Efficacy and safety of subcutaneous guselkumab induction therapy in participants with moderately to severely active ulcerative colitis (ASTRO): a double-blind, treat-through, randomised, placebo-controlled, phase 3 trial

Abstract

Background: Approved IL-23p19 subunit inhibitors, including guselkumab, require intravenous induction dosing in patients with ulcerative colitis. We aimed to evaluate the efficacy and safety of subcutaneous guselkumab induction in adults with moderately to severely active ulcerative colitis.

Methods: The ASTRO double-blind, treat-through, randomised, placebo-controlled, phase 3 trial enrolled adults (≥18 years) at 153 sites (community centres or hospitals) in 25 countries with moderately to severely active ulcerative colitis (modified Mayo score 5-9 with a Mayo endoscopic subscore [MES] ≥2 and a Mayo rectal bleeding subscore [RBS] ≥1) and current or history of inadequate response or intolerance to corticosteroids, azathioprine, 6-mercaptopurine, biologics, JAK inhibitors, or sphingosine 1-phosphate receptor (S1P) inhibitors or a history of corticosteroid dependence. By permuted blocks and stratified by inadequate response or intolerance to biologics, JAK inhibitors, or S1P inhibitors (yes/no) and baseline MES (2 or 3), eligible participants were randomly assigned (1:1:1) to receive either subcutaneous guselkumab 400 mg at weeks 0, 4, and 8 followed by 100 mg every 8 weeks (400/100 mg group), subcutaneous guselkumab 400 mg at weeks 0, 4, and 8 followed by 200 mg every 4 weeks (400/200 mg group), or matched subcutaneous placebo. Investigators, study-site personnel, and participants were masked to treatment assignment. Participants who met rescue criteria at week 16 received subcutaneous guselkumab 400 mg at weeks 16, 20, and 24 followed by 100 mg every 8 weeks (placebo group) or continued their assigned guselkumab treatment (sham rescue). The primary outcome of clinical remission at week 12 (defined as Mayo stool frequency subscore of 0 or 1 and not increased from baseline, Mayo RBS of 0, and MES of 0, or 1 with no friability) was assessed among all participants who were randomly assigned and received at least one dose of study drug according to the treatment group to which they were assigned. Safety was assessed until week 24 among all participants who were randomly assigned and received at least one dose of study drug according to the treatment they received. This trial is registered with ClinicalTrials.gov, NCT05528510, and is ongoing.

Findings: Between Sept 13, 2022, and April 2, 2024, 651 participants were screened for eligibility and 418 participants were randomly assigned to the guselkumab 400/100 mg group (n=139), the guselkumab 400/200 mg group (n=140), and the placebo group (n=139). Mean age was 41·7 years (SD 14·2), 256 (61%) of 418 participants were male, and 162 (39%) were female. Mean ulcerative colitis duration was 7·6 years (SD 6·7) and mean modified Mayo score was 6·7 (1·2). A significantly greater proportion of participants receiving guselkumab 400 mg induction versus placebo had clinical remission at week 12 (77 [28%] of 279 vs nine [6%] of 139; adjusted treatment difference 21 percentage points, 95% CI 14-28; p<0·0001). At week 24, 49 (35%) participants in the guselkumab 400/100 mg group, 51 (36%) in the guselkumab 400/200 mg group, and 13 (9%) in the placebo group were in clinical remission (the difference between both guselkumab groups and placebo was statistically significant). The frequencies of adverse events in the guselkumab groups (74 [53%] of 139 for 400/100 mg and 85 [61%] of 140 for 400/200 mg) were similar to that in the placebo group (91 [65%] of 139). There were no treatment-related deaths, and no new safety concerns were identified. The most frequently reported adverse events were worsening of ulcerative colitis (14 [10%] in the 400/100 mg group, nine [6%] in the 400/200 mg group, and 29 [21%] in the placebo group), arthralgia (11 [8%], seven [5%], and three [2%]), and upper respiratory tract infection (ten [7%], five [4%], and nine [6%]). Serious adverse events occurred in five (4%) participants in the 400/100 mg group, six (4%) in the 400/200 mg group, and 17 (12%) in the placebo group.

Interpretation: Subcutaneous guselkumab induction and maintenance was safe and efficacious for 24 weeks in participants with moderately to severely active ulcerative colitis, establishing a fully subcutaneous guselkumab regimen as a treatment option in this patient population.

Funding: Johnson & Johnson.