Guselkumab studied as investigational option in Crohn's disease: phase 3 head-to-head results.

Evidence before this study

We surveyed the evidence base for biological therapies in Crohn's disease, searching PubMed for articles published in English between database inception and Nov 15, 2024, using the following search terms: “Crohn's disease”, “biologic therapy”, “biological therapy”, “anti-integrin”, and “selective Janus kinase inhibitor”. To date, most trials assessing the efficacy of maintenance therapy with biological agents in patients with Crohn's disease did not include statistically robust, head-to-head comparisons with established therapies. Additionally, most trials used designs (eg, randomised withdrawal) that selected only participants with a response to induction therapy for the evaluation of maintenance therapy, making it difficult to apply their results to clinical practice. Inadequate response, loss of response over time, and discontinuation due to side-effects are common with available therapies for Crohn's disease. Guselkumab, an inhibitor of the p-19 subunit of IL-23, was approved in 2024 for the treatment of ulcerative colitis. In a phase 2 study enrolling participants with moderately to severely active Crohn's disease, induction with intravenous guselkumab followed by maintenance therapy with subcutaneous guselkumab for 48 weeks was associated with high rates of clinical and endoscopic efficacy and had an acceptable safety profile.

Added value of this study

GALAXI-2 and GALAXI-3 were two identically designed, phase 3, randomised, double-blind, triple-dummy, registrational trials with head-to-head comparisons with an active comparator (ustekinumab) and a placebo in the treat-through design. These studies provide consistent evidence of the long-term efficacy and safety of guselkumab in adults with moderately to severely active Crohn's disease. Endpoints were assessed at the participant level, adding to the robustness of the results. Both guselkumab dose regimens (intravenous induction with 200 mg every 4 weeks followed by subcutaneous maintenance with either 100 mg every 8 weeks or 200 mg every 4 weeks) showed efficacy at week 48 and provided greater improvements than did ustekinumab for endpoints including an objective endoscopic evaluation. The benefits of guselkumab were also evident among participants who were naive to biological therapy, and among those with a history of intolerance or inadequate response to biological therapy, a difficult-to-treat subpopulation. The use of a treat-through study design, in which clinical outcomes at a specific timepoint were not a prerequisite for maintenance therapy, more closely mimicked clinical practice than previous studies. Importantly, this study design also showed that a substantial proportion of participants without a clinical response after induction improved with subcutaneous guselkumab treatment. Guselkumab was well tolerated in participants with Crohn's disease, showing a safety profile consistent with its approved uses in patients with ulcerative colitis, plaque psoriasis, and psoriatic arthritis.

Implications of all the available evidence

GALAXI-2 and GALAXI-3 are the first registrational studies of an inhibitor of the p-19 subunit of IL-23 with a double-blind, triple-dummy design to show head-to-head superiority to ustekinumab in participants with moderately to severely active Crohn's disease, regardless of their previous history with biological therapy. In the prespecified pooled analyses, guselkumab was superior to ustekinumab for endpoints incorporating an objective endoscopic outcome, in which endoscopic response is integral to long-term disease control and aligned with treatment targets of the consensus of Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II). Superiority was also shown for composite endpoints that included both symptom and endoscopic measures in the same participant, such as deep remission. Other head-to-head trials in patients with Crohn's disease comparing inhibitors of the p-19 subunit of IL-23 with ustekinumab either did not show superiority to ustekinumab (ie, mirikizumab in the VIVID-1 study) or used an open-label design and were conducted in participants with previous inadequate response or intolerance to TNF antagonists only (ie, rizankizumab in the SEQUENCE study). Overall, based on the observed benefit and favourable safety profile of guselkumab, the results of GALAXI-2 and GALAXI-3— in particular, the head-to-head comparison with ustekinumab, a standard of care in patients with moderate to severe Crohn's disease—could position guselkumab as a first-line or second-line option in this patient group.

Source: The Lancet