Efficacy and safety of mirikizumab as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis: Summary results from the Phase 3 LUCENT-1 and LUCENT-2 trials

Background Mirikizumab (miri) is an IgG4 monoclonal antibody directed against the p19 subunit of IL-23, a key mediator in inflammatory bowel diseases. Here we report the efficacy and safety of miri in two phase 3 induction (LUCENT-1; multi-center, randomized, parallel-arm, double-blind) and maintenance (LUCENT-2; double-blind, re-randomized responder withdrawal) placebo (PBO) controlled trials, involving patients with moderately to severely active ulcerative colitis (UC) who had inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, biologic therapies, or tofacitinib.

Methods In LUCENT-1, 1281 patients were randomized in a 3:1 ratio to receive blinded intravenous administration of 300 mg miri or PBO every 4 weeks (Wks) for 12 Wks. In LUCENT-2, 544 miri induction clinical responders were re-randomized to receive blinded miri 200 mg or PBO subcutaneously every 4 Wks in a 2:1 ratio for 40 Wks. The primary objective for each trial was determining if miri was superior to PBO in inducing clinical remission at Week (Wk) 12 and Wk 40, respectively. Key secondary objectives for LUCENT-1 were clinical response, endoscopic remission, symptomatic remission, clinical response in bio-failed patients, histologic-endoscopic mucosal improvement, and improvement in bowel urgency at Wk 12. Key secondary objectives for LUCENT-2 included corticosteroid-free remission, endoscopic remission, histologic-endoscopic mucosal remission, improvement in bowel urgency, bowel urgency remission at Wk 40 and maintenance of clinical remission from Wk 12 to Wk 40.

Results A significantly greater number of miri-treated patients achieved clinical remission at Wk 12 ([Fig 1]) and Wk 40 ([Fig 2]) compared to PBO. Miri-treated patients achieved all key secondary endpoints at both induction and maintenance, with a significantly greater number of patients who maintained clinical remission and reduction in bowel urgency severity compared to PBO ([Fig 3]).

Therewere numerically fewer serious adverse events (SAEs) and discontinuations due to AEs in miri-treated patients compared to PBO. The most common treatment-emergent AEs were nasopharyngitis and injection site reactionswith miri and UC with PBO (Table 2).

Conclusion Treatment with miri for both induction and maintenance studies demonstrated clinically meaningful and statistically significant improvements in primary and key secondary endpoints. The safety profile was consistent with previous miri studies in UC.

Fig. 1 Primary and key seconday outcomes LUCENT-1 Induction trail.

Fig. 2 Primary and key seconday outcomes LUCENT-2 Maintenance trail.

Fig. 3 Improvement in bowel urgency ( change from baseline in the Urgency Numeric Scale (NRS)) for both induction and maintenance trails.

Table 1 Baseline demographics and disease characteristics for LUCENT-1 and 2 trials

LUCENT-1 Induction
	Treatment groups
	PBO N=294	Miri N=868
Age, mean years (SD)	41.3 (13.8)	42.8 (13.9)
Male, n (%)	165 (56.1)	530 (61.1)
Weight (kg), mean (SD)	70.9 (16.7)	72.6 (17.3)
Disease duration (years), mean (SD)	6.9 (7.0)	7.2 (6.7)
Modified Mayo Score Severe [7-9] category, n (%)	155 (52.9)	463 (53.3)
Prior UC Therapy, n (%)
Biologic or tofacitinib failure	118 (40.1)	361 (41.6)
anti-TNF failure	97 (33.0)	325 (37.4)
Number of failed biologics or tofacitinib:
0	176 (59.9)	507 (58.4)
1	65 (22.1)	180 (20.7)
2	49 (16.7)	154 (17.7)
>2	4 (1.4)	27 (3.1)
Baseline UC Therapy, n (%)
Corticosteriods	113 (38.4)	351 (40.4)
Immunomodulators	69 (23.5)	211 (24.3)
Aminosalicilates	217 (73.8)	646 (74.4)
LUCENT-2 Maintenance
	Miri Induction Responders Treatment groups
	PBO N=179	Miri N=365
Age (years), mean (SD)	41.2 (12.8)	43.4 (14.2)
Male, n (%)	104 (58.1)	214 (58.6)
Weight (kg), mean (SD)	72.4 (17.2)	71.8 (17.3)
Disease duration (years), mean (SD)	6.7 (5.6)	6.9 (7.1)
Modified Mayo Score Severe [7-9] category, n (%)	102 (57.0)	184 (50.4)
Prior UC Therapy, n (%)
Biologic or tofacitinib failure	64 (35.8)	128 (35.1)
anti-TNF failure	58 (32.4)	112 (30.7)
Number of failed biologics or tofacitinib:
0	115 (64.2)	237 (64.9)
1	35 (19.6)	77 (21.1)
≥2	29 (16.2)	51 (14.0)
Baseline UC Therapy, n (%)
Corticosteroids	68 (38.0)	135 (37.0)
Immunomodulators	39 (21.8)	78 (21.4)

