Efficacy of mirikizumab in patients with moderate-to-severe Crohn’s disease in comparison to ustekinumab: Summary results from the double-blind Phase 3 VIVID-1 trial

Introduction: Mirikizumab (miri) is a selective IL23p19 monoclonal antibody approved for the treatment of ulcerative colitis. The primary focus of the VIVID-1 trial (NCT03926130) was to demonstrate the efficacy and safety of miri compared to placebo (PBO) with the secondary endpoints including the comparisons of miri to ustekinumab (uste). Objectives: We present the results of miri treatment compared to uste at Week 52 (W52) from the Phase 3, randomised, double-blind, double-dummy, active- and PBO-controlled, treat-through (TT) VIVID-1 study. Methodology: Adult patients (pts) (N=1065) were randomised 6:3:2 to miri (N=579) 900mg intravenously (IV) every 4 weeks (Q4W) to W12, then 300mg subcutaneously (SC) Q4W to W52, uste (N=287) one ~6 mg/kg IV dose, then 90mg SC Q8W to W52 or PBO (N=199). At W12 PBO responders continued PBO to W52; PBO non-responders received the same blinded miri regimen described above. Multiplicity-controlled endpoints comparing miri vs uste were endoscopic response (ER) at W52 (superiority test), and clinical remission (CR) by Crohn’s Disease Activity Index (CDAI) at W52 (non-inferiority test using 10% margin). Additional non-multiplicity-adjusted endpoints included endoscopic remission, corticosteroid-free (CSF) CR by CDAI, and the composite of CDAI CR and ER at W52. Pre-specified endpoint of change from baseline (CFB) in inflammatory biomarkers C-reactive protein (CRP) and faecal calprotectin (FCP) was assessed through W52. Outcome: Baseline characteristics were similar across treatment groups([ Table 1 ]). Miri achieved non-inferiority to uste for CR by CDAI, with numerically higher response rates for miri in bio-failed pts ([ Fig. 1a, b ]). Although superiority to uste in ER was not achieved, in bio-failed pts miri demonstrated a numerical trend towards greater response rates([ Fig. 1c, d ]). Rates of endoscopic remission and CSF-CDAI CR were not statistically different for miri vs uste. Miri had significantly greater rates compared to uste in achieving combined CDAI CR and ER at W52([ Fig. 2 ]). Miri had a nominal statistical difference to uste in decreasing FCP and CRP([ Fig. 3 ]). The overall safety profile was consistent with the known safety profile of miri([ Table 2 ]). Conclusion: In this phase 3 TT design study, miri achieved non-inferiority to uste for clinical remission by CDAI. In biologic failed pts miri had a numerical trend towards greater response compared to uste in clinical and endoscopic endpoints and an acceptable safety profile. Fig. 1 Fig. 2 Fig. 3 Table 1 Baseline demographics and disease characteristics. MIRI USTE PBO TOTAL N=579 