Introduction

The efficacy and safety of mirikizumab (miri) for moderately to severely active ulcerative colitis (UC) was demonstrated in the Phase 3 LUCENT trials (LUCENT-1 and -2; NCT03518086, NCT03524092). 1,2 Some patients may improve more slowly and require a prolonged course of induction before achieving clinical response. Therefore, we evaluated clinical response in patients who had not responded by the end of the 12-week(W) induction period and who received extended induction treatment for an additional 12W.

Aims & Methods

^​Patients not responding to intravenous (IV) administration of 300 mg miri every 4 weeks (Q4W) (n=272) at W12 (LUCENT-1), received extended 12-W induction treatment of open label 300 mg miri IV Q4W for 3 additional doses (LUCENT-2). Patients responding at W24 (n=144) of continuous IV treatment, entered open label maintenance and received 200 mg miri Q4W subcutaneously (SC) until W52. Key outcomes through 52W are reported (Definitions in Table).

Results

Among the 272 patients who failed to achieve a clinical response after 12W of induction treatment, 72.4% had a Mayo endoscopic subscore of 3, indicating severe disease. Of these patients, 146 (53.7%) achieved a clinical response and 31 (11.4%) achieved clinical remission at W24. Of the 144 responders at 24W entering the open label maintenance study, 52 (36.1%) patients achieved clinical remission, 104 (72.2%) achieved clinical response, 62 (43.1%) achieved endoscopic remission and 60 (41.7%) patients achieved histologic improvement at W52. Furthermore, for these patients, there was a 3.8 (±2.7) point reduction from baseline in bowel urgency (BU) severity and 58.8% achieved clinically meaningful improvement in BU (defined as change from baseline in Urgency Numeric Rating Scale ≥3 in patients with Urgency Numeric Rating Scale ≥3 at induction baseline). Among these patients, 38.3% demonstrated treatment-emergent adverse events (TEAEs). Most TEAEs were mild (21.4%), while only 5.4% were serious. Overall, there was a 3.2% of discontinuation due to TEAEs. No new safety signals or deaths were reported.

Table: Clinical outcomes for the mirikizumab induction non-responder patient population at Weeks 12, 24 and 52 of extended induction

Outcomes for miri IV extended induction	W12 (end of induction) Miri induction non-respondersa N= 272	W24 (W12 extended induction) Miri induction non-respondersa 300 miri IV, Q4W N= 272	W52 (W40 extended induction) Miri induction non-respondersb 200 miri SC, Q4W N= 144
Symptomatic remissionc (NRI response) n, (%)	13 (4.8)	101 (37.1)	91 (63.2)
Clinical remissiond (NRI response) n, (%)	0	31 (11.4)	52 (36.1)
Clinical response (MMS)e (NRI response) n, (%)	0	146 (53.7)	104 (72.2)
Symptomatic responsef (NRI response) n, (%) HEMIg (NRI response) n, (%)	83 (30.5) 13 (4.8)	197 (72.4) 28 (10.3)	112 (77.8) 45 (31.3)
fCal change from baseline, [mBOCF; mean (SD)]	-1291.9 (5664.2)	-1638.8 (5558.9)	-2164.8 (4631.3)
CRP change from baseline, [mBOCF; mean (SD)]	-4.7 (11.5)	-4.5 (12.8)	-4.3 (10.4)
Endoscopic remissionh (NRI response) n, (%)	21 (7.7)	45 (16.5)	62 (43.1)
BU change from baselinei [mBOCF; mean (SD)]	-1.2 (2.2)	-2.5 (2.7)	-3.8 (2.7)
Abbreviations: BU=bowel urgency; CRP=C-reactive protein; fCal=faecal calprotectin; HEMI=histologic-endoscopic mucosal improvement; IV=intravenous; mBOCF=modified baseline observation carried forward; miri=mirikizumab; MMS= modified Mayo-Score; N=patient population; n=patient subpopulation; Nx=number of patients with Urgency Numeric Rating Scale ≥3 at induction baseline; NRI=non-response imputation; Q4W= every four weeks; SC=subcutaneous; W=weeks a The miri induction non-responder population only included patients who continued on to the maintenance trial (LUCENT-2) b Extended induction responders continued on 200 miri SC until W40 (52W of continuous treatment). Non-responders at extended induction W12 were discontinued. c Stool frequency =0 or stool frequency =1 with ≥1-point decrease in MMS from baseline; rectal bleeding=0 d stool frequency =0 or stool frequency =1 with ≥1-point decrease in MMS from baseline; rectal bleeding =0; and Endoscopic subscore =0 or 1 (excluding friability) e ≥2-point and ≥30% decrease in MMS from baseline; rectal bleeding =0 or 1 or, ≥1-point decrease from baseline f Symptomatic Response: defined as at least a 30% decrease from baseline in the composite clinical endpoint of the sum of stool frequency and rectal bleeding subscores g Endoscopic subscore=0 or 1 (excluding friability) + Geboes≤3.1 h Endoscopic subscore =0 or 1 (excluding friability); score ranges 0 to 4; a lower score indicates less mucosal damage i Change from baseline in Urgency Numeric Rating Scale score; range 0 to 10; a lower score indicates less severe bowel urgency

