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.

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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.

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Artikel online veröffentlicht:
26. September 2024