Efficacy and safety of Mirikizumab for ulcerative colitis: a systematic review and meta-analysis of randomized controlled trials

Abstract

Ulcerative colitis (UC) is a widespread incurable chronic inflammation of the colon mucosa. Currently, oral small-molecule medications targeting Janus kinase or sphingosine-1-phosphate and monoclonal antibodies to TNF-α,α4β7 integrins and Ustekinumab are the lines of treatment for UC. Up to 50% of patients either do not react to initial treatment or lose response over time, emphasizing the need for innovative treatment. Mirikizumab, a humanized IgG4-variant monoclonal antibody, binds to subunit p19 of interleukin-23. This systematic review aims to evaluate Mirikizumab compared to placebo in treating moderate-to-severe active UC. Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and using the Population, Intervention, Comparison, Outcome, Study design (PICOS) model for inclusion and exclusion criteria, we systematically reviewed the literature. Our inclusion criteria encompassed randomized controlled trials assessing Mirikizumab efficacy in treating UC across demographics. We employed the Cochrane Risk of Bias tool (RoB1) to investigate bias within included studies across its seven domains. The statistical analysis was conducted using Review Manager Version 5 software. Four studies were included, comparing patients treated with mirikizumab to placebo groups. All doses of mirikizumab administered intravenously demonstrated clinical remission, specifically, the 200 mg and 300 mg doses showed significant efficacy, with risk ratios of 4.74 (95% CI [1.43, 15.69]) and 1.82 (95% CI [1.33, 2.50]), respectively. During the maintenance phase of extension trials, symptoms subsided with a subcutaneous 200 mg dose (RR = 1.46, 95% CI [0.47, 4.51], P = 0.51). To conclude, mirikizumab demonstrates significant efficacy in treating UC, substaintially improving clinical, endoscopic, and histological outcomes.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12876-025-03627-2.

Introduction

Inflammatory Bowel Disease (IBD), a term that refers to Crohn’s disease and ulcerative colitis (UC), represents increasing trends in incidence and burden over the past decade [1]. IBD affects > 0.3% of the world population in the 21st century [2]. In 2023, the global prevalence of ulcerative colitis was around 5 million cases, with increasing values [3].

UC is an idiopathic, immune-mediated chronic inflammation of the large intestine, causing diffuse friability, erosions, bleeding, and haustral loss in the colon. UC typically involves the rectum, extending proximally in a steady manner throughout a part of the colon [4]. The classical presentation of UC includes urgency, fatigue, increased frequency of bowel movements, incontinence, mucus discharge, abdominal discomfort, and nocturnal defecations [5]. According to the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), moderate to severe UC is determined through an endoscopic score of 5–6 calculated by summing the sub-scores for vascular patterns (0–2), hemorrhage (0–3), and ulcers (0–3) [6].

An imbalance between regulatory and effector T cells is an instrumental part of the pathophysiology of UC [7]. Such an imbalance is a consequence of events disturbing the mucosal barrier and disrupting the healthy stability of the gut microbiota [8]. When macrophages and dendritic cells are stimulated by antigens, they release IL-23. This cytokine has a role in inflammation, correlated with the dysregulated innate and adaptive immune response to the gut microbiota. IL-23 induces activation of memory T cells expressing IL-23 receptor, and increased levels of IL-23 have been observed in murine models of inflammatory bowel disease (IBD) and confirmed in patients with UC [9].

The primary aim of UC management is to induce and maintain remission while preventing colectomy and colorectal cancer. Other treatment goals include the normalization of C-reactive protein, erythrocyte sedimentation rate, and fecal calprotectin, in addition to the prevention of disability, restoring quality of life, and normal growth in children [10]. Current lines of treatment for moderate to severe UC are monoclonal antibodies to TNF-α and α4β7 integrins, as well as oral small-molecule therapies targeting Janus kinase or sphingosine-1-phosphate [11]. Additionally, Ustekinumab has been approved for the treatment of moderate-to-severe ulcerative colitis in adult patients [12]. Despite these options, colectomy is necessary for up to 15% of patients diagnosed with UC [13].

Furthermore, the treatments can induce significant adverse reactions. For instance, TNF-α inhibitors have multiple adverse effects. Common adverse effects of all TNF-α inhibitors include headaches, rashes, anemia, transaminitis, infections, and, most frequently, a reaction at the site of injection when administered subcutaneously. Patients with autoimmune disorders have a notable deterioration in heart failure and a heightened susceptibility to acquiring Tuberculosis (TB) and lymphoma, in contrast to individuals without these conditions [14]. Janus kinase inhibitors are mostly linked to the occurrence of herpes virus infections, nasopharyngitis, as well as upper respiratory tract and urinary tract infections. Furthermore, the occurrence of acne and gastrointestinal adverse effects, such as nausea and diarrhea, were noted [15]. Oral small-molecule treatments that target sphingosine-1-phosphate can potentially cause side effects including bradycardia, hypertension, macular edema, impaired pulmonary function, and neoplasms [15]. Ustekinumab’s most prevalent noninfectious adverse effects were arthralgia, rash or pruritus, and headache [16]. Ustekinumab-associated infections were primarily pulmonary or gastrointestinal. Infections of the urinary tract, skin, and flu-like symptoms were reported in 4–5% of cases [17]. Moreover, UC poses a huge economic burden; the annual direct and indirect costs are thought to be as costly as €12.5–29.1 billion in Europe and US$8.1–14.9 billion in the USA [18]. Despite the growing number of current therapeutic options for UC, both surgical and nonsurgical, around half of patients do not react to initial treatment or lose response with time, underscoring the need for innovative treatment [19].

