Table 1.
Summary of clinical trials of anti-IL-23 agents in IBD
| Agent | Mechanism of action | Trial [s] | Population studied | Study design | Primary outcome | Secondary outcomes/additional analyses |
|---|---|---|---|---|---|---|
| Risank izumab |
Monoclonal IgG1 antibody to IL23p19 | Randomised, double-blind, placebo-controlled Phase II clinical trial [NCT02031276, Feagan et al.13] with subsequent open-label extension14]; two randomised, double-blind, placebo-controlled Phase III clinical trials (ADVANCE [NCT03105128] and MOTIVATE [NCT03105128], D’Haens et al.15) | Feagan et al. 108 patients 18–75 years old, with minimum 3-month history of CD, with moderate-severely active disease based on CDAI 220–450, ulcers in the colon, ileum, or both, CDEIS-19 of at least 4 if isolated ileitis and at least 7 if ileocolitis Patients could have had prior exposure to anti-TNF agents or vedolizumab; 93% had prior exposure to anti-TNF; 79% had failed Patients excluded if: • prior ustekinumab exposure • exposure to any biologic within 8 weeks/5 half-lives of randomisation D’Haens et al. 850 patients [ADVANCE] and 569 patients [MOTIVATE] 16–80 years old with moderate-to-severe CD based on CDAI 220–450, average daily abdominal pain score [APS] ≥2 and average daily stool frequency [SF] ≥4, and endoscopic disease activity defined as SES-CD ≥6 [≥4 if ileal disease only] ADVANCE: patients had to have prior inadequate response to or intolerance of biologic therapy [Bio-IR] or conventional therapy [non-Bio-IR] MOTIVATE: patients had to have prior inadequate response to or intolerance of biologics [Bio-IR] |
Feagan et al. Treatment period one: patients randomised 1:1:1 as follows: • placebo • 200 mg IV risankizumab • 600 mg IV risankizumab, all patients dosed at Weeks 0, 4, 8 Analyses performed looking at each treatment group as well as the pooled risankizumab group [all patients who received the study drug] Treatment period two: following induction, patients received either 12 weeks of open-label 600 mg IV risankizumab [if not in deep remission] at Weeks 14, 18, and 22 or had a 12-week wash-out period [if in deep remission] Treatment period three: open-label extension with maintenance therapy [180 mg subcutaneously] up to 52 weeks in patients in deep remission at Week 26 D’Haen’s et al.: ADVANCE: randomised 2:2:1 as follows: • placebo • 600 mg IV • 1200 mg IV Dosed at Weeks 0, 4, 8. MOTIVATE: randomised 1:1:1 to receive: • placebo • 600 mg IV • 1200 mg IV |
Feagan et al. Treatment period one: clinical remission [defined as CDAI <150] at Week 12 met in 31% of risankizumab patients, vs 15% of placebo, with observed difference of 15%; p = 0.0489 Treatment period two: 26-week efficacy outcomes: clinical response or remission greater in all groups at Week 26 compared with the same groups at Week 12: • 55% of original placebo group, vs 18% at Week 12 • 59% of original group 200 mg group, vs 21% at Week 12 • 47% of the original 600-mg group, vs 26% at Week 12 Overall: clinical remission at Week 26: 53% of pooled treatment group clinical response at Week 26: 73% of pooled treatment group Total 61 patients [56%] in clinical remission at Week 26 Treatment period three: 52-week efficacy outcomes: clinical remission at Week 52: 71% of pooled treatment group clinical response at Week 52: 81% of pooled treatment group endoscopic remission at Week 52: 35% of pooled treatment group |
Feagan et al. Treatment period one: Clinical response [CDAI <150 or CDAI reduction from baseline ≥100]-met in 600mg group [p = 0.0366] and pooled group [p = 0.0273] Endoscopic remission [CDEIS ≤4; ≤2 in patients with ileitis only]-met in 200mg group [p = 0.0375], 600mg group [p = 0.0107], and pooled group [p = 0.0015] Endoscopic response [CDEIS reduced by >50% from baseline]-met in 600mg group [p = 0.0106] and pooled group [p = 0.0104] Deep remission [clinical and endoscopic remission]- not met in any group [p200mg = 0.97; p600mg = 0.31; ppooled = 0.50] Deep remission [both clinical and endoscopic remission]-met in 600mg group [p = 0.0164] and pooled group [p = 0.0107] Health-related quality of life based on changes in the Inflammatory Bowel Disease Questionnaire [IBDQ] -met in all groups, including placebo, with dose-dependent increase in score from baseline [p600mg = 0.0009] Reduction in median CRP from baseline-met in both 200mg and 600mg groups [p < 0.0001 for each] Reduction in median FC from baseline-met in 600mg group [p = 0.0003] Reduction in plasma IL-22 level from baseline-met in 600mg group [p = 0.0180] |