Conclusion

^​Among patients who did not initially respond to induction treatment with miri at 12W, 3 additional miri induction doses induced clinical response and remission in patients, highlighting the potential benefit of extended induction treatment with miri in those patients with more severe inflammation at baseline.

References

1. D’Haens et al., OP26: Efficacy and safety of mirikizumab as induction therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 LUCENT-1 study, Crohn's and Colitis, Vol. 16, Iss. Supplement_1, Jan. 2022, i028–i029
2. Dubinsky et al., 867e: Efficacy and safety of mirikizumab as maintenance therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 Lucent-2 study, Gastroenterology, Vol. 162, Iss. 7, S-1393-94

Disclosure

G. D’Haens has served as an advisor for: AbbVie, Ablynx, Active Biotech, Agomab Therapeutics, Allergan, AlphaBiomics, AM-Pharma, Amaken, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, AstraZeneca, Avaxia Biologics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Celltrion, Cosmo Pharmaceuticals, Dr. Falk Pharma, DSM Pharma Solutions, Echo Pharmaceuticals, Eli Lilly and Company, enGene, Exeliom Biosciences, Ferring Pharmaceuticals, Galapagos NV, Genentech/Hoffmann-La Roche, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Immunic Therapeutics, Johnson & Johnson, Kintai Therapeutics, Lycera, Medimetrics, Medtronic, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Mundipharma, Nextbiotics, Novo Nordisk, Otsuka, Pfizer, PhotoPills, ProciseDx, ProDigest, Progenity, Prometheus Laboratories/Nestlé, Protagonist Therapeutics, RedHill, Robarts Clinical Trials, Salix Pharmaceuticals, Samsung Bioepis, Sandoz, Seres Therapeutics/Nestec/Nestlé, Setpoint Medical, Shire, Takeda, Teva, TiGenix, Tillotts Pharma AG, Topivert, Versant and Vifor Pharma; and has received speaker fees from: AbbVie, Biogen, Ferring Pharmaceuticals, Galapagos NV/Gilead Sciences, Johnson & Johnson, Merck Sharp & Dohme, Millenium/Takeda, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Tillotts Pharma AG and Vifor Pharma; P. Higgins has served as an advisor for: AbbVie, Arena Pharmaceuticals, Eli Lilly and Company, Genentech/Hoffmann-La Roche, Johnson & Johnson, Lycera and Pfizer; L. Peyrin-Biroulet has received consulting fees and/or grants and/or support for attending meetings and/or honoraria from and/or has participated on a data safety monitoring board or advisory board for: AbbVie, Alimentiv, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, Gossamer Bio, InDex Pharmaceuticals, Inotrem, Janssen, Merck Sharp & Dohme, Mylan, Norgine, Ono Pharmaceutical, OSE Immunotherapeutic Pandion Therapeutics, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Theravance Biopharma, Thermo Fisher Scientific, Tillotts Pharma AG, Viatris and Vifor Pharma; and is a shareholder of: CTMA; B. E. Sands has served as a consultant or received speaker’s fees from: AbbVie, Abivax, Adiso Therapeutics, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Calibr/Scripps Research, Celltrion, ClostraBio, Connect Biopharma, Cytoki Pharma, Eli Lilly and Company, Enthera, Evommune, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Highlightll Pharma, HMP Acquisition, Imhotex, Immunic Therapeutics, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido Biosciences, Kallyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill, Sun Pharma, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma, USWM Enterprises, Ventyx Biosciences and Viela Bio; and has stock options from: Ventyx Biosciences; S. Lee has received consulting fees and/or grants from: AbbVie, Applied Molecular Transport, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Janssen and Protagonist Therapeutics; R. E. Moses, I. Redondo, R. Escobar and N. Morris are employees and shareholders of: Eli Lilly and Company; T. Kobayashi has received grants and/or contracts from: AbbVie, ActivAid, Alfresa Pharma, Bristol Myers Squibb, EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Google Asia Pacific, Janssen Pharmaceutical K.K., JIMRO, JMDC, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Otsuka, Pfizer Japan K.K., Takeda and Zeria Pharmaceutical; has received lecture payments or honoraria from: AbbVie, ActivAid, Alfresa Pharma, Galapagos NV, Janssen Pharmaceutical K.K., JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Nippon Kayaku, Pfizer Japan K.K., Takeda, Thermo Fisher Scientific and Zeria Pharmaceutical; has received payment for expert testimony from: AbbVie, ActivAid, Alfresa Pharma, EA Pharma, Janssen Pharmaceutical K.K., Kissei, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan K.K. and Takeda; and has participated on data safety monitoring boards or advisory boards for: Bristol Myers Squibb, EA Pharma, Eli Lilly and Company and Janssen.

