S715 Clinical and Endoscopic Improvements With Risankizumab Induction and Maintenance Dosing versus Placebo Are Observed Irrespective of Number of Prior Failed Biologics

Introduction: In phase 3 induction (ADVANCE, MOTIVATE) and maintenance (FORTIFY) studies, risankizumab (RZB), was well-tolerated and efficacious in patients with moderate to severe Crohn’s disease (CD) who failed/were intolerant to conventional or biologic therapy. This post-hoc analysis examined efficacy and safety of RZB induction and maintenance dosing based on number of prior biologics failed. Methods: Clinical and endoscopic endpoints (see Table footnotes for endpoints, definitions) were assessed for RZB versus (vs) PBO following intravenous (IV) induction and subcutaneous (SC) maintenance dosing based on prior failure of 1, 2, or ≥3 biologics. Pooled induction data are reported for PBO and RZB 600 mg IV q4w groups at Week (Wk) 12. Data from withdrawal (PBO SC), RZB 180 mg, and RZB 360 mg SC q8w groups are reported at FORTIFY Wk 52. Results: At induction baseline (BL), 48%, 25%, and 27% of patients failed 1, 2, and ≥3 prior biologics, respectively, with 6%, 27%, and 75% having prior vedolizumab exposure and 2%, 12%, and 59% having prior ustekinumab exposure. Most (90%) patients who failed 1 biologic and all who failed ≥2 biologics were anti-TNF refractory. BL characteristics were generally balanced across subgroups, although disease duration and steroid use were slightly higher in the ‘≥3 subgroup’. Across the subgroups, patients achieved greater rates of clinical remission and endoscopic response with RZB 600 mg IV vs PBO at induction Wk 12, with greater efficacy generally observed in patients failing fewer biologics. At FORTIFY Wk 52, patients achieved greater endoscopic remission and response rates with RZB 180 mg and RZB 360 mg SC vs withdrawal (PBO SC) across most subgroups, while the endpoints of ulcer-free endoscopy and deep remission were significant with RZB 360 mg SC. Patients who failed 2 and ≥3 prior biologics achieved higher clinical remission rates with RZB 360 mg SC vs withdrawal (PBO SC) at Wk52. There were no differences in treatment emergent adverse events among subgroups at induction Wk 12 or maintenance Wk 52. Conclusion: Induction and maintenance dosing of RZB was efficacious and well tolerated in patients with CD irrespective of number of prior biologics failed. Endoscopic response and remission rates were greater with both RZB SC doses vs PBO across all subgroups at induction Wk 12 and maintenance Wk 52. Rates of ulcer-free endoscopy and deep remission at maintenance Wk 52 were greater with RZB 360 mg SC across all subgroups. Table 1. - Achievement of Clinical and Endoscopic Outcomes at Week 12 of Induction and Week 52 of Maintenance by Number of Prior Biologics Failed (ITT#) Outcome ADVANCE + MOTIVATE, Week 12% Patients Achieving Endpoint [95% CI]P-value FORTIFY, Week 52% Patients Achieving Endpoint [95% CI]P-value PBO,Failed1 biologic RZB600 mg IV,Failed1 biologic PBO,Failed2 biologics RZB600 mg IV,Failed2 biologics PBO,Failed≥3 biologics RZB600 mg IV,Failed≥3 biologics PBO,Failed1 biologic RZB180 mg SC,Failed1 biologic RZB360 mg SC,Failed1 biologic PBO,Failed2 biologics RZB180 mg SC,Failed2 biologics RZB360 mg SC,Failed2 biologics PBO,Failed≥3 biologics RZB180 mg SC,Failed≥3 biologics RZB360 mg SC,Failed≥3 biologics Number of Patients, n/N (%) 129/362(35.6) 192/527(36.4) 75/362(20.7) 94/527(17.8) 80/362(22.1) 100/527(19.0) 61/166(36.7) 43/159(27.0) 51/141(36.2) 37/166(22.3) 44/159(27.7) 27/141(19.1) 27/166(16.3) 28/159(17.6) 24/141(17.0) SF/APS Clinical Remission 24 [16.7, 31.4] 39.6 [32.7, 46.5] P=0.004 21.3 [12.1, 30.6] 41.5 [31.5, 51.4] P=0.004 