ABSTRACT
Introduction: In patients with moderate to severe Crohn's disease (CD), the ADVANCE and MOTIVATE phase 3 induction studies showed intravenous (IV) risankizumab (RZB), an anti-p19 interleukin-23 inhibitor, to be superior to placebo (PBO) for achieving clinical and endoscopic endpoints at Week (Wk) 12.1 Here, we evaluated the long-term efficacy and safety of RZB during the FORTIFY maintenance study in patients with delayed clinical response to IV RZB induction. [...]patients receiving RZB SC (180 mg or 360 mg) also achieved endoscopic response (36.7%, 45.5%), endoscopic remission (40.0%, 42.4%), deep remission (40.0%, 39.4%), ulcer free endoscopy (27.6%, 24.2%), and the combined endpoint of SF/APS clinical remission + endoscopic response (23.3%, 36.4%). [...]a dose-response trend was observed, with numerically higher response rates observed with RZB 360 mg SC relative to 180 mg SC for most outcomes, including clinical remission (CDAI and SF/APS), CDAI clinical response, enhanced clinical response, endoscopic response, endoscopic remission, and the composite endpoint of SF/APS clinical remission + endoscopic response. Efficacy and Safety after 52-Weeks Maintenance SC RZB Dosing in Delayed Responders (NRI-NCa) Responder Group Treatment Group, n (%) [95% CI] CDAI Clinical Response Enhanced Clinical Response CDAI Clinical Remission SF/APS Clinical Remission Endoscopic Response Ulcer Free Endoscopy Endoscopic Remission SF/APS Clinical Remission and Endoscopic Response Deep Remission RZB 180 mg SC delayed responders, Wk 24 53.3 (6/30) [35.5, 71.2] 56.7 (17/30) [38.9, 74.4] 53.3 (16/30) [35.5, 71.2] 43.3 (13/30) [25.6, 61.1] 36.7 (11/30) [19.4, 53.9] 27.6 (8/29) [11.3, 43.9] 40.0 (12/30) [22.5, 57.5] 23.3 (7/30) [8.2, 38.5] 40.0 (12/30) [22.5, 57.5] RZB 360 mg SC delayed responders, Wk 24 75.8 (25/33) [61.1, 90.4] 66.7 (22/33) [50.6, 82.8] 66.7 (22/33) [50.6, 82.8] 54.5 (18/33) [37.6, 71.5] 45.5 (15/33) [28.5, 62.4] 24.2 (8/33) [9.6, 38.9] 42.4 (14/33) [25.6, 59.3] 36.4 (12/33) [20.0, 52.8] 39.4 (13/33) [22.7, 56.1] Responder Group Treatment Group, (E/100PYs) Deaths Serious infections All treatment emergent adverse events AE related to COVID-19 Serious AE Hepatic events Injection site reactions AE leading to discontinuation of study drug Crohn's Disease RZB 180 mg SC (N=31) (PYs=27.5) delayed responders, Wk 24 0 0 132 (479.8) 0 6 (21.8) 0 6 (21.8) 2 (7.3) 7 (25.4) RZB 360 mg SC (N=33) (PYs=32.1) delayed responders, Wk 24 0 1 (3.1) 83 (258.9) 0 4 (12.5) 1 (3.1) 2 (6.2) 0 7 (21.8)
ABSTRACT
Here, the patient reported outcomes (PROs) of AP score (APS) and SF, and their correlation with endoscopic outcomes, were examined during induction and maintenance treatment. Methods: Pooled data from the ADVANCE/MOTIVATE induction studies (PBO, RZB 600 mg intravenous (IV) groups), and data from the FORTIFY maintenance study (180 mg, 360 mg and RZB withdrawal/PBO subcutaneous [SC] groups), were examined for AP and SF clinical outcomes. Patient Reported Outcomes of Abdominal Pain Score (APS) and Stool Frequency (SF) during Induction and Maintenance Dosing