Introduction

The 52-week, phase 3 True North (TN) study (NCT02435992) demonstrated the efficacy and safety of ozanimod (OZA), a highly selective sphingosine 1-phosphate receptor 1 and 5 modulator, in patients (pts) with moderately to severely active ulcerative colitis (UC). A prior analysis reported the long-term safety of OZA up to ~4 y from TN baseline through Week (W) 142 of the ongoing TN open-label extension (OLE; NCT02531126).

Aims & Methods

This analysis assessed the cumulative long-term safety of OZA with an additional year of exposure (pt disposition available until OLE W190 [up to ~5 y of OZA]). All pts who entered the OLE from TN (ie, clinical nonresponders at W10 and those who lost response during maintenance or completed maintenance at W52) were included in this analysis. Treatment-emergent adverse events (TEAEs) were monitored from the first dose of OZA in TN or the OLE through data cutoff; exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) are presented. Lab abnormalities, including absolute lymphocyte count (ALC) reductions, were assessed during the OLE through data cutoff.

Results

A total of 823 pts entered the TN OLE. At data cutoff, 43.0% of pts had completed OLE W190 and total OZA exposure was 2681 PY. Overall, the cumulative safety assessments did not meaningfully change with an additional year of OZA exposure (Table). EAIRs of TEAEs, serious TEAEs, and TEAEs leading to treatment discontinuation remained consistent, and there were no new cases of malignancy, bradycardia, third-degree atrioventricular (AV) block, myocardial ischemia, ischemic stroke, pulmonary embolism, deep vein thrombosis, or macular edema with an additional year of OZA exposure. Three pts newly developed infections; however, only 1 pt had a serious infection (keratouveitis), which was not related to treatment. Two additional pts experienced mild hypertension. Reductions in ALC <500 cells/µl were common in the OLE (57.2%), but few pts had ALC <200 cells/µl(6.6%). Occurrence of ALC <200 cells/µl was not temporally associated with serious or opportunistic infections. Most alanine aminotransferase and aspartate aminotransferase elevations were transient and resolved without treatment interruption, and no serious hepatic events occurred.

