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Introduction Guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, is highly efficacious in participants (pts) with Crohn’s disease (CD). Phase 3 studies (GALAXI 2, GALAXI 3, and GRAVITI) showed that GUS administered via intravenous (IV) or subcutaneous (SC) induction followed by SC maintenance has similar efficacy after induction and through week (W)48. We report GUS W96 efficacy data from the long-term extension (LTE) periods of these studies and safety data from W0 to W96.Methods The studies had double-blind, placebo-controlled, treat-through designs with blinding until the W48 database lock. GALAXI 2 and 3 evaluated IV GUS induction (200 mg at W0, W4, and W8) followed by SC maintenance (100 mg q8w or 200 mg q4w). GRAVITI assessed SC GUS induction (400 mg at W0, W4, and W8) and the same GUS maintenance regimens used in GALAXI. Pts entered the LTE receiving the treatment they received at W48. Between W52 and W80 (GALAXI only), pts on GUS 100 mg SC q8w who were not in clinical response received dose escalation to 200 mg SC q4w; pts on GUS 200mg SC q4w received a ‘sham’ adjustment to GUS 200 mg SC q4w. Efficacy analyses included all pts randomized at W0 with a Simple Endoscopic Activity Score for CD (SES-CD) ≥6 (≥4 for pts with isolated ileal disease) who received ≥1 study drug dose. Pts with missing data or who met treatment failure criteria were considered non-responders. As observed data are also presented. Safety analyses comprised all randomized pts who received study drug.Results Between W0 and W96, 127/582 pts (21.8%) from GALAXI 2 and 3 and 31/230 pts (13.5%) from GRAVITI discontinued treatment. Across studies, high rates of long-term endoscopic response, endoscopic remission, clinical remission, and deep remission were observed after treatment with both GUS doses. Respective W96 rates for IV vs SC induction were 44.1% vs 47.8% (100 mg SC q8w) and 44.6% vs 59.1% (200 mg SC q4w) for endoscopic response, 28.3% vs 38.3% (100 mg SC q8w) and 31.4% vs 47.0% (200 mg SC q4w) for endoscopic remission, 59.4% vs 62.6% (100 mg SC q8w) and 63.2% vs 71.3% (200 mg SC q4w) for clinical remission, and 26.2% vs 34.8% (100 mg SC q8w) and 29.4% vs 39.1% (200 mg SC q4w) for deep remission. Safety data through 2 years were comparable across studies and consistent with the safety profile of the label indications.Conclusions Long-term efficacy outcomes show the durability of GUS treatment in CD through 2 years across multiple studies. No new safety concerns were identified.