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Mirikizumab
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What were the results of the phase 2 clinical trial of mirikizumab for the treatment of Crohn's disease in adults?
Patients with moderate-to-severe Crohn’s disease who received mirikizumab achieved endoscopic response at week 12, and the efficacy of mirikizumab was sustained to week 52. Incidences of adverse events were similar for mirikizumab and placebo.
Study Design
A phase 2, multicenter, randomized, parallel-arm, double-blind, placebo-controlled study evaluated the safety and efficacy of mirikizumab in 191 adults with moderately-to-severely active Crohn's disease.1
Induction Period
Participants were randomized to receive intravenous administration of mirikizumab 200 mg, mirikizumab 600 mg, mirikizumab 1000 mg, or placebo every 4 weeks through week 12. Randomization to treatment groups was stratified by previous use of biologics for the treatment of Crohn's disease.1
During the study, patients were allowed to receive concomitant treatment with
- oral 5-aminosalicylic compounds
- oral corticosteroids
- azathioprine
- 6-mercaptopurine
- methotrexate, or
- antibiotics specific for Crohn's disease.1
Study Design of the Phase 2 Study of Mirikizumab in Patients With Crohn's Disease shows the design of the overall trial.
Figure 1 description: In the 12-week induction period, 191 patients were randomized 2 to 1 to 1 to 2 to receive treatment with mirikizumab 200 mg, mirikizumab 600 mg, mirikizumab 1000 mg, or placebo intravenously every 4 weeks. Patients were stratified by previous biologic therapy. The patients received maintenance dosing after week 12 through week 52.
Abbreviations: CD = Crohn's disease; IV = intravenous; Q4W = every 4 weeks; SC = subcutaneous; SES CD = Simple Endoscopic Score for Crohn's disease.
* At week 12, all patients were rerandomized in regard to endoscopic improvement (decrease of SES CD ≥1) to receive IV or SC mirikizumab.
Maintenance Period
Rerandomized Maintenance Cohort
Patients who received mirikizumab during the induction period and had an improvement from baseline to week 12 of at least 1 point in their Simple Endoscopic Score for Crohn's Disease (SES-CD) were randomized to receive treatment through week 52 with either
- the assigned induction treatment of mirikizumab (200 mg, 600 mg, or 1000 mg) intravenously plus subcutaneous placebo every 4 weeks, or
- mirikizumab 300 mg subcutaneously plus placebo intravenously every 4 weeks.1
Randomization was stratified by endoscopic response (reduction in SES-CD score from baseline of 50%).1
Nonrandomized Maintenance Cohort
Patients in the nonrandomized maintenance cohort was composed of
- all patients who received mirikizumab during the induction period and did not have an improvement from baseline to week 12 of at least 1 point in their SES-CD score, and
- all patients who received placebo during the induction period.1
Patients in this cohort received treatment with mirikizumab 1000 mg intravenously plus subcutaneous placebo every 4 weeks through week 52.1
Inclusion and Exclusion Criteria
Inclusion and Exclusion Criteria in the Phase 2 Study of Mirikizumab for the Treatment of Crohn's Disease shows selected inclusion and exclusion criteria for participation in the study.
Inclusion Criteria |
Exclusion Criteria |
|
|
Abbreviations: IL23p19 = interleukin 23, alpha subunit p19; SES-CD = Simple Endoscopic Score for Crohn's Disease.
aModerate-to-severe disease was defined as: 1) stool frequency ≥4 and/or abdominal pain ≥2 at baseline, and 2) a centrally read SES-CD ≥7 for patients with ileal-colonic or ≥4 for patients with isolated ileal disease within 14 days of first dose of study treatment.
bSuch as tumor necrosis factor (TNF) antagonists, vedolizumab, or experimental biologic drug for the treatment of Crohn's disease except those targeting IL23p19. The treatment must have been discontinued according to the following timeline: anti-TNF therapy ≥8 weeks before baseline, vedolizumab treatment ≥12 weeks before baseline, and experimental Crohn's disease therapy ≥8 weeks before baseline.
cIn the United States, an addendum to the criteria allowed a single dose of ustekinumab if received at least 12 weeks prior to baseline.