with RZB (ITT#) (NRI-NC&) Endpoint ADVANCE + MOTIVATE RZB 600 mg IV PBO RZB 600 mg IV PBO RZB 600 mg IV PBO Wk 4 Wk 8 Wk 12 Decrease in APS from BL 59.4 [54.3, 64.5] 71.7 [67.9, 75.6] P < 0.001 63.8 [58.9, 68.8] 75.9 [72.2, 79.6] P< 0.001 58.8 [53.8, 63.9] 76.9 [73.2, 80.5] P< 0.001 Decrease in SF from BL 65.7 [60.9, 70.6] 81.6 [78.3, 84.9] P< 0.001 63.5 [58.6, 68.5] 84.1 [80.9, 87.2] P< 0.001 58 [52.9, 63.1] 85.4 [82.4, 88.4] P< 0.001 AP =0 in patients with APS ≥1 at Baseline 2.6 [0.9, 4.3] 5.6 [3.6, 7.6] P= 0.052 3.2 [1.3, 5.0] 11.5 [8.7, 14.3] P< 0.001 6.4 [3.8, 8.9] 17.9 [14.5, 21.2] P<0.001 SF ≤1 in patients with SF >2.8 at Baseline 4.8 [2.5, 7.1] 9.8 [7.1, 12.5] P=0.004 6 [3.4, 8.5] 18.2 [14.7, 21.6] P<0.001 11.6 [8.2, 15.1] 26.1 [22.2, 30.0] P<0.001 Endpoint FORTIFY Withdrawal (PBO SC) RZB 180 mg SC RZB 360 mg SC Withdrawal (PBO SC) RZB 180 mg SC RZB 360 mg SC Withdrawal (PBO SC) RZB 180 mg SC RZB 360 mg SC Withdrawal (PBO SC) RZB 180 mg SC RZB 360 mg SC Withdrawal (PBO SC) RZB 180 mg SC RZB 360 mg SC Wk 8 Wk 16 Wk 24 Wk 32 Wk 52 APS Remission (APS ≤1) 67.7 [60.5, 74.8] 72.6 [65.6, 79.6] P=0.413 75.9 [68.8, 82.9] P= 0.033 70.1 [63.1, 77.1] 65.6 [58.2, 73.0] P= 0.311 70.2 [62.7, 77.8] P= 0.743 61 [53.5, 68.4] 66.2 [58.8, 73.6] P= 0.306 68.1 [60.4, 75.8] P= 0.052 54.3 [46.6, 61.9] 66.2 [58.8, 73.6] P = 0.027 63.1 [55.2, 71.1] P= 0.035 46.3 [38.7, 54.0] 57.3 [49.6, 65.1] P= 0.027 55.3 [47.1, 63.5] P= 0.028 SF Remission (SF ≤2.8) 66.5 [59.2, 73.7] 68.2 [60.9, 75.4] P= 0.807 67.4 [59.6, 75.1] P= 0.420 64.6 [57.3, 72.0] 66.2 [58.8, 73.6] P = 0.783 67.4 [59.6, 75.1] P = 0.266 59.8 [52.3, 67.3] 59.9 [52.2, 67.5] P = 0.990 63.8 [55.9, 71.8] P = 0.154 57.3 [49.7, 64.9] 58.6 [50.9, 66.3] P= 0.881 58.2 [50.0, 66.3] P= 0.437 44.5 [36.9, 52.1] 51.6 [43.8, 59.4] P= 0.113 56 [3.6, 24.3] P= 0.008 AP =0 18.3 [12.4, 24.2] 30.6 [23.4, 37.8] P= 0.009 30.6 [23.4, 37.8] P= 0.009 SF ≤1 28.7 [21.7, 35.6] 35.7 [28.2, 43.2] P=0.081 39.0 [31.0, 47.1] P=0.006 AP =0 and SF ≤1 14.6 [9.2, 20.0] 21.7 [15.2, 28.1] P=0.092 23.4 [16.4, 30.4] P=0.021 BL = baseline;Wk = Week;Endoscopic remission = SES-CD ≤4 and at least 2-point reduction from baseline;Ulcer-free endoscopy = SES-CD ulcerated surface subscore =0 in patients with subscore ≥1 at baseline;#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 non-responder imputation with no special data handling for missing data due to COVID-19 pandemic. 95% CI and p-value for adjusted response rate difference compared to PBO calculated according to the Cochran-Mantel-Haenszel test adjusted for strata.
ABSTRACT
BACKGROUND: Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease. METHODS: ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete. FINDINGS: Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14-30; 146/336) with risankizumab 600 mg and 41% (19%, 11-27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6-24; 66/191) with risankizumab 600 mg and 40% (20%, 12-29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug. INTERPRETATION: Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease. FUNDING: AbbVie.