Efficacy and safety of mirikizumab as induction and maintenance therapy in patients with moderately to severely active Crohn’s disease: Summary results from the Phase 3 VIVID-1 trial

Introduction: Mirikizumab is a selective IL23p19 monoclonal antibody approved for the treatment of ulcerative colitis (UC). We present efficacy and safety data for mirikizumab vs placebo (PBO) in patients with moderately-to-severely active Crohn’s disease (CD) up to Week (W) 52 from the Phase 3 treat-through VIVID-1 trial (NCT03926130). Methods: Adult patients (N=1065) were randomized 6:2:3 to receive intravenous (IV) mirikizumab (n=579) 900mg at W0, 4, and 8, then 300mg subcutaneously (SC) every 4Ws (Q4W) from W12 to W52, PBO (n=199), or ustekinumab (n=287; results vs mirikizumab previously presented) ~6 mg/kg IV at W0, then 90 mg SC Q8W from W8 to 48. PBO responders at W12 continued PBO to W52; PBO non-responders switched to mirikizumab induction then maintenance. The co-primary composite endpoints were: 1) Patient-Reported Outcome (PRO) clinical response at W12 and endoscopic response (by Simple Endoscopic Score SES-CD) at W52, and 2) PRO clinical response at W12 and clinical remission by Crohn’s Disease Activity Index (CDAI) at W52. Adjusted risk differences were calculated, with comparisons performed by CMH test. Fisher's exact test was used for comparisons performed within subgroups. Non-responder imputation was used. Fig. 1 Results: Baseline characteristics were similar across treatment groups ([ Table 1 ]). Both co-primary composite endpoints ([ Figs 1a, c ]; all p<0.000001) were achieved for mirikizumab vs PBO, with 38% of mirikizumab patients achieving W12 PRO response and W52 endoscopic response, and 45% achieving W12 PRO response and W52 clinical remission by CDAI compared with 9% and 20%, respectively, for those receiving PBO. Similar response rates and treatment effects were observed for mirikizumab in patients with and without prior biologic failure ([ Figs 1b, d ]). All key secondary endpoints with mirikizumab vs PBO were also achieved ([ Fig. 2 ]). Mirikizumab treatment resulted in significantly greater reductions in fecal calprotectin and C-reactive protein at W12 and W52 compared to PBO ([ Fig. 3 ]; all p<0.000001). Mirikizumab was well tolerated with no unexpected adverse events and a safety profile consistent with that observed in patients with UC ([ Table 2 ]). Fig. 2 Fig. 3 Table 1 Patient baseline demographics and clinical characteristics. Characteristic Placebo (N=199) Mirikizumab (N=579) Mean (SD) age, years 36.3 (12.7) 36.0 (13.2) Male, n (%) 118 (59.3) 332 (57.3) Mean (SD) weight, kg 69.6 (19.0) 68.0 (18.3) Mean (SD) BMI, kg/m 2 23.8 (5.8) 23.2 (5.4) Mean (SD) duration of CD, years 7.8 (7.4) 7.4 (8.2) Baseline CDAI 318.9 (86.2) 323.1 (85.8) SF daily average (SD) 5.8 (3.2) 5.7 (3.0) AP daily average (SD) 2.1 (0.6) 2.1 (0.6) SES-CD total mean (SD)score 13.1 (6.0) 13.5 (6.6) Disease location, n (%) Ileum only 19 (9.5) 65 (11.2) Colon only 77 (38.7) 225 (38.9) Ileum and colon 103 (51.8) 289 (49.9) Corticosteroid use, n (%) 58 (29.1) 177 (30.6) Immunomodulator use, n (%) 58 (29.1) 146 (25.2) Prior biologic failure, n (%) 97 (48.7) 281 (48.5) Number of failed biologics, n (%) None 102 (51.3) 298 (51.5) 1 66 (33.2) 175 (30.2) ≥2 31 (15.6) 106 (18.3) Note: Data are mean (SD) unless stated otherwise; Primary Analysis Set population AP=abdominal pain; BMI=body mass index; CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; SD=standard deviation; SES-CD=Simple Endoscopic Score for Crohn’s disease; SF=stool frequency. Table 2 Safety outcomes up to Week 52. Treatment groups Placebo (N=211) PYE=119.5 Miri (N=630) PYE=593.6 TEAE, n (%) [EAIR] 154 (73.0) [291.8] 495 (78.6) [201.9] Most common TEAEs a , n (%) [EAIR] COVID-19 29 (13.7) [26.4] 104 (16.5) [19.3] Anaemia 14 (6.6) [12.2] 42 (6.7) [7.4] Arthralgia 11 (5.2) [9.6] 41 (6.5) [7.2] Headache 9 (4.3) [7.8] 41 (6.5) [7.2] Upper respiratory tract infection 9 (4.3) [7.8] 38 (6.0) [6.7] Nasopharyngitis 9 (4.3) [7.7] 36 (5.7) [6.3] Diarrhoea 10 (4.7) [8.6] 35 (5.6) [6.1] AEs of interest, n (%) [EAIR] Infections: (All) 73 (34.6) [81.3] 261 (41.4) [59.7] Serious Infections: 6 (2.8) [5.1] 14 (2.2) [2.4] Opportunistic b Infections: 0 (0.0) [0] 7 (1.1) [1.2] Injection-site reaction 8 (3.8) [10.4] 66 (10.5) [15.3] Cerebrocardiovascular events 2 (0.9) [1.7] 3 (0.5) [0.5] Major adverse cardiac event 1 (0.5) [0.8] 0 (0.0) [0] Malignancies c 1 (0.5) [0.8] 2 (0.3) [0.3] Suicide/self-injury d 0 (0.0) [0] 2 (0.3) [0.3] Hepatic event 9 (4.3) [7.8] 39 (6.2) [6.8] SAE, n (%) [EAIR] 36 (17.1) [32.5] 65 (10.3) [11.5] Discontinuation due to AE, n (%) [EAIR] 20 (9.5) [17.1] 32 (5.1) [5.4] Safety population: all patients who received at least 1 dose of study drug a : ≥5% of miri treated patients; b : Most opportunistic infections were Herpes Zoster, one Candida; c : Malignancies include non-melanoma skin cancer (NMSC) and breast cancer; d : Both events were suicidal ideation; 1 participant had prior history of suicide attempt, the other had a history of anxiety; Abbreviations: EAIR=exposure adjusted incidence rates; TEAE=treatment-emergent adverse event; SAE=serious adverse event; AE=adverse events; PYE=patient years of exposure; n=number of patients in the specified category; N=number of patients in the analysis population; PBO=placebo; Miri=mirikizumab. Conclusion: In this Phase 3 study, mirikizumab demonstrated statistically significant and clinically meaningful improvements vs PBO in both co-primary composite endpoints and all key secondary endpoints. A significant reduction in key biomarker levels was also observed. No new safety signals were observed. Publication History Article published online: 26 September 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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