Outcomes
The primary endpoint of the phase 2 study of mirikizumab in adults with moderate-to-severe Crohn's disease was endoscopic response of mirikizumab compared with placebo at week 12. Endoscopic response was defined as a 50% reduction from baseline in SES-CD.1
Secondary endpoints included
- evaluation of safety and tolerability
- endoscopic response at week 52
- endoscopic remission, defined as SES-CD <4 for ileal-colonic disease or <2 for isolated ileal disease, with no subscore >1, at weeks 12 and 52
- patient-reported outcome (PRO) remission, defined as an average daily abdominal pain score ≤1 and average daily stool frequency ≤2.5, at weeks 12 and 52, and
- change from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ) score.1
Exploratory endpoints included
- change from baseline in high-sensitivity C-reactive protein and fecal calprotectin
- Crohn's Disease Activity Index (CDAI) response at weeks 12 and 52, defined as
- a decrease in CDAI score of at least 100 points from baseline, or
- CDAI score <150
- CDAI remission at weeks 12 and 52, defined as CDAI score <150
- PRO response, defined as ≥30% reduction in abdominal pain and/or stool frequency and no worse than baseline, and
- durability of outcomes at week 52.1
Baseline Patient Demographics and Disease Characteristics
Baseline characteristics were similar across treatment groups (Baseline Demographics and Disease Characteristics of Participants in the Phase 2 Study of Mirikizumab for the Treatment of Crohn's Disease, ITT Population).1
Parametera |
MIRI 200 mg IV |
MIRI 600 mg IV |
MIRI 1000 mg IV |
PBO IV |
Age, years |
38.1 (11.8) |
40.4 (13.3) |
37.7 (13.1) |
39.0 (13.0) |
Male, n (%) |
17 (54.8) |
14 (43.8) |
34 (53.1) |
28 (43.8) |
Disease duration, years |
8.9 (7.4) |
10.8 (9.7) |
8.6 (6.7) |
10.2 (9.8) |
Disease location, n (%) |
||||
Ileal |
6 (19.4) |
5 (15.6) |
11 (17.2) |
11 (17.2) |
Colonic |
14 (45.2) |
10 (31.3) |
26 (40.6) |
25 (39.1) |
Ileocolonic |
11 (35.5) |
17 (53.1) |
27 (42.2) |
28 (43.8) |
SES-CD |
14.4 (7.9) |
15.2 (7.4) |
13.1 (6.8) |
11.9 (5.6) |
PRO scores |
||||
SF |
7.4 (3.0) |
6.4 (3.8) |
6.6 (5.5) |
6.4 (3.1) |
AP |
2.0 (0.6) |
1.7 (0.7) |
1.9 (0.6) |
1.9 (0.6) |
CDAI |
348.3 (92.1) |
298.2 (103.7) |
304.5 (94.4) |
304.7 (93.1) |
Previous biologic use, n (%)b |
19 (61.3) |
19 (59.4) |
39 (60.9) |
43 (67.2) |
Previous biologic failure, n (%)c |
15 (48.4) |
16 (50.0) |
31 (48.4) |
36 (56.3) |
Prior vedolizumab use, n (%) |
5 (16.1) |
5 (15.6) |
6 (9.4) |
14 (21.9) |
Prior anti-TNF use, n (%) |
||||
0 |
14 (45.2) |
14 (43.8) |
26 (40.6) |
25 (39.1) |
1 |
10 (32.3) |
9 (28.1) |
22 (34.4) |
16 (25.0) |
2 |
7 (22.6) |
5 (15.6) |
14 (21.9) |
22 (34.4) |
3+ |
0 |
4 (12.5) |
2 (3.1) |
1 (1.6) |
Concomitant oral corticosteroid use, n (%) |
14 (45.2) |
7 (21.9) |
15 (23.4) |
21 (32.8) |
Concomitant immunosuppressant use, n (%) |
12 (38.7) |
10 (31.3) |
21 (32.8) |
19 (29.7) |
IBDQ |
104.77 (34.31) |
127.03 (35.47) |
120.31 (32.40) |
113.88 (37.07) |
hsCRP (median, Q1, Q3) |
7.4 (2.3, 31.4) |
