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5 Special Supplement, May 2023 remission. 20 Therefore, these clinical trials have raised the bar with respect to what clinicians and patients should expect to achieve with advanced therapy in CD. The results are more generalizable to clinical care, where endoscopic improvement is an important therapeutic target for ultimately altering the natural history of progressive CD. 21 Induction Efficacy At Week 12, risankizumab 600 mg IV was demonstrated to be significantly more effective than placebo for achieving the coprimary endpoints of clinical remission and endoscopic response. In ADVANCE, clinical remission defined by the PRO2, was achieved in 43.4% (146/336) of patients on risankizumab vs 21.7% (38/175) of patients receiving placebo (P<0.0001). In the biologic failure-only population in the MOTIVATE study, 39.8% (76/191) of patients receiving risankizumab achieved clinical remission vs 19.3% (36/187) of patients receiving placebo (P=0.0007). Similar results were observed when using a CDAI definition for clinical remission. Treatment responses were achieved rapidly: Statistically significant differences in the proportion of patients achieving endoscopic remission were observed as early as week 4. Beyond symptoms, early endoscopic efficacy at 12 weeks was also demonstrated: 50% reductions in SES-CD from baseline were observed in 40.2% (135/336) of patients receiving risankizumab in ADVANCE vs 12.0% of patients in the placebo group (P<0.0001). Numerically, higher rates of endoscopic response were achieved in biologic naïve patients, among whom half (50.3%, 71/141) achieved week 12 endoscopic response vs 12.8% (10/78) in the placebo group. However, risankizumab was still highly effective vs placebo in achieving endoscopic response in patients with prior biologic failure: 32.8% (64/195) vs 11.3% (11/97) in ADVANCE and 28.8% (51/191) vs 11.2% (21/187) in MOTIVATE (P<0.0001). Finally, approximately 1 in 4 patients treated with risankizumab (24.1% [81/336] in ADVANCE and 19.4% [37/191] in MOTIVATE) achieved endoscopic remission by week 12, defined by an SES-CD≤4 with at least a 2-point reduction vs baseline and with no SES-CD subscore >1 (adjusted treatment vs placebo: Δ15% [95% confidence interval CI 9-21%], P<0.0001 in both trials). The efficacy of risankizumab for inducing both clinical and endoscopic endpoints is further highlighted by the baseline characteristics of patients entering the FORTIFY maintenance trial. Whereas the baseline SES-CD was approximately 13-15 in ADVANCE/ MOTIVATE, the mean SES-CD approximately halved to 7.6-8.5 in FORTIFY. Similar reductions in biomarkers, including fecal calprotectin (mean 960-1367 mg/kg in ADVANCE/MOTIVATE to 307-424 mg/kg in FORTIFY) and high-sensitivity C-reactive protein (mean 7.3-11.7 mg/L in ADVANCE/ MOTIVATE to 3.7-4.1 mg/L in FORTIFY) were also observed. Maintenance Efficacy The durability of treatment response to induction therapy was evaluated among risankizumab responders in the re-randomized FORTIFY trial, where participants were randomized 1:1:1 to receive risankizumab 180 mg or 360 mg SC, or withdrawal of risankizumab (placebo) for 52 weeks (Figure 2). At week 52, risankizumab 360 mg SC every 8 weeks was demonstrated to be significantly more effective than withdrawal of therapy for maintaining PRO2- defined clinical remission (51.8% [73/141] vs. 39.6% [65/164], P=0.004). The remission rate in the withdrawal arm is notable: To be eligible for FORTIFY, all participants must have responded to risankizumab induction therapy; the long half-life of risankizumab (approximately 21 days) should be considered when comparing treatment efficacy in the withdrawal group. A post-hoc analysis of participants who received placebo only during both induction and maintenance therapy (a "true" placebo group) demonstrated that only 16.3% (17/104) of placebo participants were in clinical remission at Week 52. 22 Rates of clinical remission were highest in patients who were biologic-naïve: 61.5% (24/39) of this subgroup achieved Week 52 clinical remission with risankizumab 360 mg. Treatment differences between risankizumab and the withdrawal group were more pronounced for evaluation of endoscopic efficacy. Nearly half (46.8% [66/141]) of participants receiving maintenance risankizumab achieved week 52 endoscopic response vs 21.9% (36/164) of participants in the withdrawal (placebo) arm (p<0.0001). Efficacy was observed in both biologic-naïve (53.9% [21/39]) and bio- failure (44.1% [45/102]) populations. At week 52, endoscopic remission was achieved in a significantly higher proportion of patients receiving risankizumab 360 mg compared to withdrawal (placebo) (adjusted treatment difference vs. placebo 28% [95% CI: 20-37%], p<0.0001), and nearly 1/3 patients achieved the STRIDE-II recommended long-term treatment target of complete ulcer-free endoscopy (defined

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