Gastroenterology

Gastroenterology

Volume 158, Issue 3, February 2020, Pages 537-549.e10
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Ulcerative Colitis

https://doi.org/10.1053/j.gastro.2019.08.043Get rights and content
Under a Creative Commons license
open access

Background & Aims

Interleukin 23 contributes to the pathogenesis of ulcerative colitis (UC). We investigated the effects of mirikizumab, a monoclonal antibody against the p19 subunit of interleukin 23, in a phase 2 study of patients with UC.

Methods

We performed a trial of the efficacy and safety of mirikizumab in patients with moderate to severely active UC, enrolling patients from 14 countries from January 2016 through September 2017. Patients were randomly assigned to groups given intravenous placebo (N = 63), mirikizumab 50 mg (N = 63) or 200 mg (N = 62) with exposure-based dosing, or mirikizumab 600 mg with fixed dosing (N = 61) at weeks 0, 4, and 8. Of assigned patients, 63% had prior exposure to a biologic agent. Clinical responders (decrease in 9-point Mayo score, including ≥2 points and ≥35% from baseline with either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 who had received mirikizumab were randomly assigned to groups that received maintenance treatment with mirikizumab 200 mg subcutaneously every 4 weeks (N = 47) or every 12 weeks (N = 46). The primary endpoint was clinical remission (Mayo subscores of 0 for rectal bleeding, with 1-point decrease from baseline for stool frequency, and 0 or 1 for endoscopy) at week 12. A multiple testing procedure was used that began with the 600-mg dose group, and any nonsignificant comparison result ended the formal statistical testing procedure.

Results

At week 12, 15.9% (P = .066), 22.6% (P = .004), and 11.5% (P = .142) of patients in the 50-mg, 200-mg, and 600-mg groups achieved clinical remission, respectively, compared with 4.8% of patients given placebo. The primary endpoint was not significant (comparison to 600 mg, P > .05). Clinical responses occurred in 41.3% (P = .014), 59.7% (P < .001), and 49.2% (P = .001) of patients in the 50-mg, 200-mg, and 600-mg groups, respectively, compared with 20.6% of patients given placebo. At week 52, 46.8% of patients given subcutaneous mirikizumab 200 mg every 4 weeks and 37.0% given subcutaneous mirikizumab 200 mg every 12 weeks were in clinical remission.

Conclusions

In a randomized trial of patients with UC, mirikizumab was effective in inducing a clinical response after 12 weeks. Additional studies are required to determine the optimal dose for induction of remission. Mirikizumab showed durable efficacy throughout the maintenance period. Clinicaltrials.gov, Number NCT02589665

Keywords

EB Dosing
Drug
Cytokine
Inhibitor

Abbreviations used in this paper

AE
adverse event
CD
Crohn’s disease
CRP
C-reactive protein
EB
exposure-based
IBDQ
Inflammatory Bowel Disease Questionnaire
IL
interleukin
SAE
serious adverse event
SC
subcutaneous
Th17
T helper 17
UC
ulcerative colitis

Cited by (0)

Conflicts of interest The authors disclose the following: William J. Sandborn reports research grants from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, AbbVie, Janssen, Takeda, Lilly, Celgene/Receptos; consulting fees from AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Avexegen Therapeutics, BeiGene, Boehringer Ingelheim, Celgene, Celltrion, Conatus, Cosmo, Escalier Biosciences, Ferring, Forbion, Genentech, Gilead Sciences, Gossamer Bio, Incyte, Janssen, Kyowa Kirin Pharmaceutical Research, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pfizer, Precision IBD, Progenity, Prometheus Laboratories, Reistone, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust, HART), Series Therapeutics, Shire, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, TiGenix, Tillotts Pharma, UCB Pharma, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals; and stock or stock options from BeiGene, Escalier Biosciences, Gossamer Bio, Oppilan Pharma, Precision IBD, Progenity, Ritter Pharmaceuticals, Ventyx Biosciences, Vimalan Biosciences; in addition, his spouse has been a consultant for and holds stock options in Ophthotech and Progenity and has been an employee of and holds stock options in Oppilan Pharma, Escalier Biosciences, Precision IBD, Ventyx Biosciences, and Vimalan Biosciences. Marc Ferrante has received research grants from Janssen and Takeda; has done consulting for AbbVie, Boehringer Ingelheim, Ferring, Janssen, Mitsubishi Tanabe, Merck Sharp Dome, and Pfizer; and has received speaker fees from AbbVie, Boehringer Ingelheim, Chiesi, Ferring, Janssen, Lamepro, Mitsubishi Tanabe, MSD, Pfizer, Tramedico, Tillotts, and Zeria. Bal R. Bhandari reports personal fees from Delta Research Partners. Elina Berliba reports payment for research from Eli Lilly and Company. Brian G. Feagan reports grants and/or personal fees from AbbVie, ActoGeniX, Akros, Albireo Pharma, Allergan, Amgen, AstraZeneca, Avaxia Biologics Inc, Avir Pharma, Atlantic Pharma, Baxter Healthcare Corporation, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb (BMS), Calypso Biotech, Celgene, Elan/Biogen, enGene, Ferring, Genentech/Roche, gIcare Pharma, Gilead, Given Imaging, GlaxoSmithKline, Ironwood, Janssen Biotech/Centocor, Johnson & Johnson/Janssen, Kyowa Hakko Kirin Co Ltd, Lilly, Lycera Biotech, Merck, Mesoblast Pharma, Millennium, Nestles, Novo Nordisk, Novartis, Pfizer, Prometheus Therapeutics & Diagnostics, Protagonist, Receptos, and Salix; grants from Sanofi, Shire, Sigmoid Pharma, Synergy Pharma, Takeda, Teva Pharma, TiGenix, Tillotts, UCB, Vertex, VHsquared, Wyeth, Zealand, Zyngenia, Galapagos, Inception IBD Inc, Lexicon, Vivelix Pharma, Japan Tobacco Company, Ablynx, Progenity, Nextbiotix, Gossamer Pharma, Qu Biologics; and being the senior scientific officer for Robarts Clinical Trials Inc, Western University, London, Ontario, Canada. Toshifumi Hibi has received grants from Zeria Pharmaceutical, Otsuka Holdings Co Ltd, AbbVie Japan, EA Pharma, and Japan Immunoresearch Laboratories Company Limited. Jay L. Tuttle, Paul Klekotka, Stuart Friedrich, Michael Durante, MaryAnn Morgan-Cox, Janelle Laskowski, and Jochen Schmitz are current employees and shareholders of Eli Lilly and Company. Geert R. D’Haens has served as advisor for AbbVie, Ablynx, Allergan, Amakem, Amgen, AM Pharma, Arena Pharmaceuticals, AstraZeneca, Avaxia, Biogen, Bristol-Meyers Squibb, Boehringer Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Covidien/Medtronic, Ferring, Dr Falk Pharma, Eli Lilly, enGene, Galapagos, Genentech/Roche, Gilead, Glaxo Smith Kline, Hospira/Pfizer, Immunic, Johnson & Johnson, Lycera, Medimetriks, Millennium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novo Nordisk, Otsuka, Pfizer/Hospira, PhotoPill, Prometheus Laboratories/Nestle, Progenity, Protagonist, Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Seres/Nestlé, Setpoint, Shire, Teva, TiGenix, Tillotts, TopiVert, Versant, and Vifor; and has received speaker fees from AbbVie, Biogen, Ferring, Johnson & Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millennium/Takeda, Tillotts, and Vifor.

Funding This study was funded by Eli Lilly and Company.