The IL-23 pathway has emerged as an important therapeutic target for UC [19]. Mirikizumab is an IgG4 monoclonal antibody targeted against the p19 subunit of IL-23. It efficiently restrains the interaction of IL-23 with its receptor. While maintaining the function of IL-12, Mirikizumab causes blockade of IL-23-induced IL-17 production in cell-based assays [20]. Mirikizumab has currently reached Phase 3 clinical trials; therefore, it is crucial to assess its efficacy and safety profile on a wider scope. Through our systematic review, we aim to reduce the burden of UC by providing evidence-based guidance on Mirikuzimab for the treatment of moderate to severe UC.

Methods

Protocol registration

We have registered our meta-analysis protocol with the International Prospective Register of Systematic Reviews under the registration number [CRD 42024512315].

Literature search

Following the PRISMA guidelines and using the PICOS model for inclusion and exclusion criteria, we systematically reviewed the literature. We searched five databases [PubMed, Medline, Web of Science Core Collection, SCOPUS, and Cochrane Library].

Our inclusion criteria encompassed Randomized Controlled Trials (RCTs) assessing Mirikizumab efficacy in treating UC across all demographics, published in English. Exclusion criteria included observational, non-randomized controlled trials, in vitro and animal studies, and non-English articles [21].

Our search terms across databases were: (“Mirikizumab” OR “LY3074828”) AND (“Ulcerative Colitis” OR “Inflammatory Bowel Disease” OR “Inflammatory Bowel Diseases” OR “Colonic Diseases”) AND (“Biological Therapy” OR “Pharmacotherapy” OR “Drug Therapy” OR “Therapeutics” OR “Clinical Trial” OR “Intervention Studies”) AND (“Efficacy” OR “Safety” OR “Patient Outcomes” OR “Health-related Quality of Life” OR “Treatment Response” OR “Disease Remission” OR “Immunogenicity” OR “Adverse Events”).

Two reviewers independently screened studies based on titles and abstracts, with disagreements resolved by a third reviewer. Full-text screening against the criteria was conducted using Rayyan software [22]. Detailed screening procedures are presented in the PRISMA flowchart in Fig. 1.

Fig. 1.

PRISMA flowchart of the study selection process

Data extraction strategy

Two independent reviewers examined databases, excluding studies based on predetermined eligibility criteria from titles and abstracts. They collaboratively assessed each paper’s relevance to our review and resolved conflicts or disagreements through team discussions.

The primary outcomes assessed were as follows:

• Clinical Remission: Defined as a Mayo score ≤ 2, with no subscore > 1, and a rectal bleeding score of 0.

• Endoscopic Remission: Defined as a Mayo endoscopic subscore of 0 or 1, indicating minimal or no visible mucosal inflammation.

• Clinical Response: Defined as a reduction in the total Mayo score by ≥2 points and ≥30% from baseline, along with a rectal bleeding subscore reduction of ≥1 or an absolute score of 0 or 1.

• Histological Remission: Assessed based on Geboes scoring, with a score <2 indicating remission. Secondary outcomes include an alteration in bowel urgency and other adverse events such as anemia, headache, rash, nausea, gastroenteritis, nasopharyngitis, opportunistic infections, and injection site pain.

Risk of bias assessment

We employed the Cochrane Risk of Bias tool (RoB1) to investigate the bias within our included studies across its seven domains. Two reviewers independently assessed and cross-checked the quality of each study to reach a consensus. In cases of disagreement, a third reviewer made the final decision. The pooled data were then analyzed using Review Manager Version 5, which generated graphs depicting the risk of bias in our included studies [23].

Statistical analysis

We conducted a statistical analysis using Review Manager (RevMan) Version 5 software. Dichotomous data were analyzed using risk ratios (RR), and continuous data were evaluated using mean differences (MD), both with 95% confidence intervals. Heterogeneity among the included studies was assessed using the I² test. A p-value of less than 0.05 was considered statistically significant. If I² exceeded 50%, a random effects model was used; if not, a fixed effects model was utilized [23].

Results

Characteristics of the included studies

All studies are recent multicentric randomized controlled trials on patients diagnosed with moderate-to-severe active UC. Studies were conducted by Eli Lilly and Company across 34 countries. The total number of participants in the induction phase was 1539 patients, and there were 819 patients in the maintenance phase. Sandborn 2020 is a phase 2 extension trial on patients with UC from a previous trial (I6T-MC-AMAC). Sandborn 2022 is an extension of Sandborn 2020 for patients who did not respond to the induction phase of Mirkizumab over the first 12-week period in Sandborn 2020. D’Haens 2023 is a phase 3 clinical trial, while D’Haens 2024 is its extension. D’Haens 2024 involves an additional 40 weeks for drug induction responders who were given further subcutaneous maintenance doses and for drug non-responders who went through another induction phase before transitioning to the subcutaneous maintenance phase. The summary of the included studies is shown in Table 1.

Table 1.