6.8 (2.7, 20.7) |
4.5 (2.7, 15.5) |
6.8 (1.8, 19.0) |
FCP (median, Q1, Q3) |
877.0 |
822.5 |
773.0 |
799.5 |
Abbreviations: AP = abdominal pain; CDAI = Crohn's Disease Activity Index; FCP = fecal calprotectin; hsCRP = high-sensitivity C-reactive protein; IBDQ = Inflammatory Bowel Disease Questionnaire; ITT = intent-to-treat; IV = intravenous; MIRI = mirikizumab; PBO = placebo; PRO = patient-reported outcome; Q1 = quartile 1; Q3 = quartile 3; SES-CD = Simple Endoscopic Score for Crohn's Disease; SF = stool frequency; TNF = tumor necrosis factor.
aData are presented as mean (SD) unless otherwise noted.
bNo patients had received prior treatment with ustekinumab.
cIncludes inadequate response, loss of response, or intolerance to medication.
Efficacy Results
Induction Period (Week 12)
A total of 191 patients were randomized to study treatment, and 92.1% of patients completed the induction period of the trial.1
At week 12, the proportion of patients meeting the primary endpoint of endoscopic response was
- 10.9% for placebo
- 25.8% for mirikizumab 200 mg (p=.079 vs placebo)
- 37.5% for mirikizumab 600 mg (p=.003), and
- 43.8% for mirikizumab 1000 mg (p<.001) (Efficacy Results at the End of the 12-Week Induction Period in the Phase 2 Study of Mirikizumab for the Treatment of Crohn's Disease, ITT Population).1
Efficacy Results at the End of the 12-Week Induction Period in the Phase 2 Study of Mirikizumab for the Treatment of Crohn's Disease, ITT Population shows data for the secondary and exploratory efficacy endpoints.
Parameter |
MIRI 200 mg IV |
MIRI 600 mg IV |
MIRI 1000 mg IV |
PBO IV |
Endoscopic responsea |
8 (25.8)b |
12 (37.5)c |
28 (43.8)d |
7 (10.9) |
Difference vs PBO (95% CI) |
14.9 (-2.3, 32.1) |
26.6 (8.1, 45.0) |
32.8 (18.5, 47.2) |
NA |
Endoscopic remissione |
2 (6.5) |
5 (15.6)f |
13 (20.3)c |
1 (1.6) |
Difference vs PBO (95% CI) |
4.9 (-4.3, 14.1) |
14.1 (1.1, 27) |
18.8 (8.4, 29.1) |
NA |
PRO responseg |
19 (61.3)f |
22 (68.8)c |
39 (60.9)f |
23 (35.9) |
Difference vs PBO (95% CI) |
25.4 (4.6, 46.1) |
32.8 (12.9, 52.7) |
25.0 (8.2, 41.8) |
NA |
PRO remissionh |
4 (12.9) |
9 (28.1)f |
14 (21.9)b |
4 (6.3) |
Difference vs PBO (95% CI) |
6.7 (-6.6, 19.9) |
21.9 (5.2, 38.5) |
15.6 (3.9, 27.4) |
NA |
CDAI responsei |
15 (48.4)f |
18 (56.3)c |
27 (42.2)f |
15 (23.4) |
Difference vs PBO (95% CI) |
24.9 (4.5, 45.4) |
32.8 (12.7, 52.9) |
18.8 (2.8, 34.7) |
NA |
CDAI remissionj |
5 (16.1) |
13 (40.6)d |
17 (26.6)f |
6 (9.4) |
Difference vs PBO (95% CI) |
6.8 (-8, 21.5) |
31.3 (12.8, 49.7) |
17.2 (4.2, 30.2) |
NA |
hsCRP % change from BL, median (Q1, Q3) |
-29.9d |
-39.8d |
-48.6d |
43.8 |
FCP % change from BL, median (Q1, Q3) |
-60.7 |
-62.1f |
-76.2d |
0.0 |
Abbreviations: BL = baseline; CDAI = Crohn's Disease Activity Index; FCP = fecal calprotectin; hsCRP= high-sensitivity C-reactive protein; ITT = intent-to-treat; IV = intravenous; MIRI = mirikizumab; NA = not applicable; PBO = placebo; PRO = patient-reported outcome; SES-CD = Simple Endoscopic Score for Crohn's disease.
