Subcutaneous guselkumab shows strong remission in phase 3 UC trial

Subcutaneous guselkumab improved clinical, endoscopic, and histological outcomes in patients with moderately to severely active ulcerative colitis, according to results from the phase 3 ASTRO trial. The findings, published in The Lancet Gastroenterology & Hepatology, address a practical limitation of existing interleukin (IL)-23 inhibitors, which typically require intravenous induction before subcutaneous maintenance.

ASTRO was a double-blind, randomized, placebo-controlled, treat-through phase 3 trial conducted at 153 sites in 25 countries. The study enrolled adults with moderately to severely active ulcerative colitis (UC) (modified Mayo score 5–9) who had an inadequate response, intolerance, or dependence on conventional therapies or advanced treatments, including biologics, JAK inhibitors, or sphingosine 1-phosphate receptor modulators. A total of 418 participants were randomized to receive subcutaneous guselkumab (400 mg at weeks 0, 4, and 8 followed by maintenance dosing) or placebo. The primary endpoint was clinical remission at week 12, with outcomes assessed through week 24.

“ASTRO shows that fully subcutaneous guselkumab induction achieved significantly higher week-12 clinical remission (28% vs 6%), endoscopic improvement (37% vs 13%), and histo-endoscopic mucosal improvement (30% vs 11%)," said corresponding author Millie Long, MD, MPH, in an interview with GI & Hepatology News. "In addition, ASTRO demonstrates sustained advantages across week-24 endpoints vs placebo, confirming that IL-23 blockade is sufficient to rapidly and durably control mucosal inflammation in moderate–severe UC. These data independently replicate and extend the prior QUASAR IV-induction findings. Targeting IL-23p19 with a dual-acting agent like guselkumab yields deep molecular, histologic, and clinical remission.”

By week 24, adverse event rates were similar or lower in the guselkumab groups compared with placebo (53%–61% vs 65%), and serious adverse events occurred in 4% of guselkumab-treated patients versus 12% in the placebo group. The most commonly reported events were worsening ulcerative colitis, arthralgia, and upper respiratory tract infection. No new safety concerns were identified, and serious infections were infrequent.

“Guselkumab’s safety profile is at least as favorable — and in several domains potentially better — than current biologics, particularly compared with anti-TNFs (infection risk) and JAK inhibitors (potential for VTE, serious infection),” said Dr. Long, of the Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, NC. “It closely resembles the strong safety profile seen with the other IL-23p19 inhibitors. There is also minimal immunogenicity, thus no concomitant immunomodulators are required. Clinicians should consider the excellent safety, efficacy, and patient preference for modality of delivery when selecting patients for this therapy.”

The study is the first to demonstrate that an IL-23 inhibitor can be administered entirely subcutaneously for both induction and maintenance in ulcerative colitis. This may reduce reliance on infusion-based care and offer greater flexibility for patients and health care systems. The findings also support the role of IL-23 as a central pathway in ulcerative colitis pathogenesis and reinforce the therapeutic potential of IL-23p19 inhibition.

Looking ahead, Dr. Long explained these results may influence treatment sequencing in ulcerative colitis as therapeutic options continue to expand. “Guselkumab is one of the safest long-term advanced therapies for UC with strong evidence of achieving and maintaining deep remission. The fully subcutaneous regimen also enhances access and adherence. From a treatment sequencing perspective, I suspect that IL-23 agents will move earlier in the therapeutic algorithm for UC. Guselkumab provides an excellent choice for patients and clinicians where safety, efficacy, and convenience are priorities.”

The authors noted that the study excluded patients previously treated with IL-12 or IL-23 inhibitors, which may limit generalizability to this population. In addition, histological outcomes were not assessed at week 24, and placebo-treated patients were eligible for rescue therapy at week 16, which may affect longer-term comparisons with placebo.

The study was funded by Johnson & Johnson. Several authors reported financial relationships with industry, including consulting fees, research support, or employment with the sponsor. Full disclosures are detailed in the published findings.