| Dosed at Weeks 0, 4, 8 | endoscopic response at Week 52: 55% of pooled treatment group mucosal healing at Week 52: 24% of pooled treatment group deep remission at Week 52: 29% of pooled treatment group D’Haen’s et al.: Clinical remission [defined as CDAI ≤150 [US] or SF ≤2.8 and APS ≤1, neither worse than baseline [outside USA] and endoscopic response [defined as >50% reduction in SES-CD from baseline, or at least 2-point reduction from baseline in patients with ileal disease only with baseline score of 4]: • CDAI <150: met in 45.2% of 600-mg group and 41.6% of 1200-mg group, vs 25.2% of placebo group, with treatment differences of 20.2% and 16.1%, respectively [p600mg ≤0.001, p1200mg ≤0.001] • APS ≤1 and SF ≤2.8 with no worsening from baseline: met in 43.5% of 600-mg group and 41% of 1200-mg group, vs 21.7% of placebo group, with treatment differences of 21.9% and 18.8%, respectively [p600mg ≤0.001, p1200mg ≤0.001] • endoscopic response: met in 40.3% of 600-mg group and 32.2% of 1200-mg group, vs 12% of placebo group, with treatment differences of 28.3% and 20.2%, respectively [p600mg ≤0.001, p1200mg ≤0.001] |
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| Brazikumab | Monoclonal IgG2 antibody to IL23p19 | Double-blind, placebo-controlled Phase IIa clinical trial [NCT01714726, Sands et al.16] with open-label extension | Total of 119 patients 18–65 years old with minimum 6-month history of CD, with active disease based on CDAI 220–450, active inflammation based on CRP ≥5 mg/L, FC ≥250 ug/g, or endoscopic disease activity within 12 weeks of screening; 104 patients continued through the open-label period Patients had to have prior TNF exposure [primary or secondary loss of response or intolerance] |
Patients randomised 1:1 to receive placebo or 700 mg IV brazikumab at Weeks 0 and 4 during the 12-week induction period Open-label extension with maintenance therapy [brazikumab 210 mg subcutaneously every 4 weeks] in all patients for 100 weeks |
Clinical response [defined as reduction of ≥100 points on the CDAI from baseline] at Week 8 met in 49.2% of brazikumab patients, vs 26.7% of placebo, with absolute difference of 22.25% [p = 0.010] | Secondary outcomes: Clinical remission [defined as CDAI < 150] at Week 8 not statistically significant: met in 27.1% of brazikumab patients vs 15% of placebo, with absolute difference of 12.2% [p = 0.10] Clinical response at Week 12 not statistically significant:met in 37.3% of brazikumab patients vs 28.3% of placebo, with absolute difference of 9.1% [p = 0.29] Clinical remission at Week 12 not statistically significant: met in 20.3% of brazikumab patients, vs 13.3% of placebo, with absolute difference of 7% [p = 0.31] Exploratory analyses: sustained response and remission at Week 8 and Week 24: • Week 8: 42.8% of brazikumab patients, vs 23.1% of placebo • Week 24: 23.1% of brazikumab patients, vs 11.5% of placebo [similar rates of clinical remission and response and composite outcome in treatment and placebo groups at Week 24] |
| Composite outcome: clinical response and ≥50% reduction in either CRP or FC from baseline at Weeks 8, 12, 24 • Week 8 met, with 42.4% of brazikumab patients, vs 10% of placebo, absolute difference 12.2% [p <0.001] • Week 12 met, with 37.3% of brazikumab patients, vs 8.3% of placebo, absolute difference 29% [p <0.001] • Week 24 not met, with 46.2% of brazikumab patients, vs 48.1% of placebo Change from baseline in CRP, FC, IL-22: • CRP Week 8: significant reduction, p = 0.007 • CRP Week 12, significant reduction, p = 0.008 • FC Week 8, significant reduction, p = 0.027 • FC Week 12, significant reduction, p = 0.034 • IL-22 Week 8, significant reduction, p = 0.04 Value of baseline IL-22 as predictor of response: baseline median level of ≥15.6 pg/mL associated with greater rates of clinical response and remission at Week 8 |
