by improved stool frequency, rectal bleeding, and endoscopic findings. Responders from both the phase 2b and phase 3 induction studies then entered the maintenance study, randomized to SC guselkumab (either 200 mg Q4W or 100 mg Q8W) or placebo (withdrawal, meaning patients who had previously responded to guselkumab). The primary endpoint for the maintenance phase was clinical remission at Week 44 in the primary analysis population. Key secondary outcomes included endoscopic improvement, histological remission, corticosteroid-free remission, and patient-reported measures.

Results: A total of 701 patients with a baseline mMayo score of 5-9 (primary analysis population) were evaluated in the phase 3 induction study. By Week 12, a higher proportion of those receiving IV guselkumab (23%) achieved clinical remission compared to placebo (8%; p<0.0001). Patients also demonstrated improvement in endoscopic outcomes and had early symptomatic relief (notably a reduction in rectal bleeding as early as Week 1). In the subsequent maintenance phase, 568 guselkumab induction responders from both phase 2b and phase 3 studies (primary analysis population) were randomized. At Week 44, clinical remission was significantly more frequent in patients receiving guselkumab SC (50% on 200 mg Q4W, 45% on 100 mg Q8W) vs 19% on placebo (both p<0.0001). Endoscopic and histological indices indicated improved mucosal healing with active therapy. Most patients in remission were free of corticosteroids, highlighting a significant steroid-sparing effect.

Conclusions: Guselkumab induction (200 mg IV every 4 weeks) followed by either of the two SC maintenance regimens (200 mg Q4W or 100 mg Q8W) demonstrated substantial efficacy in adults with moderate-to-severe UC, with improved clinical, endoscopic, and histological endpoints relative to placebo. No new safety concerns were observed compared to the known safety profile of guselkumab.

Implications for Practice: Guselkumab offers a new therapeutic option for UC, particularly for individuals who have not responded to, or could not tolerate, other treatments. The study suggests that guselkumab can be considered for both biologic-naive and biologic-experienced patients. As with any novel therapy, careful patient selection and close follow-up are advisable.

Study Strengths and Limitations: Strengths include the rigorous, global, phase 2b/3 design with objective assessments of clinical, endoscopic, and histological response. The large population permitted detailed subgroup analyses (e.g., efficacy was observed in both biologic-naive and biologic-experienced populations). Limitations include the exclusion of certain therapy-refractory cases and lack of active comparator arms. The randomized-withdrawal maintenance design means only induction responders were evaluated further, potentially enhancing observed effect sizes.

Future Research: Extended follow-up will elucidate the durability of remission beyond one year and clarify long-term safety considerations. Head-to-head trials against other IL-23 antagonists or advanced therapies could further guide treatment algorithms. Real-world evidence evaluating diverse populations will be instrumental in determining broader applicability.

Reference: Rubin DT, Allegretti JR, Panés J, Shipitofsky N, Yarandi SS, Huang K-HG, Germinaro M, Wilson R, Zhang H, Johanns J, Feagan BG, Hisamatsu T, Lichtenstein GR, Bressler B, Peyrin-Biroulet L, Sands BE, Dignass A; QUASAR Study Group. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. The Lancet. 2025;405(10472):33–49. DOI: http://doi.org/10.1016/S0140-6736(24)01927-5