Summary of the included studies

						Intervention Group			Control Group		Results
ID	Study Design	Site	Duration	Total Sample Size	Inclusion Criteria	Intervention	Sample Size	Route	Name	Sample Size	Duration of follow up	Outcomes Indicators	Results
Sandborn,2020 [24]	RCT	conducted at 75 sites in 14 countries.	January 2016 through September 2017	Induction Phase: 249, Maintainance phase: 63	18–75 years old, a diagnosis of UC for 3 months,evidence of UC proximal to the rectum,Mayo score of 6 to 12,an endoscopic subscore ≥ 2.	Mirikizumab Intravenous doses administered at weeks 0, 4, and 8 for induction period, Subcutaneous doses administered every 4 or 12 weeks for maintenance period	186(induction) 50(maintenance)	Induction administered intravenously. Maintenance administered SC.	Induction phase:Placebo IV Q4WMainainance phase:Placebo SC Q4W	63(induction) 13(maintenance)	12 Weeks for Induction40 Weeks for Maintenance	Clinical Remission at Week 12Safety and TolerabilityWeek 52 Clinical RemissionWeek 12 and 52 Clinical ResponseDurable Clinical RemissionEndoscopic RemissionEndoscopic ImprovementChanges in Baseline IBDQCRPFecal CalprotectinIL17AIL22Histologic RemissionChange in Baseline Symptomatic Score (SF+RB)Symptomatic RemissionAdverse Events	At week 12, 15.9%, 22.6%, and 11.5% of patients in the 50-mg, 200-mg, and 600-mg groups achieved clinical remission, respectively, compared with 4.8% of patients given placebo.At week 52, 46.8% of patients given SC miri 200 mg every 4 weeks and 37.0% given SC miri 200 mg every 12 weeks were in clinical remission.
Sandborn,2022 [25]	RCT	performed at 75 sites in 14countries	January 2016 through September 2017	Induction Phase: 128, Maintainance phase: 68	18–75 years old, diagnosis of UC for 3 months,Mayo score of 6 to 12 with an endoscopic subscore 2 within 14 days, evidence of UC extending proximal to therectum	This study was a continuation of I6T-MC-AMAC, Patientswithout a clinical response after 12 weeks induction therapy offered the opportunity to participate in this extended induction study for another 12 weeks, in which they received either 600 mg intravenous mirikizumab or 1000 mg intravenous mirikizumab	84(induction) 38(maintenance)	Induction administered intravenously. Maintenance administered SC.	Placebo IV Q4W	44(induction) 30(maintenance)	12 Weeks for Induction40 Weeks for Maintenance	endoscopic remission and endoscopic improvementat study week 24 and study week 52histologic remissionInflammatory Bowel Disease Questionnaire (IBDQ)IL17AIL22biomarkers C-reactive protein (CRP)fecal calprotectin (fCLP)HealthSurvey Version 2 Standard (SF-36)	50.0% of patient receivedat 12-week extension 600 mg mirikizumab and 43.8% who received the extension of 1000 mgmirikizumab achieved a clinical response; 15.0% and 9.4% achieved clinical remission, respectively. 20.0% of subjects in the 600 mg mirikizumabgroup and 15.6% of subjects in the 1000 mg mirikizumab group achieved Endoscopic improvementat week 24 initial nonresponders and continued into maintenancetherapy, 65.8% maintained the clinical response, 26.3% achieved clinical remissionat week 52 34.2%had endoscopic improvement
D’Haens,2023 [26]	RCT	34 countries	Induction trial was conducted from June 18, 2018, to January 21, 2021. Maintenance trial from October 19, 2018, to November 3 2021	Induction Phase: 1162, Maintainance phase: 544	18–80 years old, moderately to severely active UC, Mayo score of 4 to 9, endoscopic subscore of 2 to 3, Patients had to have an inadequate response to, a loss of response to, or an inability to take one or more: 1-glucocorticoids/ corticosteroids 2-immunomodulators 3-Janus kinase (JAK) inhibitor (tofacitinib) 4-biologic agent	IV 300 mg mirikizumab every 4 weeks for 12 weeks for induction. SC 200 mg mirikizumab every 4 weeks for 40 weeks	868(induction) 365(maintenance)	Induction administered intravenously. Maintenance administered SC.	Placebo IV Q4WPlacebo SC Q4W	294(induction) 179(maintenance)		clinical remission, stool-frequency subscore of 1 with a decrease of ≥1 point from baseline, rectal-bleeding subscore of 0, endoscopic subscore of 0 or 1 [excluding friability]) at week 12, histologic–endoscopic mucosal improvement, Remission of symptoms assessed at weeks 4 and 12, Glucocorticoid-free clinical remission/ clinical remission at week 40, remission of symptoms at week 28, no glucocorticoid use for at least 12 weeks before week 40, Maintenance of clinical remission, Bowel-urgency remission	Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (includ_x0002_ing the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received pla_x0002_cebo in the induction trial, 1 had herpes zoster infection and none had cancer
D’Haens,2024 [27]	RCT			Induction Phase: 272, Maintainance phase: 144	18–80 years old, moderately to severely active UC, Mayo score of 4 to 9, endoscopic subscore of 2 to 3, Patients had to have an inadequate response to, a loss of response to, or an inability to take one or more: 1-glucocorticoids/ corticosteroids 2-immunomodulators 3-Janus kinase (JAK) inhibitor (tofacitinib) 4-biologic agent	IV 300 mg mirikizumab at weeks 12,16,20 for induction, SC 200 mg mirikizumab every 4 weeks for 40 weeks	272(induction) 144(maintenance)	extended induction & Re-induction (IV), maintainance for extended induction responders (SC)	Placebo SC Q4W	179	12 Weeks for Extended Induction,40 Weeks for Maintenance for extended induction responders	at weeks 12, 24 and 52 Clinical Remission , Clinical Response , Symptomatic response,Symptomatic remission, histologic-endoscopic mucosal improvement, Histologic improvement, Endoscopic remission, fCal change from baseline , CRP change from baseline, BU Clinically meaningful Improvement , BU change from baseline, Geometric Mean,	Of patients not achieving clinical response during induction, 53.7% achieved response following extended induction. After 52W, 72.2%, 43.1%, and 36.1% of patients achieved clinical response, endoscopic, and clinical remission, respectively. Of induction responders who subsequently lost response, 63.2% and 36.8% achieved symptomatic response and remission