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| Mirikizumab | Monoclonal IgG4 antibody to IL23p19 | Randomised, double-blind, parallel arm, placebo-controlled Phase 2 clinical trial [I6T-MC-AMAC, Sandborn et al.,17 Sands et al.18 | Sandborn et al.: 249 patients 18–75 years old with UC for at least 3 months [based on endoscopy, pathology] with extension beyond the rectum [at least 15 cm of colon involved], with moderate-severely active disease based on total Mayo score of 6–12 with subscores of at least 2 [notably, total Mayo score used for inclusion, modified Mayo score used to assess efficacy] Patients could have prior biologic exposure, with discontinuation of anti-TNFs or experimental UC biologics ≥8 weeks before inclusion and discontinuation of vedolizumab ≥12 weeks before inclusion • >63% had prior biologic exposure Patients excluded if: • prior UC surgery • likely need for UC surgery during study • prior exposure to any anti-IL-23 agent [including ustekinumab] • prior ileostomy, colostomy, or fixed area of intestinal stenosis with associated symptoms |
Sandborn et al.: Patients randomised to 1:1:1:1 as follows, with stratification by prior biologic exposure: • placebo • 50 mg mirikizumab, with subsequent dosing by level checked at Weeks 2 and 6 [maximum dose 600 mg] • 200 mg mirikizumab, with subsequent dosing by level checked at Weeks 2 and 6 [maximum dose 600 mg] • 600 mg mirikizumab [fixed dose] All patients dosed at Weeks 0, 4, 8. Analyses performed looking at each treatment group as well as the combined mirikizumab group [all patients who received the study drug] At Week 12, mirikizumab responders then randomised 1:1 to receive maintenance therapy [200 mg subcutaneous mirikizumab] either every 4 or every 12 weeks until Week 52; placebo responders given subcutaneous sham injections every 4 weeks through Week 52 |
Sandborn et al.: Clinical remission [defined based on Mayo subscores: 0 for rectal bleeding, 0–1 for stool frequency [with decrease in 1 point from baseline], 0 for endoscopy] at Week 12 not statistically significant for 600 mg group vs placebo, p = 0.142. Other doses not compared with placebo as a result. Higher number of patients in remission across all treatment groups in biologic-naïve patients, compared with biologic-exposed. Sands et al.: Endoscopic response at Week 12, defined as reduction of >50% from baseline SES-CD score: met in all three treatment groups [statistical significance based on a p-value ≤0.1], with response achieved in 25.8% of the 200-mg group, 37.5% of the 600-mg group, and 43.8% of the 1000-mg group vs 10.9% of placebo [p200mg = 0.079, p600mg = 0.003, p1000mg <0.001] |
Sandborn et al.: Secondary outcomes: Clinical remission at Week 52 met in 53.7% of patients on every 4-week dosing and 39.7% of patients on every 12-week dosing Clinical response [defined as decrease in 9-point Mayo score of ≥2 points and ≥35% from baseline, with decrease in rectal bleeding ≥1 point or rectal bleeding score of 0 or 1] at Weeks 12 and 52: • Week 12-met in all treatment groups, regardless of prior biologic exposure [p50mg = 0.014, p200mg <0.001, p600mg = 0.001, pcombined <0.001] • Week 52 met in 80.9% of patients on every 4-week dosing and 76.1% of patients on every 12-week dosing Durable clinical remission [remission at Weeks 12 and 52] met in 61.1% of patients on every 4-week dosing and 38.5% of patients on every 12-week dosing Durable clinical response [response at Weeks 12 and 52]- met in 80.9% of patients on every 4-week dosing and 75% of patients on every 12-week dosing |
| Sands et al.: 191 patients ages 18–75 years, with at least 3-month history of moderate-to-severe CD (based on stool frequency ≥4 and/or abdominal pain ≥2 + SES-CD ≥7 [ileocolonic] or ≥4 [ileal disease only]) |