a50% reduction from baseline in SES-CD score.
bp<.1.
cp<.01.
dp<.001.
eSES-CD score of <4 for ileal-colonic disease or <2 for isolated ileal disease, and no subscore >1.
fp<.05.
g≥30% decrease in abdominal pain and/or stool frequency and no worse than baseline.
hStool frequency ≤2.5 and abdominal pain ≤1 and no worse than baseline.
iDecrease from baseline in CDAI score of 100 points or more or a CDAI score <150.
jCDAI score of <150 points.
Maintenance Period (Week 52)
At week 52, the proportion of patients with endoscopic response was
- 58.5% of patients who continued induction intravenous treatment, and
- 58.7% of patients who were rerandomized to 300-mg mirikizumab subcutaneously during the maintenance period (see Efficacy Results at the End of the 52-Week Maintenance Period in the Phase 2 Study of Mirikizumab for the Treatment of Crohn's Disease, ITT Population).1
At week 52, the proportion of patients with endoscopic remission was
- 19.5% of patients who continued induction intravenous treatment, and
- 32.6% of patients who were rerandomized to 300-mg mirikizumab subcutaneously during the maintenance period (see Efficacy Results at the End of the 52-Week Maintenance Period in the Phase 2 Study of Mirikizumab for the Treatment of Crohn's Disease, ITT Population).1
Parametera |
IV-C Q4Wb |
MIRI 300 mg SC Q4W |
Placebo/MIRI 1000 mg IV Q4W |
Endoscopic Nonimprovers/MIRI 1000 mg IV Q4W |
Randomized Maintenancec |
Nonrandomized Maintenance |
|||
Week 12 |
||||
Endoscopic responsed |
23 (56.1) |
24 (52.2) |
7 (11.9) |
0 |
Endoscopic remissione |
6 (14.6) |
14 (30.4) |
1 (1.7) |
0 |
PRO remissionf |
14 (34.1) |
9 (19.6) |
4 (6.8) |
4 (13.3) |
CDAI remissiong |
13 (31.7) |
15 (32.6) |
6 (10.2) |
6 (20.0) |
Week 52h |
||||
Endoscopic responsed |
24 (58.5) |
27 (58.7) |
25 (42.4) |
6 (20.0) |
Endoscopic response in W12 responders, n/N (%) |
16/23 (69.6) |
16/24 (66.7) |
4/7 (57.1) |
NA |
Endoscopic remissione |
8 (19.5) |
15 (32.6) |
11 (18.6) |
4 (13.3) |
Endoscopic remission in W12 remitters, n/N (%) |
3/6 (50.0) |
9/14 (64.3) |
0/1 (0.0) |
NA |
PRO responsei |
28 (68.3) |
33 (71.7) |
36 (61.0) |
18 (60.0) |
PRO remissionf |
19 (46.3) |
21 (45.7) |
24 (40.7) |
11 (36.7) |
PRO remission in W12 remitters, n/N (%) |
10/14 (71.4) |
6/9 (66.7) |
3/4 (75.0) |
3/4 (75.0) |
CDAI responsej |
22 (53.7) |
32 (69.6) |
31 (52.5) |
14 (46.7) |
CDAI remissiong |
16 (39.0) |
26 (56.5) |
24 (40.7) |
7 (23.3) |
CDAI remission in W12 remitters, n/N (%) |
9/13 (69.2) |
13/15 (86.7) |
5/6 (83.3) |
4/6 (66.7) |
Abbreviations: CDAI = Crohn's Disease Activity Index; IV = intravenous; IV-C = continued intravenous induction treatment; MIRI = mirikizumab; NA = not applicable; PBO = placebo; PRO = patient-reported outcome; Q4W = every 4 weeks; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn's disease; W12 = week 12.