13.8 [6.2, 21.3] 30 [21.0, 39.0] P=0.019 43.3 [30.8, 55.9] 54.8 [39.7, 69.8] P=0.046 45.2 [31.3, 59.1]P=0.250 27.8 [13.1, 42.4] 30.2 [16.5, 44.0P=0.951 44.4 [25.7, 63.2]P=0.186 22.2 [6.5, 37.9] 35.7 [18.0, 53.5]P=0.153 58.3 [38.6, 78.1] P=0.009 CDAI Clinical Remission 24 [16.7, 31.4] 42 [35.0, 49.0] P=0.001 25.3 [15.5, 35.2] 49.1 [39.0, 59.3] P=0.001 15 [7.2, 22.8] 36 [26.6, 45.4] P=0.004 45 [32.4, 57.6] 57.1 [42.2, 72.1] P=0.045 50.1 [36.2, 64.1]P=0.168 25 [10.9, 39.1] 51.2 [36.2, 66.1] P=0.040 48.1 [29.3, 67.0] P=0.045 25.9 [9.4, 42.5] 32.1 [14.8, 49.4] P=0.533 41.7 [21.9, 61.4]P=0.275 Endoscopic Response 14.7 [8.6, 20.8] 35.8 [29.0, 42.6] P< 0.001 10.7 [3.7, 17.7] 24.5 [15.8, 33.2] P=0.016 6.3 [1.0, 11.6] 27.2 [18.4, 35.9] P< 0.001 28.3 [16.9, 39.7] 47.6 [32.5, 62.7] P=0.020 42.4 [28.7, 56.1] P=0.012 13.9 [2.6, 25.2] 39.5 [24.9, 54.1] P< 0.001 48.1 [29.3, 67.0] P=0.001 11.1 [0.0, 23.0] 32.1 [14.8, 49.4] P=0.020 41.7 [21.9, 61.4] P< 0.001 Endoscopic Remission 5.4 [1.5, 9.3] 25.6 [19.4, 31.8] P< 0.001 5.3 [0.2, 10.4] 8.5 [2.9, 14.2]P=0.414 2.5 [0.0, 5.9] 16 [8.8, 23.2] P=0.003 13.3 [4.7, 21.9] 33.3 [19.1, 47.6] P=0.011 33.5 [20.5, 46.5] P< 0.001 5.6 [0.0, 13.0] 18.6 [7.0, 30.2] P=0.030 40.7 [22.2, 59.3] P< 0.001 7.4 [0.0, 17.3] 7.1 [0.0, 16.7]P=0.903 33.3 [14.5, 52.2] P< 0.001 Ulcer-Free Endoscopy 6.3 [2.1, 10.4] 18.7 [13.1, 24.3] P< 0.001 4.0 [0.0, 8.4] 9.7 [3.7, 15.7]P=0.132 1.3 [0.0, 3.7] 10.1 [4.2, 16.0] P=0.010 10.3 [2.5, 18.2] 23.8 [10.9, 36.7]P=0.066 29.5 [17.0, 42.1] P=0.001 2.8 [0.0, 8.1] 16.3 [5.2, 27.3]P=0.097 22.2 [6.5, 37.9] P=0.004 3.7 [0.0, 10.8] 7.1 [0.0, 16.7]P=0.414 25 [7.7, 42.3] P=0.008 Deep Remission 3.1 [0.1, 6.1] 15.6 [10.5, 20.8] P< 0.001 1.3 [0.0, 3.9] 6.4 [1.4, 11.3]P=0.074 2.5 [0.0, 5.9] 9.0 [3.4, 14.6]P=0.106 11.7 [3.5, 19.8] 23.8 [10.9, 36.7]P=0.066 21.8 [10.4, 33.2] P=0.044 5.6 [0.0, 13.0] 16.3 [5.2, 27.3]P=0.097 29.6 [12.4, 46.9] P=0.002 3.7 [0.0, 10.8] 7.1 [0.0, 16.7]P=0.414 20.8 [4.6, 37.1] P=0.012 CDAI = CD Activity Index; SF = stool frequency; APS = Abdominal pain score; PBO = Placebo; RZB = Risankizumab; SF/APS Clinical Remission = Average daily SF ≤2.8 and not worse than baseline of the induction study and average daily AP score ≤1 and not worse than baseline of the induction study; CDAI Clinical Remission = CDAI < 150; Endoscopic Response = SES-CD ≤4 and at least a 2-point reduction versus baseline of the induction study and no subscore >1 in any individual variable, as scored by a central reviewer; Ulcer Free Endoscopy = SES-CD ulcerated surface subscore of 0 in subjects with SES-CD ulcerated surface subscore ≥1 at baseline of the induction study, as scored by a central reviewer; Endoscopic Remission = SES-CD ≤4 and at least a 2 point reduction versus baseline of the induction study and no subscore greater than 1 in any individual variable, as scored by a central reviewer; Deep Remission = CDAI clinical remission and endoscopic remission#Intent-to-treat (ITT) population: Includes randomized patients who (ADVANCE/MOTIVATE) received at least one dose of study drug during the 12-Week Induction Period, and had an SES-CD of ≥6 (≥4 for isolated ileal disease) or who (FORTIFY) received IV risankizumab for 12 weeks in the induction study and at least one dose of study drug in FORTIFY sub-study 1 and had an SES-CD of ≥6 (≥ 4 for isolated ileal disease) at baseline of induction.Calculations were based on multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there are no missing data due to COVID-19. P-values for pairwise treatment comparisons were provided within each bio-failure subgroup category based on the Cochran-Mantel-Haenszel test adjusted for strata.

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