The mean age of participants ranged from 40.5 to 44 years, with the proportion of males ranging from 41.7% to 75%. The UC disease duration varied from 6 to 10.1 years. The characteristics and baseline data of participants enrolled in the included studies are shown in Table 2.

Table 2.

Baseline characteristics of patients in the included studies

Study ID	Phases	Groups	Total Number	Age (Years), Mean (SD)		Gender N.(%)		Duration of UC (Years), Mean (SD)		Smoking N.(%)	Mayo score N.(%)		Mayo symptoms score, Mean (SD)
				Mean	SD	Males	Females	Mean	SD	N.(%)	Moderate	Severe	Mean	SD
Sandborn, 2020 [24]	Induction phase	600 mg IV Mirikizumab	61	42.4	13.4	38(62.3)	23 (37.7)	6	5.7	23 (37.7)	26 (42.6)	35 (57.4)	3.8	1.1
		200 mg IV Mirikizumab	62	43.4	14.7	37(59.7)	25 (40.3)	9	9	25 (40.3)	27 (44.3)	34 (55.7)	3.7	1.3
		50 mg IV Mirikizumab	63	41.8	14.1	38(60.3)	25 (39.7)	8.2	7.2	18 (28.6)	24 (38.7)	38 (61.3)	3.7	1.3
		Placebo IV	63	42.6	13.5	36(57.1)	27 (42.9)	9.5	9.6	18 (28.6)	27 (42.9)	36 (57.1)	3.9	1.1
	Maintainance phase	Mirikizumab SC every 4 weeks 200 mg	47
		Mirikizumab SC every 12 weeks 200 mg	46
		Placebo SC every 4 weeks	13
Sandborn, 2022 [25]	Induction phase	Induction miri NR miri IV 600 mg	20	45.6	14.3	15 (75.0)	5 (25.0)	9.2	11.1		11 (55.0)	9 (45.0)	3.6	0.9
		Induction miri NR miri IV 1000 mg	64	43	14.3	45 (70.3)	19 (29.7)	7.2	6.9		25 (40.3)	37 (59.7)	3.7	1.2
		Induction PBO NR miri IV 600 mg	12	40.9	13.6	5 (41.7)	7 (58.3)	9.8	9.6		6 (50.0)	6 (50.0)	3.5	1.1
		Induction PBO NR miri IV 1000 mg	32	42	12.7	18 (56.3)	14 (43.7)	10.1	9.7		11 (34.4)	21 (65.6)	4.2	1
		Induction responders	106	40.5	13.7	56 (52.8)	50 (47.2)	7.5	5.9		46 (43.4)	60 (56.6)	3.8	1.3
	Maintainance phase	Induction miri NR miri IV 600 mg	10
		Induction miri NR miri IV 1000 mg	28
		Induction PBO NR miri IV 600 mg	8
		Induction PBO NR miri IV 1000 mg	22
D’Haens, 2023 [26]	Induction phase	Mirikizumab, 300 mg IV	868	42.9	13.9	530 (61.1)	338 (38.9)	7.2	6.7		519 (62.9)	297 (36.0)
		Placebo IV	294	41.3	13.8	165 (56.1)	129(43.9)	6.9	7		186 (66.0)	93 (33.0)
	Maintainance phase	Mirikizumab, 200 mg SC	365
		Placebo SC	179
D’Haens, 2024 [27]	Extended Induction phase	Mirikizumab Extended Induction Population 300 mg Mirikizumab IV, Q4W	272	44	14.2	182 (66.9)		7.6	6.8
	Maintainance phase	Mirikizumab Extended Induction Responders 200 mg Mirikizumab SC, Q4W	144
		Placebo SC	179

