Y-ECCO Literature Review: Hajir Ibraheim
Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with Ulcerative Colitis
Sandborn WJ, Ferrante M, Bhandari BR, Berliba E, Feagan BG, Hibi T, Tuttle JL, Klekotka P, Friedrich S, Durante M, Morgan-Cox M, Laskowski J, Schmitz J, D'Haens GR
Gastroenterology. 2019;doi: https://doi.org/10.1053/j.gastro.2019.08.043. [Epub ahead of print]
© Hajir Ibraheim
Interleukin-23 (IL23) contributes to the pathogenesis of chronic inflammatory diseases, including Ulcerative Colitis (UC), by maintaining and amplifying T helper 17 cells and stimulating many innate immune cells. IL-23 is a heterodimeric cytokine composed of a p40 subunit (shared by IL12) and a p19 subunit (IL-23p19). Ustekinumab, a monoclonal antibody targeting the shared p40 subunit, is effective for treatment of Crohn’s Disease (CD) and psoriasis [1–3]. However, studies in patients with psoriasis have suggested that selective targeting of the IL23 pathway by blocking IL-23p19 is more effective than ustekinumab [4, 5]. Whilst promising phase 2 results have been observed in CD patients following treatment targeting IL-23p19 [6, 7], the role of this therapeutic strategy in UC is unknown. Mirikizumab (LY3074828) is a humanised immunoglobulin G4 (IgG4)-variant monoclonal antibody that binds to the IL-23p19 subunit. The current study evaluated the efficacy and safety of mirikizumab for the treatment of patients with moderate-to-severely active UC.
This was a phase 2 multicentre, randomised, double-blind, parallel-arm, placebo-controlled trial. Patients with moderate-to-severely active UC (defined by total Mayo score of 6–12, including an endoscopic subscore ≥2) were randomly assigned to one of four intravenously administered treatment groups: placebo (n=63), mirikizumab 50 mg (n=63), mirikizumab 200 mg (n=62) with exposure-based dosing (drug dose adjusted on the basis of serum concentrations according to a pre-specified algorithm) or mirikizumab 600 mg with fixed dosing (n=61). Mirikizumab was administered at weeks 0, 4 and 8.
Clinical responders to mirikizumab at week 12 (defined as a decrease in the modified 9-point Mayo score utilised in the study, including ≥2 points and ≥35% from baseline with either a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) were re-randomised to receive either 200 mg mirikizumab by subcutaneous (SC) injection every 4 (Q4W) or 12 (Q12W) weeks through week 52. Patients responding to placebo received SC placebo injections Q4W through week 52.
The primary endpoint was clinical remission [Mayo subscores of 0 for rectal bleeding, 0 or 1 for stool frequency (with 1-point decrease from baseline) and 0 or 1 for endoscopy] at week 12. Secondary endpoints included evaluation of safety and tolerability, week 52 clinical remission, week 12 and 52 clinical response, durable clinical remission (proportion of patients who achieved clinical remission at both week 12 and week 52), endoscopic remission (Mayo endoscopic subscore of 0), endoscopic improvement (endoscopic findings subscore of 0 or 1) and change from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ). A multiple testing procedure was applied to the primary endpoint to control the type 1 error rate. The investigators evaluated mirikizumab dose group comparisons versus placebo starting with the 600 mg group. A non-significant result from any comparison ended the formal statistical testing procedure, and all subsequent p values were considered as nominal.
Baseline characteristics among the 249 randomised patients were similar across treatment groups, except for numerically higher corticosteroid (CS) use, higher CRP levels, higher proportion of patients exposed to three or more biologics and shorter disease duration in the 600 mg group. Nearly two-thirds (63%) were biologic experienced. Approximately 73% and 44% of patients in the 50 mg and 200 mg mirikizumab treatment groups underwent dose adjustment, resulting in average dose levels of 100 mg and 250 mg, respectively.
The primary endpoint of clinical remission at week 12 for the mirikizumab 600 mg group compared with placebo was not achieved (p=0.142). Thus, all subsequent p values comparing clinical remission at week 12 were not controlled for multiplicity and considered nominal, meaning they should be interpreted with caution.
At week 12, 15.9% (n=10, p=0.066), 22.6% (n=14, p=0.004) and 11.5% (n=7, p=0.142) of patients in the 50, 200 and 600 mg groups, respectively, achieved clinical remission, compared with 4.8% (n=3) of patients administered placebo. A similar pattern was seen for clinical remission across treatment groups amongst the biologic-naïve and biologic-experienced groups, with numerically higher clinical remission rates in the biologic-naïve groups. Clinical response occurred in 41.3% (n=26, p=0.014), 59.7% (n=37, p<0.001) and 49.2% (n=30, p=0.001) of patients in the 50, 200 and 600 mg groups, respectively, compared with 20.6% (n=13) in the placebo group.
At week 52, clinical remission was observed in 53.7% (22/47) and 39.7% (17/46) of patients given SC mirikizumab 200 mg Q4W and Q12W respectively, with comparable clinical remission rates observed between biologic-naïve and biologic-experienced patients. Week 52 clinical response rates were similar between the Q4W (80.9%) and Q12W (76.1%) treated groups.
By week 12, rates of endoscopic improvement were higher in all mirikizumab-treated groups, relative to placebo. Endoscopic improvement was achieved in 23.8% (n=15, P=.012) in the 50 mg group, 30.6% (n=19, p=0.0007) in the 200 mg group and 13.1% (n=8, p=0.215) in the 600 mg group compared with 6.3% (n=4) in the placebo group. There were only one or two reports of endoscopic remission (Mayo 0) observed in each treatment group. IBDQ scores were higher and Mayo symptom scores lower at week 12 in the mirikizumab-treated groups than in the placebo group.
The most frequent treatment-emergent adverse events (AEs) (≥5% in any treatment group) included nasopharyngitis, worsening of UC, anaemia, headache, nausea, cough and worsening of gastroenteritis during induction, and worsening of UC, nasopharyngitis, headache, upper respiratory tract infection, arthralgia, hypertension and influenza during maintenance. No deaths and no hypersensitivity reactions were reported.
There were seven serious adverse events (SAEs) during the induction period (two each in the placebo and 200 mg groups, and three in the 600 mg group), with specific SAEs not identified by treatment group to preserve blinding in the ongoing trial. No clear relationship between any SAEs and study drug was determined. Numbers of discontinuations due to AEs were similar across treatment groups.
In this phase 2, dose ranging randomised trial of patients with moderate-to-severely active UC, there was evidence that mirikizumab induced clinical remission, response and endoscopic improvement at 12 weeks, although the primary endpoint was not achieved. Mirikizumab demonstrated durable efficacy throughout the maintenance period, with comparable rates between biologic-experienced and biologic-naïve patients. Few mirikizumab-treated patients discontinued due to AEs, suggesting it was well tolerated.
Additional studies are required to determine the optimal dose for induction of remission and optimal frequency of administration in the maintenance period.
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Hajir is an academic gastroenterologist with an interest in gut immunology. She is currently undertaking an MRC-funded PhD at Imperial College London, with a focus on immune check point inhibitor-induced enterocolitis. Affiliations: Division of Digestive Diseases, Faculty of Medicine, Imperial College London; IBD Department, Guy’s and St Thomas’ Hospital, London.”