aData are presented as n (%) unless otherwise noted.
bIV MIRI 200 mg, 600 mg, or 1000 mg.
cPatients with ≥1-point improvement in SES-CD at week 12.
d50% reduction from baseline in SES-CD.
eSES-CD score of <4 for ileal-colonic disease or <2 for isolated ileal disease, and no subscore >1.
fStool frequency ≤2.5 and abdominal pain ≤1 and no worse than baseline.
gCDAI score of <150 points.
hFor all efficacy endpoints, IV-C and SC confidence intervals overlap.
i≥30% decrease in abdominal pain and/or stool frequency and no worse than baseline.
jDecrease from baseline in CDAI score of 100 points or more or a CDAI score <150.
Safety Results
Induction Period (Week 12)
During the induction period, at least 1 treatment-emergent adverse event (TEAE) was reported by
- 70.3% of patients who received placebo
- 58.1% of patients who received mirikizumab 200 mg
- 65.6% of patients who received mirikizumab 600 mg, and
- 65.6% of patients who received mirikizumab 1000 mg.1
The most frequently-reported TEAEs by patients who received mirikizumab included
- headache
- worsening of Crohn's disease
- arthralgia
- nasopharyngitis
- increased weight
- anemia, and
- nausea.1
Overall, a slightly smaller proportion of patients who received mirikizumab reported at least 1 TEAE than did patients who received placebo, and the frequencies of patients who reported at least 1 TEAE were similar across the mirikizumab treatment arms.1
Safety Results From the 12-Week Induction Period of the Phase 2 Study of Mirikizumab in Patients With Moderate-to-Severe Crohn's Disease shows safety results from the induction period of the phase 2 study of mirikizumab for the treatment of Crohn's disease.
Parametera |
MIRI 200 mg IV |
MIRI 600 mg IV |
MIRI 1000 mg IV |
PBO IV |
TEAE |
18 (58.1) |
21 (65.6) |
42 (65.6) |
45 (70.3) |
SAE |
0 |
3 (9.4)b |
2 (3.1)c |
7 (10.9)d |
Discontinuations due to AE |
1 (3.2) |
3 (9.4) |
0 |
3 (4.7) |
Most common TEAEs in decreasing frequency |
||||
Headache |
2 (6.5) |
2 (6.3) |
7 (10.9) |
2 (3.1) |
Worsening Crohn’s disease |
0 |
1 (3.1) |
0 |
9 (14.1) |
Arthralgia |
1 (3.2) |
1 (3.1) |
3 (4.7) |
3 (4.7) |
Nasopharyngitis |
0 |
2 (6.3) |
4 (6.3) |
1 (1.6) |
Weight increased |
1 (3.2) |
2 (6.3) |
3 (4.7) |
0 |
Anemia |
2 (6.5) |
1 (3.1) |
2 (3.1) |
1 (1.6) |
Nausea |
0 |
2 (6.3) |
2 (3.1) |
2 (3.1) |
Abbreviations: AE = adverse event; IV = intravenous; MIRI = mirikizumab; PBO = placebo; SAE = serious adverse event; TEAE = treatment-emergent adverse event.
aData presented as n (%).
bThree patients reported a total of 4 events: chest pain, worsening of Crohn's disease, colon perforation discovered during endoscopy, and colonic stenosis.
cOne patient reported abdominal pain and one patient reported back pain.
dEvents included worsening of Crohn's disease in 3 patients, and one patient each with hypokalemia, malaise, pneumatosis intestinalis, and pyrexia.