Study ID	Phases	Groups	Total Number	Modified Mayo score Mean (SD)		Modified Mayo score N.(%)		Mayo endoscopic subscore indicating severe disease N.(%)	Faecal calprotectin, µg/g Median (IQR)	C-reactive protein (CRP) mg/L Median (IQR)	IBDQ total score, mean (SD)		Baseline Coticosteroids Use N.(%)	Previous treatment failure N.(%)
				Mean	SD	Moderate	Severe	N.(%)	Median(IQR)	Median(IQR)	Mean	SD	N.(%)	Biological or Tofacitinib N.(%)
Sandborn, 2020 [24]	Induction phase	600 mg IV Mirikizumab	61	6.5	1.3			45 (73.8)	1523 (619–2587)	6.2 (2.0–15.5)	125.5	33.9	34 (55.7)
		200 mg IV Mirikizumab	62	6.4	1.4			41 (66.1)	1560 (399–2443)	3.6 (1.4–13.7)	133	34.7	25 (40.3)
		50 mg IV Mirikizumab	63	6.6	1.3			50 (79.4)	1945 (510–2992)	4.5 (1.4–12.6)	122.5	29.2	29 (46.0)
		Placebo IV	63	6.7	1.2			47 (74.6)	1353 (618–2481)	3.9 (1.1–11.2)	124.1	29.8	33 (52.4)
	Maintainance phase	Mirikizumab SC every 4 weeks 200 mg	47
		Mirikizumab SC every 12 weeks 200 mg	46
		Placebo SC every 4 weeks	13
Sandborn, 2022 [25]	Induction phase	Induction miri NR miri IV 600 mg	20						1497.5 (61.0–13,737.0)	3.9 (0.1–41.0)	130.7	30.2	9 (45.0)	15 (75.0)
		Induction miri NR miri IV 1000 mg	64						1592.5 (15.0–31,680.0)	4.6 (0.1–67.4)	130.5	36.3	36 (56.3)	51 (79.7)
		Induction PBO NR miri IV 600 mg	12						1496.0 (275.0–3730.0)	16.8 (0.1–42.5)	142.9	39.1	7 (58.3)	8 (66.7)
		Induction PBO NR miri IV 1000 mg	32						1558.0 (15.0–12,379.0)	3.9 (0.3–138.0)	135.4	37.5	17 (53.1)	24 (75.0)
		Induction responders	106						1701 (15.0–31,680.0)	4.3 (0.10–164.0)	123.4	30	48 (45.3)	53 (50.0)
	Maintainance phase	Induction miri NR miri IV 600 mg	10
		Induction miri NR miri IV 1000 mg	28
		Induction PBO NR miri IV 600 mg	8
		Induction PBO NR miri IV 1000 mg	22
D’Haens, 2023 [26]	Induction phase	Mirikizumab, 300 mg IV	868			404 (46.5)	463 (53.3)	574 (66.1)	1559.0 (634.0–3210.0)	4.1 (1.5–9.6)			351 (40.4)	361 (41.6)
		Placebo IV	294			138 (47.1)	155 (52.9)	200 (68.3)	1471.5 (626.5–2944.5)	4.2 (1.2–9.5)			113 (38.4)	118 (40.1)
	Maintainance phase	Mirikizumab, 200 mg SC	365
		Placebo SC	179
D’Haens, 2024 [27]	Extended Induction phase	Mirikizumab Extended Induction Population 300 mg Mirikizumab IV, Q4W	272			117 (43.0)	154 (56.6)	197 (72.4)	1546.0 (650.0, 2912.0)	5.5 (2.5, 13.6)	131.3	33.75	118 (43.4)	1 therapy = 56 (20.6), >=2 therapies = 91 (33.4)
	Maintainance phase	Mirikizumab Extended Induction Responders 200 mg Mirikizumab SC, Q4W	144
		Placebo SC	179

Quality assessment

Sandborn 2022 showed a high risk of bias in the “sequence generation” and “allocation concealment” domains because it is a randomized open-label extension of Sandborn 2020, and the sequence generation was not clearly described in its methodology. All studies had a high risk of bias in the “other bias” domain because they were conducted by the same pharmaceutical company (Eli Lilly and Company). The other four domains were low-risk in all studies. The results of the risk of bias are displayed in Fig. 2.

Fig. 2.

Risk of bias summary and graph of the four included studies based on the Cochrane risk of bias assessment tool (ROB 1 tool)

Outcomes

Clinical remission

As illustrated in Fig. 3, all doses of Mirikizumab given intravenously reduced the symptoms and signs of UC. The total effect size (risk ratio) was 2.05, 95% CI [1.54, 2.72], P < 0.00001. However, 200 mg and 300 mg doses showed significant efficacy (RR = 4.74, 95% CI [1.43, 15.69] and RR = 1.82, 95% CI [1.33, 2.50], respectively).

Fig. 3.

Efficacy of different IV Mirikizumab doses on UC clinical remission at 12-week follow-up

In the extension trials, the symptoms subsided after the maintenance phase with a 200 mg dose given subcutaneously, and the analysis favored Mirkizumab over the placebo (RR = 1.46, 95% CI [0.47, 4.51], p-value = 0.51).

After doing sensitivity analysis by excluding Sandborn 2022, studies became homogeneous (Chi-square P = 1.07, I² = 6%) with significant results (RR = 2.09, 95% CI [1.35, 3.23], P = 0.0009) as shown in Fig. 4.

Fig. 4.

A Efficacy of 200 mg subcutaneous Mirikizumab dose on UC Clinical Remission at 52 Weeks. B Sensitivity analysis excluding Sandborn et al. 2022

Clinical response

All doses of Mirkizumab significantly improved the UC symptoms compared to placebo (RR = 2.01, 95% CI [1.42, 2.83], P < 0.0001) as demonstrated in Fig. 5. The heterogeneity between studies was best resolved after excluding D’Haens 2023 (Chi-square P = 0.64, I² = 0%), and the overall effect size (risk ratio) was 2.42, 95% CI [1.77, 3.32], P < 0.00001), as presented in Fig. 6.

Fig. 5.

Efficacy of different IV Mirikizumab doses on UC clinical response at 12-week follow-up

Fig. 6.