Sands et al.: Patients randomised 2:1:1:2 as follows, with stratification by prior biologic exposure: • placebo • 200 mg mirikizumab • 600 mg mirikizumab • 1000 mg mirikizumab All patients dosed at Weeks 0, 4, and 8. After Week 12, mirikizumab responders [defined as ≥1 point decrease in SES-CD from baseline] randomised to either continue their induction dosing regimen [200 mg IV, 600 mg IV, or 1000 mg IV every 4 weeks] + SC placebo every 4 weeks or 300 mg SC every 4 weeks + IV placebo every 4 weeks through Week 52 Patients in the mirikizumab induction groups without endoscopic improvement at Week 12 and those who were in the placebo group during induction were given 1000 mg IV + SC placebo every 4 weeks through Week 52 |
Endoscopic remission [Mayo endoscopic subscore of 0] at Weeks 12 and 52- • Week 12 no significant differences between treatment groups and placebo • Week 52 met in 14.9% of patients on every 4-week dosing and 28.3% of patients on every 12-week dosing Endoscopic improvement [Mayo endoscopic subscore of 0–1] at Week 12 met in 50-mg, 200-mg, and combined groups but not in 600-mg group [p50mg = 0.012, p200mg = 0.0007, p600mg = 0.215, pcombined = 0.006] Improvement in IBDQ from baseline at Weeks 12 and 52 • 12 weeks, met in 200-mg and 600-mg groups [p50mg = 0.062, p200mg = 0.0005, p600mg = 0.002, pcombined = not calculated] • 52 weeks, improved on average 61.7 points in every 4-week dosing group and 49.4 points in every 12-week dosing group |
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| Patients had to have a history of inadequate response or intolerance to 5-ASA, AZA, 6MP, steroids [or be steroid-dependent] and/or have prior biologic exposure • 67% of patients in placebo group and 60% of patients across all treatment groups had prior biologic exposure • 56.3% in the placebo group and 50% of patients across all treatment groups had a history of biologic failure Patients excluded if: • prior exposure to biologic agents targeting IL23-p19 • prior exposure to ustekinumab [exception: patients who received a single dose ≥12 weeks before inclusion] • exposure to natalizumab or B/T cell-depleting agents within 1 year of inclusion |
Exploratory objectives: Reduction in CRP, FC, IL-22 and IL-17A from baseline at Week 12: • FC lower in all treatment groups vs placebo [pcombined = 0.018] • CRP lower in all treatment groups vs placebo [pcombined = 0.004] • IL-22 lower in all treatment groups vs placebo [pcombined <0.0001] • IL-17A lower in all treatment groups vs placebo [pcombined <0.0001] Histological remission at Weeks 12 and 52 • Week 12 met in 200-mg, 600-mg and combined groups [p50mg = 0.632, p200mg = 0.001, p600mg = 0.028, pcombined = 0.006] • Week 52 met in 66% of patients on every 4-week dosing and 37% of patients on every 12-week dosing Symptomatic remission [stool frequency score 0–1, rectal bleeding score 0] at Weeks 12 and 52 |
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| • exposure to any CD drug under investigation within 8 weeks of inclusion or 5 drug half-lives • exposure to interferon within 8 weeks of inclusion • complicated CD, defined as history of strictures, stenoses, or other complications that could require operative intervention • history of bowel resection or diversion within 6 months of inclusion • history of any kind of intra-abdominal surgery within 3 months of inclusion • presence of a stoma |
• Week 12- met in all treatment groups [p50mg = 0.054, p200mg <0.001, p600mg = 0.003, pcombined =<0.001] • Week 52 [with sustained symptomatic remission from Weeks 16–52]- met in 77.5% of patients on every 4-week dosing and 75.2% of patients on every 12-week dosing Sands et al.: Secondary outcomes: Endoscopic response at Week 52 [defined as ≥50% reduction in SES-CD from baseline]: re-randomised cohorts: • among patients with endoscopic improvement [reduction in SES-CD by at least 1 point from baseline] following induction: met in 58.5% of patients in IV group and 58.7% of patients in SC group • among patients with endoscopic response following induction: met in 69.6% of IV group and 66.7% of SC group |
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| non-randomised cohorts: • among treatment group patients without endoscopic response following induction: met in 20% of patients • among placebo patients without endoscopic response following induction: met in 42.4% of patients Endoscopic remission at Weeks 12 and 52 [defined as SES-CD <4 for ileocolonic CD or <2 for isolated ileal CD, with no subscore >1]: • Week 12 met in the 600-mg and 1000-mg groups [p600mg = 0.01, p1000mg <0.001] |
