S1053 Week 48 Efficacy Of Guselkumab And Ustekinumab In Crohn’s Disease Based On Prior Response/Exposure To Biologic Therapy: Results From The GALAXI 2 and 3 Phase 3 Studies

Introduction: GALAXI 2 & 3 (NCT03466411) are identically designed 48-week (Wk), randomized, double-blind, double-dummy, placebo (PBO)- and ustekinumab (UST)-comparator, treat-through registrational trials assessing the efficacy and safety of therapy with guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, in participants (pts) with moderately to severely active Crohn’s disease (CD). Wk48 comparisons of GUS and UST in the pooled GALAXI 2 & 3 dataset were previously reported. Here we explore the impact of biologic therapy exposure on GUS and UST efficacy for these same endpoints. Methods: Pts with inadequate response or intolerance to conventional therapies or biologic therapies (BIO-ir), active CD (CDAI 220–450 + mean daily SF >3 or AP >1), and SES-CD≥6 (≥4 for isolated ileal disease) were eligible. Randomization was stratified by CDAI score, SES-CD score, BIO-ir status, and corticosteroid use with pts assigned 2:2:2:1 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 ∼6mg/kg IV (x1)→90mg SC every 8 weeks, or PBO. Pooled Wk48 analyses comparing GUS and UST (active comparator) in all pts were prespecified major secondary, multiplicity-controlled endpoints. Pooled analyses in the BIO-ir and BIO-naïve subgroups were prespecified but not controlled for multiple comparisons. Results: Across the pooled GALAXI 2 & 3 dataset, 52% (456/873) of pts randomly assigned to GUS or UST had prior history of BIO-ir and 42% (365/873) were BIO-naïve (6% [52/873] had prior exposure to biologics but no documented failure). At Wk48, in both the BIO-ir and BIO-naïve subgroups, both GUS dose groups demonstrated greater rates of endoscopic response, endoscopic remission, and the composite endpoints of clinical remission and endoscopic response and clinical remission and endoscopic remission (deep remission) compared with the UST group (Table 1). Rates of clinical remission at Wk48 in the BIO-ir subgroup were greater in both GUS dose groups compared to UST and similar in the BIO-naïve subgroup. Conclusion: Guselkumab was efficacious in pts with CD regardless of prior biologic exposure. In pooled analyses of the double-blind GALAXI 2 & 3 trials, both GUS doses demonstrated greater rates of efficacy versus UST across multiple endpoints in the BIO-naïve subgroup and the more refractory BIO-ir subgroup. Table 1. - Comparison of guselkumab (GUS) and ustekinumab (UST) for long-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)♦ GUS 100mgb N=286 GUS 200mgc N=296 USTd N=291 GUS 100mgb N=153 GUS 200mgc N=147 USTd N=156 GUS 100mgb N=116 GUS 200mgc N=128 USTd N=121 Endoscopic response at Wk48 137 (47.9%) ∆ 10.6% P =.009 156 (52.7%) ∆ 15.6% P < .001 108 (37.1%) 66 (43.1%) ∆ 11.2% P =.039 69 (46.9%) ∆ 15.4% P =.005 49 (31.4%) 68 (58.6%) ∆ 15.4% P =.018 76 (59.4%) ∆ 16.8% P =.007 52 (43.0%) Endoscopic remission at Wk48 95 (33.2%) ∆ 8.5% P =.024 110 (37.2%) ∆ 12.3% P =.001 72 (24.7%) 43 (28.1%) ∆ 7.8% P =.111 42 (28.6%) ∆ 8.3% P =.092 32 (20.5%) 51 (44.0%) ∆ 13.8% P =.027 59 (46.1%) ∆ 16.5% P =.007 36 (29.8%) Deep remission at Wk48 (composite endpoint) 85 (29.7%) ∆ 7.4% P =.040 100 (33.8%) ∆ 11.3% P =.002 65 (22.3%) 39 (25.5%) ∆ 8.4% P =.072 36 (24.5%) ∆ 7.3% P =.115 27 (17.3%) 45 (38.8%) ∆ 9.5% P =.123 56 (43.8%) ∆ 15.0% P =.013 35 (28.9%) Clinical remission at Wk48 and endoscopic response at Wk48 (composite endpoint) 119 (41.6%) ∆ 7.8% P =.049 140 (47.3%) ∆ 13.6% P < .001 98 (33.7%) 57 (37.3%) ∆ 11.3% P =.032 60 (40.8%) ∆ 15.1% P =.005 40 (25.6%) 59 (50.9%) ∆ 7.7% P =.239 70 (54.7%) ∆ 12.0% P =.055 52 (43.0%) Clinical remission at Wk48 187 (65.4%) ∆ 2.6% P =.512 208 (70.3%) ∆ 7.3% P =.058 183 (62.9%) 93 (60.8%) ∆ 8.4% P =.132 94 (63.9%) ∆ 11.5% P =.043 82 (52.6%) 85 (73.3%) ∆ –1.8% P =.755 98 (76.6%) ∆ 1.5% P =.784 91 (75.2%) Data are presented as n (%); ∆% (adjusted treatment difference) vs UST; P-value vs UST.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).Endpoint definitions: endoscopic response, ≥50% improvement from baseline in SES-CD or SES-CD ≤ 2; endoscopic remission, SES-CD ≤ 4 and a ≥2-point reduction from baseline and no subscore greater than 1 in any individual component; deep remission, clinical remission (CDAI < 150) and endoscopic remission (SES-CD ≤ 4 and a ≥2-point reduction from baseline and no subscore greater than 1 in any individual component). Participants with treatment failure or missing data were considered to not have met the endpoint.aAnti-TNF agents or vedolizumab.bParticipants assigned to GUS 200mg IV every 4 weeks (every 4 weeks) (x3)→100mg SC every 8 weeks.cParticipants assigned to GUS 200mg IV every 4 weeks (x3)→200mg SC every 4 weeks.dParticipants assigned to UST ∼6mg/kg IV (x1)→90mg SC every 8 weeks. Placebo participants who switched to UST at Wk12 are not included.*Analyses in this population were prespecified major secondary endpoints; P-values are multiplicity controlled.♦Analyses in this population were prespecified but not controlled for multiple comparisons; P-values are nominal.

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