N=287 N=199 N=1065 Age (years), mean (SD) 36∙0 (13∙2) 36∙6 (12∙7) 36∙3 (12∙7) 36∙2 (13∙0) Male, n (%) 332 (57∙3) 137 (47∙7) 118 (59∙3) 587 (55∙1) Weight (kg), mean (SD) 68∙02 (18∙3) 66∙86 (17∙6) 69∙55 (19∙0) 67∙99 (18∙3) BMI, mean (SD) 23∙2 (5∙4) 23∙3 (5∙5) 23∙8 (5∙8) 23∙4 (5∙5) Race, n (%) White 408 (71∙5) 201 (70∙3) 144 (74∙6) 753 (71∙7) Black or African American 10 (1∙8) 8 (2∙8) 5 (2∙6) 23 (2∙2) Asian 148 (25∙9) 74 (25∙9) 42 (21∙8) 264 (25∙1) Other 2 (0∙4) 2 (0∙7) 2 (1∙0) 6 (0∙6) Multiple 3 (0∙5) 1 (0∙3) 0 (0∙0) 4 (0∙4) Geographic region, n (%) Europe and Rest of World 319 (55∙1) 155 (54∙0) 117 (58∙8) 591 (55∙5) North America 77 (13∙3) 37 (12∙9) 27 (13∙6) 141 (13∙2) Central America or South America 30 (5∙2) 20 (7∙0) 9 (4∙5) 59 (5∙5) Asia 153 (26∙4) 75 (26∙1) 46 (23∙1) 274 (25∙7) Duration of Crohn’s disease (years), mean (SD) 7∙4 (8∙2) 7∙2 (7∙7) 7∙8 (7∙4) 7∙4 (7∙9) History of surgical bowel resection (yes), n (%) 89 (15.4) 29 (10.1) 33 (16.6) 151 (14.2) Disease location, n (%) Ileum only 65 (11∙2) 29 (10∙1) 19 (9∙5) 113 (10∙6) Colon only 225 (38∙9) 120 (41∙8) 77 (38∙7) 422 (39∙6) Ileum and colon 289 (49∙9) 138 (48∙1) 103 (51∙8) 530 (49∙8) Baseline CDAI, mean (SD) 323∙1 (85∙8) 318∙5 (93∙2) 318∙9 (86∙2) 321∙1 (87∙9) SF daily average, mean (SD) 5∙7 (3∙0) 5∙7 (2∙9) 5∙8 (3∙2) 5∙7 (3∙0) AP daily average, mean (SD) 2∙1 (0∙6) 2∙1 (0∙6) 2∙1 (0∙6) 2∙1 (0∙6) SES-CD Total Score, mean (SD) 13∙5 (6∙6) 13∙9 (6∙6) 13∙1 (6∙0) 13∙5 (6∙5) CRP (mg/L), median (Q1, Q3) 8∙5 (2∙9, 25∙0) 8∙9 (3∙4, 24∙8) 7∙6 (2∙9, 18∙8) 8∙3 (3∙0, 23∙7) Faecal calprotectin (mg/kg), median (Q1, Q3) 1315∙0 (444∙0, 2676∙0) 1489∙0 (519∙0, 2814∙0) 1161∙0 (324∙0, 2170∙0) 1315∙0 (452∙0, 2610∙0) Corticosteroid use, n (%) 177 (30∙6) 90 (31∙4) 58 (29∙1) 325 (30∙5) Immunomodulator use, n (%) 146 (25∙2) 87 (30∙3) 58 (29∙1) 291 (27∙3) Prior biologic failure, n (%) 281 (48∙5) 139 (48∙4) 97 (48∙7) 517 (48∙5) Prior anti-TNF failure, n (%) 265 (45∙8) 133 (46∙3) 89 (44∙7) 487 (45∙7) Prior anti-integrin failure, n (%) 68 (11∙7) 31 (10∙8) 24 (12∙1) 123 (11∙5) Number of failed biologics, n (%) None 298 (51∙5) 148 (51∙6) 102 (51∙3) 548 (51∙5) 1 175 (30∙2) 91 (31∙7) 66 (33∙2) 332 (31∙2) ≥2 106 (18∙3) 48 (16∙7) 31 (15∙6) 185 (17∙4) Abbreviations: AP=abdominal pain score; BMI=body mass index; CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; CRP=C-reactive protein; MIRI=mirikizumab; N=number of participants in the analysis population; n=number of participants in the specified category; PBO=placebo; Q=interquartile range; SD=standard deviation; SES-CD=Simple Endoscopic Score for Crohn’s disease; SF=stool frequency; TNF=tumour necrosis factor; USTE=ustekinumab. Table 2 Safety overview. Weeks 0 to 52 MIRI USTE PBO N=630, PYE=593∙6 N=309, PYE=293∙3 N=211, PYE=119∙5 n (%) [EAIR] n (%) [EAIR] n (%) [EAIR] Treatment-emergent