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| • Week 52: re-randomised cohorts: • among patients with endoscopic improvement following induction: met in 19.5% of IV group and 32.6% of SC group • among patients with endoscopic remission following induction: met in 50% of IV group and 64.3% of SC group non-randomised cohorts: • among treatment group patients without endoscopic response following induction: met in 13.3% of patients • among placebo patients without endoscopic response following induction: met in 18.6% of patients |
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| Patient-reported outcome [PRO] of remission at Weeks 12 and 52 [defined as average daily stool frequency ≤2.5and average daily abdominal pain <1]: • Week 12 met in the 600-mg and 1000-mg groups [p600mg = 0.004, p1000mg = 0.013] • Week 52 re-randomised cohorts: • overall met in 46.3% of patients in IV group and 45.7% of patients in SC group • among patients with PRO remission at Week 1 met in 71.4% of patients in IV group and 66.7% of patients in SC group non-randomised cohorts: • Among treatment group patients without endoscopic response following induction: met in 36.7% of patients • among placebo patients without endoscopic response following induction: met in 40.7% of patients Change from baseline IBD-Q score: • Week 12 met in all treatment groups [p200mg < 0.001, p600mg <0.001, p1000mg <0.001] • Week 52 re-randomised cohorts: • overall- change in baseline score of 64.3 points in IV group and 66.4 points in SC group |
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| non-randomised cohorts: Change from baseline IBD-Q • among treatment grouppatients without endoscopic response following i nduction: change from baseline 44.5 points • among placebo patients without endoscopic response following induction: change from baseline 53.6 points Exploratory objectives: Change in CRP and FC from baseline: • Week 12 median percent change in hsCRP from baseline significantly greater in all treatment groups [p200mg <0.001, p600mg <0.001, p1000mg <0.001]; greatest change in 1000-mg group • Week 12 median percent change in FC from baseline significantly greater in 600-mg and 1000-mg groups [p600mg <0.05, p1000mg <0.001]; greatest change in 1000-mg group • Week 52 median percent change in hsCRP similar across all groups, ranging from -45.9% to -59.5% • Week 52 median percent change in FC similar across all groups, ranging from -72.5% to -81% |
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| CDAI response at Weeks 12 and 52 [defined as CDAI reduction of ≥100 points from baseline score or CDAI <150]: • Week 12 met in all treatment groups [p200mg = 0.015, p600mg = 0.001, p1000mg = 0.026] • Week 52 re-randomised cohorts: •met in 53.7% of patients in IV group and 69.6% of patients in SC group non-randomised cohorts: • among treatment group patients without endoscopic response following induction: met in 46.7% of patients • among placebo patients without endoscopic response following induction: met in 52.5% of patients CDAI remission at Weeks 12 and 52 [defined as CDAI <150]: • Week 12 met in the 600-mg and 1000-mg groups [p600mg <0.001, p1000mg = 0.013] • Week 52 |
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| re-randomised cohorts: • overall- met in 39% of patients in IV group and 56.5% of patients in SC group • among patients with CDAI remission at Week 12 met in 69.2% of patients in IV group and 86.7% of patients in SC group non-randomised cohorts: • among treatment group patients without endoscopic response following induction: met in 23.3% of patients • among placebo patients without endoscopic response following induction: met in 40.7% of patients PRO response [defined as ≥30% reduction in stool frequency and/or abdominal pain; not worse than baseline]: • Week 12 met in all treatment groups [p200mg = 0.023, p600mg = 0.003, p1000mg = 0.006] • Week 52 re-randomised cohorts: • met in 68.3% of patients in IV group and 71.7% of patients in SC group non-randomised cohorts: • among treatment group patients without endoscopic response following induction: met in 60% of patients • among placebo patients without endoscopic response following induction: met in 61% of patients |