Sensitivity analysis displays the efficacy of Mirkizumab on clinical response outcome after removing D’ Haens 2023

Endoscopic remission

In the primary analysis, Mirkizumab significantly healed the inflamed lumen completely (RR = 1.72, 95% CI [1.36, 2.17], P < 0.00001). All doses revealed homogenous healing effects (Chi-square P = 0.98, I² = 0%) as shown in Fig. 7. However, a sensitivity analysis excluding the D’ Haens 2023 study, which accounted for 97.3% of the weight, revealed a significant change in the pooled estimate (RR = 1.68, 95% CI [0.40, 7.05], P < 0.48, I² = 0%, Chi-square P = 0.92), as shown in Figure S1.

Fig. 7.

Efficacy of different IV Mirikizumab doses on UC endoscopic remission after 12-week follow-up

After the maintenance phase of SC Mirkizumab (52 weeks of follow-up), Mirkizumab significantly enhanced the endoscopic remission in more patients (RR = 1.92, 95% CI [1.52,2.44], P < 0.00001), as shown in Fig. 8. There was no detected heterogeneity among the studies (Chi-square P = 0.13, I² = 51%). After excluding D’ Haens 2023 study due to its dominance in the analysis model (with weight of 97.3%), the sensitivity analysis’s pooled effect estimate was (RR = 0.93, 95% CI [0.36,2.40], P = 0.89, I² = 39%, Chi-square P = 0.20), as shown in Figure S2.

Fig. 8.

Forest plot analyzing the Mirkizumab effect on endoscopic remission after the end of the maintenance phase in patients with UC

Histological remission

In Fig. 9, the histological remission was achieved in all groups of Mirkizumab better than the placebo group regardless of the given dose (overall RR = 1.84, 95% CI [1.47, 2.32], P < 0.00001) except in the 50 mg dose group; however, it did not affect the effect significance or the homogeneity across the groups (Chi-square P = 0.16, I² = 42%).

Fig. 9.

Efficacy of different IV Mirkizumab doses on histological remission of patients with UC in the induction phase (12-week follow-up)

Figure 10 shows the Mirkizumab effect after the maintenance dose in three trials. The overall risk ratio between Mirkizumab and placebo favored Mirkizumab over placebo (RR 1.30, 95% CI [0.69,2.45], P < 0.42). The heterogeneity emerged between Sandborn 2022 and the other studies because of the methodological differences as stated before (Chi-square P = 0.03, I² = 83%).

Fig. 10.

A Forest plot analyzing the effect size of Mirkizumab on histological remission of patients with UC. B Sensitivity analysis excluding Sandborn et al. 2022

After excluding Sandborn 2022, the significant pooled risk ratio desired Mirkizumab more. (RR 1.88, 95% CI [1.45,2.43], P < 0.00001) without impacting the significance of results (Chi-square P = 0.97, I² = 0%), as shown in Fig. 10.

Symptomatic remission

Symptoms significantly disappeared in patients with chronic and recurrent UC after 12 weeks of IV Mirkizumab administration (RR = 1.79, 95% CI [1.51, 2.11], P < 0.00001), as shown in Fig. 11. There was no detected heterogeneity across the studies (Chi-square P = 0.24, I² = 29%).

Fig. 11.

Symptomatic Remission outcome after induction phase of Mirkizumab in patients with UC

Severe adverse events

The pooled results favored Mirkizumab over placebo in reducing the progression and complications of UC at the end of 52 weeks of drug administration (RR 0.43, 95% CI [0.22,0.82], P < 0.00001), as presented in Fig. 12. The pooled studies were homogenous (Chi-square P = 0.25, I² = 27%). After excluding the dominant study, D’ Haens 2023, which had a weight of 80.5% in the primary analysis model, the pooled RR became 0.43, (95% CI [0.10,1.86], P = 0.26, I² = 64%, Chi-square P = 0.10), as shown in Figure S3.

Fig. 12.

Forest plot analysis showing effect of Mirikizumab on adverse events and drug discontinuation after 52 weeks in UC patients

Discontinuation due to adverse events

As shown in Fig. 12, there was a significant difference between the Mirkizumab group and the placebo group in the number of participants who stopped the intervention and withdrew from the study. More participants quit the placebo (RR 0.23, 95% CI [0.10,0.57], P = 0.001). Pooled studies were homogenous (Chi-square P = 0.24, I² = 31%). By conducting sensitivity analysis and excluding the dominant study, D’ Haens 2023, whose weight was 84.8% in the primary analysis model, the pooled RR became 1.13 (95% CI [0.13,9.99], P = 0.91, I² = 0%, Chi-square P = 0.42), as shown in Figure S4.

Discussion

In our meta-analysis, we found moderate-to-high-quality evidence supporting the efficacy of mirikizumab for all outcomes. The analysis of randomized controlled trials demonstrated the superiority of mirikizumab over placebo in inducing a short-term clinical response. All doses of mirikizumab significantly improved UC symptoms compared to placebo (RR = 2.01, 95% CI [1.42, 2.83], P < 0.0001), with the 200 mg and 300 mg doses showing particularly significant efficacy (RR = 4.74, 95% CI [1.43, 15.69] and RR = 1.82, 95% CI [1.33, 2.50], respectively).