Maintenance Period (Week 52)
Safety Results From the 52-Week Maintenance Period of the Phase 2 Study of Mirikizumab in Patients With Moderate-to-Severe Crohn's Disease shows safety results from the maintenance period of the phase 2 study of mirikizumab for the treatment of Crohn's disease.
Parametera |
IV-C Q4W |
MIRI 300 mg SC Q4W |
PBO/MIRI 1000 mg IV Q4W |
Endoscopic Nonimprovers/MIRI 1000 mg IV Q4W |
Randomized Maintenanceb |
Nonrandomized Maintenance |
|||
TEAE |
31 (75.6) |
35 (76.1) |
45 (76.3) |
21 (70.0) |
SAE |
0 |
2 (4.3)c |
8 (13.6)d |
3 (10.0) |
Discontinuations due to AE |
1 (2.4) |
1 (2.2) |
7 (11.9) |
3 (10.0) |
Most common TEAEs (≥5%) in decreasing frequency as a percentage of the total population |
||||
Nasopharyngitis |
2 (4.9) |
6 (13.0) |
4 (6.8) |
3 (10.0) |
Headache |
3 (7.3) |
4 (8.7) |
4 (6.8) |
3 (10.0) |
Arthralgia |
3 (7.3) |
6 (13.0) |
3 (5.1) |
1 (3.3) |
Anemia |
2 (4.9) |
2 (4.3) |
5 (8.5) |
2 (6.7) |
Injection-site pain |
2 (4.9) |
4 (8.7) |
3 (5.1) |
1 (3.3) |
Upper respiratory tract infection |
2 (4.9) |
3 (6.5) |
3 (5.1) |
2 (6.7) |
Abdominal pain |
3 (7.3) |
3 (6.5) |
3 (5.1) |
0 |
Abbreviations: AE = adverse event; IV = intravenous; IV-C = continued intravenous induction treatment; MIRI = mirikizumab; PBO = placebo; Q4W = every 4 weeks; SAE = serious adverse event; SES-CD = Simple Endoscopic Score for Crohn's disease; TEAE = treatment-emergent adverse event.
aData presented as n (%).
bPatients with ≥1-point improvement in SES-CD at week 12.
cOne patient reported worsening of Crohn's disease, pyelonephritis, and dehydration, and one patient reported ileal perforation secondary to ileitis and peritonitis.
dTwo patients reported anaphylactic reaction and one patient each reported Clostridioides difficile infection, hypersensitivity, intestinal obstruction, noncardiac chest pain, osteoarthritis, and worsening of Crohn's disease.
Adverse Events of Special Interest
There were no reports of death, malignancy, or veno-occlusive disease including pulmonary embolism in either the induction or maintenance periods of the studies.1
One patient who received placebo during the induction period of the study reported an opportunistic infection (herpes zoster).1
A total of 3 patients reported an opportunistic infection during the maintenance period of the study, including
- one case of oral candidiasis in an endoscopic nonimprover who received mirikizumab 1000 mg during the maintenance period, and
- 2 cases of herpes zoster in patients who received placebo during induction and mirikizumab 1000 mg during the maintenance period.1
Reference
The published reference below is available by contacting 1-800-LillyRx (1-800-545-5979).
1Sands BE, Peyrin-Biroulet L, Kierkus J, et al. Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with Crohn's disease. Gastroenterology. 2022;162(2):495-508. https://doi.org/10.1053/j.gastro.2021.10.050
Date of Last Review: December 15, 2021