Table 2 Safety outcomes during induction and maintenance period

LUCENT-1 Induction
Treatment group	PBO N=321	Miri N=958
TEAE, n (%)	148 (46.1)	426 (44.5)
Most common TEAEs [a] , n (%)
Anemia	19 (5.9)	32 (3.3)
Nasopharyngitis	10 (3.1)	39 (4.1)
Ulcerative colitis	24 (7.5)	17 (1.8)
Headache	9 (2.8)	32 (3.3)
AEs of interest
Infections: All	45 (14.0)	145 (15.1)
Infections: Serious	2 (0.6)	7 (0.7)
Infections: Opportunistic	1 (0.3)	5 (0.5)
Cerebrocardiovascular events	2 (0.6)	1 (0.1)
Malignancies	0	2 (0.2)
Depression [b]	2 (0.6)	4 (0.4)
Hepatic	5 (1.6)	15 (1.6)
Immediate hypersensitivity events [c]	1 (0.3)	10 (1.0)
Infusion reactions	1 (0.3)	4 (0.4)
SAE, n (%)	17 (5.3)	27 (2.8)
Discontinuation due to AE, n (%)	23 (7.2)	15 (1.6)
TEAE=treatment-emergent adverse effects; SAE=serious adverse effects; AE=adverse effects; a:≥3% in any treatment group; decreasing frequency as percentage of total safety population; b: no incidences of suicide or self-injury;c: within 24 hours of drug administration p-value was computed using Fisher's exact test.
LUCENT-2 Maintenance – Miri Induction Responders
Treatment group	PBO N=192	Miri N=389
TEAE, n (%)	132 (68.8)	251 (64.5)
Most common TEAEs [a] , n (%)
Nasopharyngitis	11 (5.7)	28 (7.2)
Arthralgia	8 (4.2)	26 (6.7)
Ulcerative colitis	40 (20.8)	26 (6.7)
Injection site pain	6 (3.1)	17 (4.4)
Headache	2 (1.0)	16 (4.1)
Rash	0	14 (3.6)
Pyrexia	5 (2.6)	13 (3.3)
Anaemia	9 (4.7)	8 (2.1)
AEs of special interest
Infections: All	44 (22.9)	93 (23.9)
Infections: Serious	3 (1.6)	3 (0.8)
Infections: Opportunistic [b]	0	5 (1.3)
Cerebrocardiovascular events [c]	1 (0.5)	0
Malignancies [d]	1 (0.5)	1 (0.3)
Depression [e]	0	4 (1.0)
Suicide/self-injury [f]	0	1 (0.3)
Hepatic	4 (2.1)	12 (3.1)
Immediate hypersensitivity events [g]	2 (1.0)	7 (1.8)
Injection site reactions	8 (4.2)	34 (8.7)
SAE, n (%)	15 (7.8)	13 (3.3)
Death [h] , n (%)	1 (0.5)	0
Discontinuation due to AE, n (%)	16 (8.3)	6 (1.5)

a: ≥3% in any treatment group; by decreasing frequency in mirikizumab arm b: Specific MedDRA terms were used to identify infections considered to be opportunistic infections based on Winthrop et al. (2015). One oral candidiasis and 4 herpes zoster infections reported in the miri group. Herpes zoster was severe in 1 patient. Other opportunistic infections were mild to moderate. None resulted in discontinuation of miri. c: One adjudicated event of ischemic stroke in the PBO group d: PBO patient malignancy was basal cell carcinoma, miri patient malignancy was gastric cancer e:excluding suicide or self-injury f: one event of attempted suicide which was not considered to be related to study drug by investigator g: within 24 hours of drug administration, or on the day of drug administration when time is missing. There was one event of anaphylaxis in the PBO group h: placebo patient death was due to COVID-19 infection

Publication History

Article published online:
19 August 2022