In terms of endoscopic remission, all doses of mirikizumab completely healed the inflamed lumen. Mirikizumab also achieved better histological remission than placebo, except for the 50 mg dose group, which did not affect the overall significance. Our pooled results also favored mirikizumab over placebo in reducing the progression and complications of UC after 52 weeks of administration.

Heterogeneity in clinical remission was resolved following the exclusion of Sandborn 2022, which has an extended induction phase of non-responders from Sandborn 2020. The source of heterogeneity is most likely due to participants in Sandborn 2022 receiving two IV induction phases of Mirkizumab before transitioning to the subcutaneous maintenance phase [25]. This extended induction period probably resulted in different treatment effects than other studies that followed the standard induction-maintenance sequence. The additional IV induction phase may have resulted in a more dramatic or prolonged response, producing variability when the results were combined with studies employing different protocols.

Regarding clinical response, heterogeneity between studies was resolved following the exclusion of D’Haens 2023 in the sensitivity analysis. Possible explanations for this include the difference in defining this outcome compared to other studies. A more stringent definition of clinical response was used in the D’Haens 2023, including both a decrease in the modified Mayo score of ≥ 2 points and ≥ 30% from baseline, and endoscopic remission, specifically excluding friability, and histologic–endoscopic mucosal improvement [26]. Other studies, such as Sandborn 2020, focused on a 35% drop in the 9-point Mayo subscore with more flexible rectal bleeding criteria but did not include histologic criteria [24]. Sandborn 2022, while stricter in some aspects, including the requirement for a rectal bleeding score of 0 and centrally read endoscopy, did not include the histologic components of D’Haens 2023 [25]. These definitional variations, particularly the inclusion of histologic assessment and stricter endoscopic criteria in D’Haens 2023, are likely to have contributed to the observed heterogeneity, as they raise the bar for what constitutes a clinical response, making it less comparable to the outcomes measured in other studies.

These findings demonstrate that mirikizumab has significant efficacy in protecting against UC complications. The observed adverse effects may be due more to the disease itself than to the administered drug. Additionally, more participants discontinued the placebo than those who discontinued mirikizumab, further supporting our hypothesis.

Regarding improvement in disease parameters, the studies by D’Haens (2023, 2024) investigated the efficacy of mirikizumab in treating refractory inflammatory bowel disease and identifying predictors of treatment response. D’Haens 2023 et al. found that Mirikizumab significantly outperformed placebo in inducing various measures of disease remission, including clinical, glucocorticoid-free, endoscopic, histologic-endoscopic mucosal, and bowel urgency remission. Particularly in patients with prior biologic or tofacitinib failures, mirikizumab showed superior outcomes in achieving trial endpoints by week 40 [26]. Additionally, improvements in disease-specific quality of life scores and inflammatory markers were observed in the mirikizumab group compared to placebo [26].

In D’Haens 2024, the focus shifted to predictors of clinical response during extended induction therapy. Achieving clinical remission at week 52 was associated with sustained corticosteroid discontinuation in the majority of patients. Lower baseline levels of fecal calprotectin and C-reactive protein emerged as predictive factors for favorable treatment responses [27]. Analyses underscored the importance of early improvements in endoscopic and histologic scores, alongside demographic factors such as age and prior treatment history, in predicting clinical response at week 24 [27].

Mirikizumab has consistently shown efficacy across different phases of treatment in patients with UC. After the induction phase of Sandborn 2020, all dosage groups (50 mg, 200 mg, and 600 mg) demonstrated numerically higher rates of clinical remission by Week 12 compared to placebo. Although statistical significance was not reached in the highest dose group (600 mg), significant clinical response rates were observed across all mirikizumab groups [24]. Patients treated with mirikizumab also experienced significant improvements in endoscopic findings and achieved symptomatic and histologic remission [24].

Moving to the maintenance phase, Sandborn 2020 et al. proved mirikizumab’s effectiveness in sustaining clinical remission and response up to Week 52. Both dosing regimens (every 4 weeks and every 12 weeks) of mirikizumab (200 mg) demonstrated strong efficacy in maintaining clinical remission, with higher rates observed in the more frequent dosing schedule [24]. Notably, substantial improvements in endoscopic and histologic remission rates were observed, indicating comprehensive healing of mucosal and tissue inflammation. The maintenance of durable responses in a significant proportion of patients highlighted the potential long-term benefits of mirikizumab in managing UC [24].

In the extended intravenous induction phase, Sandborn 2022 et al. further demonstrated mirikizumab efficacy in achieving symptomatic remission and enhancing quality of life. Significant reductions in symptomatic measures and marked improvements in quality of life scores, as measured by IBDQ and SF-36, underscored enhanced symptom control and overall patient well-being [25].

Concerning safety and adverse events, the safety profile of mirikizumab, as evaluated across multiple studies (Sandborn et al., 2020; Sandborn 2022 et al.; D’Haens 2023 et al.; D’Haens 2024 et al.), generally indicated manageable adverse events consistent with biologic therapies for ulcerative colitis. Common adverse events included nasopharyngitis, worsening of UC symptoms, headaches, and upper respiratory tract infections. Serious adverse events, although infrequent, included complications such as severe exacerbations of UC and gastrointestinal issues, which were not directly attributed to mirikizumab treatment [24–27].

However, D’Haens 2023 et al. highlighted a higher incidence of opportunistic infections and elevations in liver enzymes among mirikizumab-treated patients compared to placebo. Additionally, it was reported that one patient attempted suicide during the maintenance phase; however, it was deemed unrelated to mirikizumab treatment, given previous suicidal attempts and the past medical history of depression in this patient [26].

