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4 Special Supplement, May 2023 concentrations of 1.2 µM (highest concentration tested); 2) High affinity for binding to IL-23 (dissociation constant K d <10 pM); and 3) High degree of potency for functional inhibition of IL-23 induced Th17 responses, with sparing of the IL-12 mediated Th1 pathway. 16 Overview of the ADVAVNCE, MOTIVATE, and FORTIFY Clinical Trials The efficacy and safety of risankizumab for the treatment of CD was evaluated in the Phase 3 ADVANCE (NCT03105128), MOTIVATE (NCT03104413), and FORTIFY (NCT03105102) randomized controlled trials (RCTs) (Figure 2). 17, 18 ADVANCE and MOTIVATE were placebo-controlled, double-blinded induction studies. Participants were randomized to receive risankizumab 600 mg, 1200 mg or placebo intravenously at weeks 0, 4 and 8. The ADVANCE trial (n=931) recruited participants who had failed either conventional or biologic therapy. The MOTIVATE trial (n=618) enrolled exclusively a refractory population with prior biologic failure. Responders to induction therapy were re-randomized into the 52-week maintenance FORTIFY study, and then received subcutaneous (SC) risankizumab 180 mg, 360 mg or placebo (i.e., risankizumab was withdrawn following induction) every 8 weeks. In Canada, the approved dosing is risankizumab 600 mg IV induction at Week 0, 4 and 8, followed by 360 mg SC injection maintenance therapy at week 12 and every 8 weeks thereafter. The clinical data supporting this dosing will be summarized below. Several key features of these RCTs should be noted, as they represent a substantial advance in trial methodology for the field. First, this was the first Phase 3 CD program to enroll patients not only on the basis of clinical symptoms (Crohn's disease activity index [CDAI] 220-450 at baseline), but also patient-reported outcomes (PRO) (average daily stool frequency (SF) ≥4 or average daily abdominal pain (AP) score ≥2), and centrally-evaluated confirmation of endoscopic evidence of mucosal inflammation at baseline (defined by a Simple Endoscopic Score for Crohn's Disease [SES-CD] ≥6 or ≥4 for isolated ileal disease). Requiring endoscopic confirmation of disease activity has important implications for defining the study population, as symptoms in CD are poorly correlated with objective measures. Correspondingly, participants in ADVANCE and MOTIVATE had clinically meaningful disease activity: One in three patients in ADVANCE and half of patients in MOTIVATE had failed multiple biologics, and the mean baseline SES-CD ranged from 13.4-15.1, indicating severely active endoscopic activity. For reference, the mean baseline SES-CD in the head-to-head SEAVUE trial comparing adalimumab to ustekinumab was only approximately half of that observed in the ADVANCE and MOTIVATE studies. 19 Second, the risankizumab Phase 3 RCTs were the first to evaluate the co-primary endpoint of clinical remission (CDAI <150 or daily SF ≤2.8 and daily AP ≤1 and not worse than baseline) and endoscopic response (defined by 50% reduction in SES-CD). Previously, registrational Phase 3 programs had used clinical remission alone as the primary endpoint. Requiring both symptomatic and endoscopic response to therapy not only increases the stringency of the primary readout, but also brings the findings of these clinical trials in line with clinical practice guidelines from the STRIDE-II consensus, which recommends targeting early achievement of symptomatic response and long-term endoscopic Figure 2. Design of the ADVANCE, MOTIVATE, and FORTIFY Phase 3 clinical trials. Abbreviations: bio biologic; IR inadequate response; IV intravenous; RZB risankizumab; SC subcutaneous

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