Table. Cumulative safety assessments during TN and the TN OLE in all pts who entered the OLE	Up to ~4 y of OZA exposurea (n=823) Total PYc = 2536 n (%) EAIRd		Up to ~5 y of OZA exposureb (n=823) Total PYc = 2681 n (%)e n (%)			Up to ~4 y of OZA exposurea (n=823) Total PYc = 2536 n (%) EAIRd		Up to ~5 y of OZA exposureb (n=823) Total PYc = 2681 n (%)e n (%)
TEAEs	685 (83.2)	85.5	687 (83.5)	85.1	Third-degree AV block	1 (0.1)	0.04	1 (0.1)	0.04
Serious TEAEs	158 (19.2)	7.0	163 (19.8)f	6.8	Hypertension	55 (6.7)	2.3	56 (6.8)	2.2
TEAEs leading to treatment discontinuation	64 (7.8)	2.5	66 (8.0)	2.5	Myocardial ischemia	3 (0.4)	0.12	3 (0.4)	0.11
Infection	378 (45.9)	22.7	381 (46.3)	22.1	Ischemic stroke	3 (0.4)	0.12	3 (0.4)	0.11
Herpes zoster	30 (3.6)	1.2	31 (3.8)	1.2	Pulmonary embolism	3 (0.4)	0.12	3 (0.4)	0.11
COVID-19	103 (12.5)	4.3	103 (12.5)	4.1	Deep vein thrombosis	3 (0.4)	0.12	3 (0.4)	0.11
Serious infection	44 (5.3)	1.8	45 (5.5)	1.7	Macular edema	3 (0.4)	0.12	3 (0.4)	0.11
Malignancy	18 (2.2)	0.71	17 (2.1)	0.63	Cystoid macular edema	3 (0.4)	0.12	3 (0.4)	0.11
Bradycardia	3 (0.4)	0.12	3 (0.4)	0.11

^aData cutoff of June 30, 2023. ^bData cutoff of January 10, 2024. ^cTotal PY was calculated as the sum of the number of years on study contributed by each pt from time of first dose to last date on study. ^dEAIRs were calculated as number of pts/PY × 100. ^eTN OLE is an ongoing study. Individual TEAE terms may not add up as harmonization of final data is pending. ^fFor the 5 pts who newly reported a serious TEAE, events included 1 pt each with UC exacerbation, colitis, pancreatitis, and umbilical hernia, and 1 pt with ulcerative keratitis and keratouveitis.

Conclusion

The ongoing safety profile of OZA is consistent with previous analyses, with no new safety concerns identified. Long-term OZA use representing 2681 PY of exposure continues to be well tolerated in pts with moderately to severely active UC.

Disclosure

Acknowledgment: This study was sponsored by Bristol Myers Squibb. Writing and editorial assistance was provided by Traci Stuve, MA, and Alexandra Stafford, PhD, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb.

JT: received grants from AbbVie and Janssen; received advisory board or speaker fees from AbbVie, Bristol Myers Squibb, Janssen, Pfizer, and Sandoz.
RL: consulted for Bristol Myers Squibb and Pfizer.
KK: received lecture honoraria from Gore.
SL: consulted for AbbVie, Bristol Myers Squibb, Eli Lilly, and Janssen.
TK: served as an advisory board member, consultant, or speaker for AbbVie, Alfresa Pharma, Alimentiv, Astellas, Bristol Myers Squibb, Celltrion, Covidien, EA Pharma, Eli Lilly, Ferring, Galapagos, Gilead Sciences, Janssen, JIMRO, JMDC, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, ThermoFisher Scientific, and Zeria Pharmaceutical; received research funding from AbbVie, Alfresa Pharma, EA Pharma, Gilead, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Pfizer, Sekisui Medical, Takeda, ThermoFisher Scientific, and Zeria Pharmaceutical.
DB: served as advisory board member or consultant for AbbVie, Amgen, Arena, Atheneum, BNG Service GmbH, Bristol Myers Squibb, CED Service GmbH, Celltrion, DGVS, Diaplan, Doctorflix, Eli Lilly, Else Kröner-Fresenius-Stiftung, Falk Foundation, Ferring, Galapagos, Gastroenterology Today, GlaxoSmithKline, Guidepoint, Impulze, Janssen-Cilag, Medical Tribune, MedTrix, MSD, Mylan, Onkowissen, Pfizer, Pharmacosmos, Roche, Sandoz, Streamed Up, Takeda, Tetrameros, Thieme, Tillotts, UCB, Viatris, and Vifor Pharma.
LK: reported no conflicts of interest.
DM, NRS, AP, MD, HW, DW, MTO, and AJ: employees and/or shareholders of Bristol Myers Squibb.
BPA: consulted for AbbVie, Bristol Myers Squibb, Celltrion, Eli Lilly, Janssen, Medtronic, Pfizer, Prometheus, Samsung Bioepis, and Takeda; lectured for AbbVie, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, and Takeda.