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| Guselkumab | Monoclonal IgG1 lambda antibody to IL23p19 | Phase II, double-blind, placebo-controlled, multicentre clinical trial [NCT0346641, Sands et al.,19, D’Haens et al.20] | 250 patients with moderate-severe CD with failure of other therapies (biologics, i.e. anti-TNFs, vedolizumab; ‘conventional therapies’, i.e. corticosteroids, other immunosuppressants [not explicitly defined]); 50% had failed biologics previously |
Patients randomised 1:1:1:1:1 as follows: • 200 mg IV guselkumab at 0, 4, and 8 weeks • 600 mg IV guselkumab at 0, 4, and 8 weeks • 1200 mg IV guselkumab at 0, 4, and 8 weeks • ~6 mg/kg IV ustekinumab at Week 0 and 90 mg subcutaneously at Week 8[reference group] • Placebo [IV] Analyses performed looking at each treatment group as well as the combined guselkumab group [all patients who received the study drug] |
Sands et al.: Change in CRP from baseline, median change in combined guselkumab group, -2.17, vs -1.68 in ustekinumab group and 0 in placebo group Normalisation of CRP [≤3 mg/L] in patients with abnormal CRP at baseline, 35.4% in combined guselkumab group, vs 25% in ustekinumab group and 19.4% in placebo group Change in FC from baseline -176 in combined guselkumab group, vs -135.5 in ustekinumab group and +20 in placebo group Normalisation of FC [≤250 ug/g] in patients with abnormal FC at baseline, 33.3% in combined guselkumab group, vs 25% in ustekinumab group and 27.3% in placebo group Change in ‘clinical-biomarker response’ [defined as ≥100-point reduction in CDAI or CDAI <150 and ≥50% reduction in FC or CRP compared with baseline] • Overall 48% of combined guselkumab group, vs 7.8% in placebo group • Patients with history of biologic failure, 46.1% of combined guselkumab group, vs 8.7% of placebo • Patients with history of conventional treatment failure, 50% of combined guselkumab group, vs 7.1% of placebo |
D’Haens et al.: Dose-response or exposure-response relationship between guselkumab and endoscopic response, remission or healing, no significant relationships appreciated |
| D’Haens et al.: SES-CD change from baseline, mean reduction of -4.6 in combined guselkumab group, vs -4.1 in ustekinumab group and -0.5 in placebo group Endoscopic response [≥50% improvement from baseline or SES-CD <2] • Overall- 37.3% in combined guselkumab group, vs 30.6% in ustekinumab group and 11.8% in placebo group • Patients with history of biologic failure, 30.3% in combined guselkumab group, vs 19.6% in ustekinumab group and 13% in placebo group • Patients with history of conventional treatment failure, 44.6% in combined guselkumab group, vs 43.5% in ustekinumab group and 10.7% in placebo group Endoscopic healing [absence of mucosal ulcerations] • Overall: 17.3% in combined guselkumab group, vs 18.4% in ustekinumab group and 3.9% in placebo group • Patients with history of biologic failure, 11.8% in combined guselkumab group, vs 7.7% in usekinumab group and 8.7% in placebo group |
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| • Patients with history of conventional treatment failure, 23% in combined guselkumab group, vs 30.4% in ustekinumab group and 0% in placebo group Endoscopic remission [SES-CD <2] • Overall, 14% in combined guselkumab group, vs 14.3% in ustekinumab group and 3.9% in placebo group • Patients with a history of biologic failure, 10.5% in guselkumab group vs 3.8% in ustekinumab group and 8.7% in placebo group • Patients with history of conventional treatment failure-17.6% in combined guselkumab group, vs 26.1% in ustekinumab group and 0% in placebo group |
IBD, inflammatory bowel diseaase; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; CDEIS, Crohn’s Disease Endoscopic Index of Severity; SES-CD, Simple Endoscopic Score-CD; SC, subcutaneous; IV, intravenous; CRP, C-reactive protein; FC, faecal calprotectin; TNF, tumour necrosis factor; 5-ASA, 5-aminosalicylic acid; AZA, azathioprine; 6MP, 6-mercaptopurine; IBDQ, Inflammatory Bowel Disease Questionnaire.