In contrast, D’Haens 2024 et al. focused on safety outcomes during the extended induction phase and reported a generally low incidence of treatment-emergent adverse events. Importantly, no new safety concerns or deaths were noted during this phase, supporting the favorable safety profile of mirikizumab over extended use [27].

Regarding the cost-effectiveness ofmirikizumab, a recent comprehensive cost-effectiveness analysis compared the use of mirikizumab and ustekinumab in patients suffering from moderately to severely active UC, particularly those who had not responded to anti-TNF therapies previously. This evaluation used methodologies such as a Markov model to assess key metrics like the cost per quality-adjusted life year gained or per clinical remission achieved [28]. The findings from this analysis concluded that using mirikizumab was economically advantageous within the U.S. healthcare system [28]. Despite mirikizumab’s higher initial costs, the analysis suggested that these were justified by improved health outcomes and potentially reduced adverse events compared to ustekinumab [28].

Moreover, a budget impact analysis was conducted to evaluate the financial implications associated with adopting mirikizumab versus ustekinumab in the healthcare system. This analysis specifically focused on the cumulative incremental costs related to mirikizumab use among patients who had previously failed advanced therapies, including anti-TNF agents. Surprisingly, the results showed that despite mirikizumab’s potentially higher drug acquisition costs, its overall healthcare expenditure, which includes disease management and adverse events, was lower than that associated with ustekinumab. This was attributed to mirikizumab’s demonstrated superior efficacy or reduced need for subsequent treatments [29].

Although other IL-23 inhibitors, such as ustekinumab, risankizumab and guselkumab, have demonstrated efficacy in improving UC outcomes, mirikizumab’s specific targeting of the p19 subunit of IL-23 offers a distinct advantage in achieving clinical remission and histologic improvement [30]. While risankizumab has demonstrated potential for treating Crohn’s disease, it has not been authorized for use in ulcerative colitis; however, ustekinumab has been effective for treating both Crohn’s disease and UC. The mode of action of mirikizumab and the positive results seen in phase III trials indicate that it may offer greater benefits compared to other IL-23 inhibitors, suggesting it could be a more effective treatment choice for UC compared to current or future IL-23 inhibitors [30].

Limitations and future directions

As is customary with such data, the results should be interpreted cautiously as there are methodological differences between studies, small sample sizes, impact of a dominant study in some outcomes, and potential bias from the pharmaceutical company conducting all studies. Moreover, including only RCTs studies may possess a source of limitation. Furthermore, the inadequate evaluation of long-term efficacy and safety, lack of demographic information, and absence of comparisons with other treatment options present additional limitations. The review focused on Mirkizumab’s efficacy and safety compared to placebo without determining its position among other treatments for UC. Therefore, caution is required when interpreting the results due to their limited generalizability.

Future research should concentrate on collecting longer-term safety data and conducting comparative studies that assess mirkizumab against other treatment options for UC, particularly against other IL-23 inhibitors such as risankizumab, in terms of safety and tolerability. Additionally, it is crucial to acknowledge the limitations arising from heterogeneity and the absence of treatment comparisons when concluding the position of Mirkizumab in the overall landscape of UC treatment. In future studies, researchers must address the study’s limitation by conducting subgroup analyses based on previous exposure to specialized treatments, such as distinguishing between patients who are biologic-naive and those who are biologic-experienced. This method has the potential to yield valuable insights into the differing effectiveness and safety of mirikizumab among these specific patient groups.

Conclusion

Mirikizumab demonstrates significant efficacy in treating UC, substantially improving clinical, endoscopic, and histological outcomes. Its safety profile and cost-effectiveness analyses favor its use. The findings of our study highlight the crucial clinical implications of Mirikizumab and underscore its potential impact on treatment guidelines in treating UC. This research advocates for its integration into standard treatment protocols for improved patient outcomes and enhanced clinical care. Further research is still necessary to confirm its long-term benefits, select the best induction and maintenance doses, and directly compare its effectiveness against other treatments.

Abbreviations

UC

Ulcerative colitis

IBD

Inflammatory bowel disease

Ig

Immunoglobulin

TNF-α

Tumor Necrosis Factor alpha

IL-23

Interleukin-23

IL-23R

Interleukin-23 Receptor

IBDQ

Inflammatory Bowel Disease Questionnaire

RR

Risk Ratio

MD

Mean Difference

CI

Confidence Interval

RevMan

Review Manager

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Authors’ contributions

Mohamed A. Abu Elainein , Sama S. ElSherefy, and Nada G.Hamam conducted statistical analysis and wrote the main manuscript text. Salma Allam and Ahmed Nour Eldin Hassan designed the research study, defining the main research questions and objectives. Norhan M Yousef and Sama M. ElKady were responsible for retrieving the relevant literature and selecting studies that met the inclusion criteria and handled data extraction and quality assessment. Abdelrahman Elgarawany and Darin W. Aswa integrated the results and drafted the discussion section of the manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

Data is provided within the manuscript or supplementary information files

Declarations

Ethics approval and consent to participate

Does not apply. There was no involvement of new human participants in this study.

Consent for publication

Does not apply. There was no involvement of new human participants in this study.

Competing interests

The authors declare no competing interests.