adverse events (TEAE) 495 (78∙6) [201∙9] 239 (77∙3) [180∙4] 154 (73∙0) [291∙8] Common TEAEs a COVID-19 104 (16∙5) [19∙3] 47 (15∙2) [17∙3] 29 (13∙7) [26∙4] Anaemia 42 (6∙7) [7∙4] 15 (4∙9) [5∙3] 14 (6∙6) [12∙2] Arthralgia 41 (6∙5) [7∙2] 8 (2∙6) [2∙8] 11 (5∙2) [9∙6] Headache 41 (6∙5) [7∙2] 15 (4∙9) [5∙3] 9 (4∙3) [7∙8] Upper respiratory tract infection 38 (6∙0) [6∙7] 22 (7∙1) [7∙8] 9 (4∙3) [7∙8] Nasopharyngitis 36 (5∙7) [6∙3] 19 (6∙1) [6∙7] 9 (4∙3) [7∙7] Serious infection 14 (2∙2) [2∙4] 9 (2∙9) [3∙1] 6 (2∙8) [5∙1] Opportunistic infection 7 (1∙1) [1∙2] 1 (0∙3) [0∙3] 0 (0∙0) [0∙0] Adjudicated cerebro-cardiovascular events 3 (0∙5) [0∙5] 2 (0∙6) [0∙7] 2 (0∙9) [1∙7] Female 0 (0∙0) [0∙0] 1 (0∙3) [0∙3] 1 (0∙5) [0∙8] Cancer 2 (0∙3) [0∙3] 0 (0∙0) [0∙0] 1 (0∙5) [0∙8] Non-melanoma skin cancer (NMSC) 1 (0∙2) [0∙2] 0 (0∙0) [0∙0] 1 (0∙5) [0∙8] Malignancies excluding NMSC 1 (0∙2) [0∙2] 0 (0∙0) [0∙0] 0 (0∙0) [0∙0] Hepatic laboratory b 39 (6∙2) [6∙8] 8 (2∙6) [2∙8] 9 (4∙3) [7∙8] ALT ≥3× ULN 12 (1∙9) 6 (2∙0) 0 (0∙0) ≥5× ULN 3 (0∙5) 1 (0∙3) 0 (0∙0) AST ≥3× ULN 9 (1∙4) 7 (2∙3) 2 (1∙0) ≥5× ULN 2 (0∙3) 4 (1∙3) 0 (0∙0) ALT/ AST ≥3× ULN and TB ≥2× ULN 0 (0∙0) 0 (0∙0) 1 (0∙2) ALP ≥2× ULN and Bilirubin ≥2× ULN 0 (0∙0) 0 (0∙0) 0 (0∙0) ALP ≥2× ULN 7 (1∙1) 0 (0∙0) 2 (1∙0) Serious adverse events (SAE) 65 (10∙3) [11∙5] 33 (10∙7) [11∙8] 36 (17∙1) [32∙5] Treatment discontinuation due to adverse event 32 (5∙1) [5∙4] 8 (2∙6) [2∙7] 20 (9∙5) [17∙1] Death c 0 (0∙0) [0∙0] 1 (0∙3) [0∙3] 1 (0∙5) [0∙8] Safety population: all patients who received at least one dose of study drug; a: Events that occurred in at least 5% of the patients in any trial group. Events are listed according to decreasing frequency in the mirikizumab group.; b: No ALT or AST shifts ≥10× ULN were reported in the mirikizumab treatment or placebo groups. One participant (EAIR=0∙3 per 100 PYE) in the ustekinumab group reported ALT shifts ≥10× ULN. Two participants (EAIR=0∙7 per 100 PYE) in the ustekinumab group reported AST shifts ≥10× ULN.; c: A 35-year-old male patient who died due to pulmonary embolism, one additional 23-year-old male placebo non-responder patient who switched to mirikizumab after week 12 died due to worsening of CD, and a 63-year-old female patient who died due to sepsis.; Abbreviations: AE=adverse events; ALT=alanine aminotransferase; AST=aspartate transferase; EAIR=exposure adjusted incidence rates; MIRI=mirikizumab; N=number of patients in the analysis population; n=number of patients in the specified category; PBO=placebo; PYE=patient years of exposure; SAE=serious adverse event; TEAE=treatment-emergent adverse event; TB=total bilirubin; ULN=upper limit of normal; USTE=ustekinumab. 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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