S1445 Efficacy of Guselkumab vs Placebo in Crohn’s Disease Based on Prior Response/Exposure to Biologic Therapy: Results of the GALAXI 2 and 3 Phase 3 Studies

Introduction: GALAXI 2 & 3 are identically designed 48-week, randomized, double-blind, double-dummy, placebo (PBO)- and active-comparator, treat-through registrational trials assessing the efficacy and safety of intravenous (IV) induction and subcutaneous (SC) maintenance therapy with guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, in participants (pts) with moderately to severely active Crohn’s disease (CD). Primary results of each study were previously reported; here we explore the impact of biologic therapy exposure on efficacy outcomes with GUS compared to PBO in the pooled GALAXI 2 & 3 dataset. Methods: Patients with inadequate response or intolerance to conventional therapy or biologic therapy (BIO-ir), active CD (CDAI 220–450 + mean daily SF >3 or AP >1), and SES-CD≥6 (≥4 for isolated ileal disease) were randomly assigned 2:2:2:1 at week (Wk) 0 to GUS 200mg IV every 4 weeks (x3)→100mg SC every 8 weeks, GUS 200mg IV every 4 weeks (x3)→200mg SC every 4 weeks, UST IV→SC, or PBO. In each trial, the composite co-primary endpoints were 1) clinical response at Wk12 and clinical remission at Wk48, and 2) clinical response at Wk12 and endoscopic response at Wk48, comparing each GUS regimen to PBO. Major secondary endpoints included clinical remission at Wk12 and endoscopic response at Wk12. Analyses of BIO-ir and BIO-naïve subgroups in the individual trials were prespecified; pooled analyses were performed post hoc. Results: In the pooled dataset, 52% (378/730) of pts randomized to PBO or GUS had a prior history of BIO-ir and 42% (305/730) were BIO-naïve (6% [47/730] had prior exposure to biologics but no documented failure). At Wk12, GUS achieved higher rates of clinical remission and endoscopic response compared to PBO in the overall population and BIO-ir and BIO-naïve subgroups (Table 1). For the composite co-primary endpoints, both GUS regimens also achieved higher rates of 1) clinical response at Wk12 and clinical remission at Wk48 and 2) clinical response at Wk12 and endoscopic response at Wk48 compared to PBO in the overall population and BIO-ir and BIO-naïve subgroups (Figure 1). Conclusion: In pooled analyses of the double-blind GALAXI 2 & 3 trials, GUS was efficacious versus PBO in pts with CD regardless of prior biologic therapy exposure in both short-term (Wk12) endpoints and long-term (Wk12 and Wk48) composite endpoints.Figure 1.: Efficacy of guselkumab (GUS) and placebo (PBO) for long-term (Wk 12 and Wk 48) clinical and endoscopic endpoints in all participants and BIO-ir and BIO-naïve subgroups in the pooled GALAXI 2 & 3 dataset. Table 1. - Efficacy of guselkumab (GUS) and placebo (PBO) for short-term clinical and endoscopic endpoints in all participants and BIO-ir and BIO-naïve subgroups in the pooled GALAXI 2 & 3 dataset Overall population Participants with a history of inadequate response or intolerance to at least 1 prior biologica (BIO-ir) Participants with no history of exposure to biologicsa (BIO-naïve) PBON=148 GUS 200mg IV combinedb N=582 PBON=78 GUS 200mg IV combinedb N=300 PBON=61 GUS 200mg IV combinedb N=244 Clinical remission at Wk12 28 (18.9%) 274 (47.1%) ∆ 28.0% P < .001* 15 (19.2%) 138 (46.0%) ∆ 26.9% P < .001* 10 (16.4%) 121 (49.6%) ∆ 32.1% P < .001* Endoscopic response at Wk12 18 (12.2%) 274 (47.1%) ∆ 28.0% P < .001* 5 (6.4%) 87 (29.0%) ∆ 22.6% P < .001* 11 (18.0%) 113 (46.3%) ∆ 27.7% P < .001* Data are presented as n (%); ∆% (adjusted treatment difference) vs PBO; P-value vs PBO.Adjusted treatment differences and P-values were based on the common risk difference by use of Mantel-Haenszel stratum weights and the Sato variance estimator. The stratification variables used are baseline CDAI score (≤300 or >300), baseline SES-CD score (≤12 or >12), BIO-ir status (Yes or No; this variable used only in analyses of the overall population), and baseline corticosteroid use (Yes or No). Population N values reflect the primary analysis set, defined as all randomized participants who received at least 1 (partial or complete) dose of study intervention and had a screening SES-CD score ≥6 (or ≥4 for participants with isolated ileal disease). PBO pts not in clinical response at week (Wk) 12 switched to UST.Endpoint definitions: clinical remission, CDAI < 150; endoscopic response, ≥50% improvement from baseline in SES-CD or SES-CD ≤ 2. Participants with treatment failure or missing data were considered to not have met the endpoint.a. Anti-TNF agents or vedolizumab.b. Participants assigned to either GUS 200mg IV every 4 weeks (every 4 weeks) (x3)→100mg SC every 8 weeks or GUS 200mg IV every 4 weeks (x3)→200mg SC every 4 weeks. At the Wk 12 assessment, GUS participants had only received GUS IV.*Nominal P-value.

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