Early Symptomatic Improvement With Guselkumab Induction Treatment in Moderately to Severely Active Ulcerative Colitis: Results From the Phase 3 QUASAR Study

Guselkumab is a human selective interleukin-23 (IL-23) p19 subunit antagonist approved for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis, and is currently under investigation in patients with ulcerative colitis (UC).¹ The QUASAR protocol is a phase 2b/3 clinical development program evaluating the safety and efficacy of 12 weeks of guselkumab in patients with moderately to severely active UC.² Patients enrolled in QUASAR had an inadequate response, loss of response, or intolerance to conventional therapies (corticosteroids and immunomodulators) and/or advanced therapies (tumor necrosis factor α [TNFα] antagonists, integrin receptor antagonists [vedolizumab], and/or Janus kinase [JAK] inhibitors [tofacitinib]). The phase 2b portion of this trial was previously reported, demonstrating the activity of guselkumab at week 12 in achieving clinical response and remission.³

At the American College of Gastroenterology (ACG) 2023 Annual Scientific Meeting, Lichtenstein and colleagues reported results from the phase 3 QUASAR study, focusing on the early onset of symptomatic improvement with guselkumab as induction therapy.⁴ Patients 18 years of age or older were enrolled in this phase 3 study. All patients had moderately to severely active UC, defined at baseline as a modified Mayo score of 5 to 9 by central review, with a Mayo rectal bleeding subscore (RBS) of at least 1 and a Mayo endoscopic subscore of at least 2. After screening, 701 patients were randomized 3:2 to treatment with either guselkumab (200 mg intravenously [IV]; n=421) or placebo (n=280) at weeks 0, 4, and 8. Concomitant treatment with conventional immunosuppressants, oral 5-aminosalicylic compounds, and corticosteroids (up to 20 mg/day prednisone or equivalent) was allowed. Randomization was stratified by a history of inadequate response or intolerance to advanced therapy, region, and concomitant use of corticosteroids at baseline. Patients underwent an endoscopy at baseline and again at week 12. Symptomatic remission at weeks 2, 4, and 12 were major secondary endpoints.

Overall, baseline characteristics were well balanced between the guselkumab and placebo arms. In the overall population, the mean age was 40.5 years (SD, 13.72), and 56.9% were male. Patients had a mean duration of UC disease of 7.52 years (SD, 7.282), and 47.8% had extensive disease. The mean modified Mayo score was 6.9 (SD, 1.10), and most patients (64.5%) had a severe modified Mayo score of 7 to 9; 67.9% of patients had a severe Mayo endoscopic subscore of 3. At baseline, 72.5%, 43.1%, and 20.8% were using oral aminosalicylates, oral corticosteroids, and immunosuppressants, respectively. About one-half of patients (49.1%) had a history of inadequate response or intolerance to advanced therapies. Of these 344 patients, most had a history of inadequate response or intolerance to TNFα antagonists (87.5%), followed by integrin receptor antagonists (54.1%), and JAK inhibitors (18.0%). A total of 163 patients (47.4%) had a history of inadequate response or intolerance to 2 or more advanced therapy classes.

Symptomatic response was defined as a decrease from induction baseline in the symptomatic Mayo score by at least 30% and at least 1 point, with a 1 or greater point decrease from baseline in the RBS or an RBS of 0 or 1. The symptomatic Mayo score was defined as the sum of the stool frequency and the RBS. By week 12, 71.7% of guselkumab-treated patients had achieved a symptomatic response, compared with 35.0% of placebo-treated patients (P<.001) (Figure 1). This improvement in symptomatic response was evident as early as week 1 and 2, with a statistically significant improvement with guselkumab vs placebo (week 1: 28.3% vs 18.9%, P<.01; week 2: 34.0% vs 23.6%; P<.01). Symptomatic remission was defined as a stool frequency sub-score of 0 or 1 and not increased from baseline, and an RBS of 0. A statistically significant difference in the proportion of patients who achieved symptomatic remission in the guselkumab arm vs the placebo arm was observed by week 4 (22.6% vs 12.9%; P<.001) and maintained through week 12 (49.9% vs 20.7%; P<.001). Both stool frequency and rectal bleeding outcomes were improved with guselkumab compared with placebo as early as week 1 and increased over time. At week 12, significantly more patients in the guselkumab arm had achieved a stool frequency subscore (SFS) of 0 or 1 (60.1% vs 31.8%, P<.001) and there was also a significant improvement in the absolute stool number between the guselkumab and placebo arms (-3.15 vs -1.36). At week 12, significantly more patients in the guselkumab arm had achieved an RBS of 0 (64.6% vs 28.6%; P<.001), and there was also a significant improvement in the absolute RBS (-1.2 vs -0.6; P<.001).

Figure 1.

Symptomatic outcomes of patients with moderately to severely active ulcerative colitis who received guselkumab through week 12 from the QUASAR phase 3 induction study.

^aA decrease from induction baseline in the symptomatic Mayo score by ≥30% and ≥1 point, with either a ≥1 point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. The symptomatic Mayo score was defined as the sum of the stool frequency and the rectal bleeding subscores.

^bA stool frequency subscore of 0 or 1 and not increased from baseline, and a rectal bleeding subscore of 0. GUS, guselkumab; IV, intravenous; PBO, placebo.

Adapted from Lichtenstein et al. Abstract 34. Presented at: ACG 2023; October 20-25, 2023; Vancouver, Canada.⁴

The study investigators concluded that these outcomes were clinically relevant in this patient population, showing a relatively rapid onset of benefit with guselkumab induction therapy in patients with refractory moderately to severely active UC.