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Introduction

Data on bowel urgency (BU) in Crohn’s disease (CD) are limited, and associated factors are not well identified. Here we evaluate the association of BU with baseline (BL) disease characteristics in patients with moderately to severely active CD in the randomized, double-blind, double-dummy, treat-through design Phase 3 VIVID-1 trial (NCT03926130).

Aims & Methods

BU was assessed using the average Urgency Numeric Rating Scale (UNRS) (range 0-10) from 7 days prior to the visit. Adult patients as previously described¹, that had an UNRS ≥3 and no missing values at BL were included in this analysis. The association of UNRS with Crohn’s Disease Activity Index (CDAI), abdominal pain (AP), stool frequency (SF), Simple Endoscopic Score for CD (SES-CD) total score, disease location, count of inflamed intestinal segments, rectal involvement, presence of narrowing, presence of perianal fistulae, number of bowel resections and inflammatory biomarkers were analyzed. Other factors explored included sex, age, age at diagnosis, duration of CD, BL corticosteroid and immunomodulator use, and prior biologic failure. Random forest method (RFM) was applied to rank variables by importance associated with BU score at BL. Pearson correlation coefficients (r-value) were calculated for continuous baseline variables.

Results

At BL, 73.4% (782/1065) patients randomized to placebo (n=141), MIRI (n=433), or ustekinumab (n=208) reported a UNRS ≥3 with a median UNRS of 7.0 Among BL disease characteristics, CDAI total score and AP were the top two important factors based on RFM (CDAI=0.701; AP=0.398) and had moderate positive correlations (CDAI=0.479; AP=0.384) with UNRS (Table). Notably, disease characteristics such as SF (RFM=0.236; r=0.286), SES-CD total score (RFM=0.056; r=0.118 ), age at diagnosis (RFM=0.037; r=-0.018), age (RFM=0.033; r=-0.022), faecal calprotectin (RFM=0.029; r=0.031), C-reactive protein (RFM=0.028; r=0.050), count of inflamed segments (RFM=0.021; r=0.069), duration of CD (RFM=0.015; r=-0.007), presence of perianal fistula (RFM=0.009; r=0.090), and number of bowel resections (RFM=0.000; r=-0.036) all had weak correlations with UNRS. BL corticosteroid (RFM=0.015) and immunomodulator (RFM=0.007) use, disease location (RFM=-0.005), rectal involvement (RFM=0.011), presence of narrowing (RFM=0.007), prior biologic failure (RFM=0.003), and sex (RFM=0.007) had weak correlations with UNRS implied by RFM.

Patient baseline variables	Importance value based on random forest	Pearson correlation coefficient (r)
CDAI Total Score	0.701	0.479
Abdominal pain score	0.398	0.384
Stool frequency score	0.236	0.286
SES-CD total score	0.056	0.118
Age at diagnosis	0.037	-0.018
Age	0.033	-0.022
Faecal calprotectin	0.029	0.031
C-reactive protein	0.028	0.050
Correlation strength defined as: r>0.5=strong, 0.5≥r≥0.3 =moderate, 0.3>r≥0.1 =weak, r<0.1=insubstantial² RFM is used to rank the relative importance of the patient baseline variables to UNRS. The higher values mean more important with a stronger association with UNRS. Abbreviations: CDAI=Crohn’s Disease Activity Index; CI=confidence interval; RFM = random forest method; SES-CD=Simple Endoscopic Score for Crohn’s Disease; UNRS = Urgency Numeric Rating Scale

Conclusion

Most patients reported BU ≥3 at BL. The only moderate positive correlations were observed between BU, clinical disease severity (CDAI), and AP. Even though the association of BU with other disease characteristics such as extent and severity of endoscopic inflammation, rectal involvement, presence of active perianal disease, disease location, previous resection, and duration of CD were weak, they potentially interact and contribute together resulting in BU.

References

M Ferrante, S Danese, M Chen, G D'Haens, S Ghosh, T Hisamatsu, V Jairath, J Kierkus, L Peyrin-Biroulet, B Siegmund, S M Bragg, W Crandall, T Hunter Gibble, Z Lin, M Ugolini Lopes, N Morris, H Carlier, B Sands, VIVID Study Group, OP05 Primary efficacy and safety of mirikizumab in moderate to severe Crohn’s Disease: results of the treat-through VIVID 1 study, Journal of Crohn's and Colitis, Volume 18, Issue Supplement_1, January 2024, Pages i7–i9, https://doi.org/10.1093/ecco-jcc/jjad212.0005

Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Routledge; 1988

Disclosure

GD-H: has served as adviser and/or speaker for Abbvie,Alimentiv,Amgen,BristolMeiersSquibb,BoehringerIngelheim,Celltrion,Ferring,Lilly,Engene,Galapagos,GlaxoSmithKline,Immunic,IndexPharmaceuticals,JohnsonandJohnson,Merck, Polpharm, Prometheusbiosciences, PrometheusLaboratories,Procisediagnostics,Protagonist,Sandoz,Takeda,Tillotts,andVentyx.
BES: reports consulting fees from Abbvie,Alimentiv,Amgen,ArenaPharmaceuticals,ArtugenTherapeutics,Astra eneca,BoehringerIngelheim,BostonPharmaceuticals,Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, FreseniusKabi, Galapagos, Roche, GileadSciences, GlaxoSmithKline, GossamerBio, IndexPharmaceuticals, InnovationPharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, MorphicTherapeutics, MRM Health, Progenity, PrometheusBiosciences, PrometheusLaboratories, ProtagonistTherapeutics, Q32Bio, SunPharma, Surrozen, TargetRWE,Teva, TLL Pharmaceutical, VentyxBiosciences; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees and other support from BristolMyersSquibb, Janssen, Pfizer, Takeda; research grants and consulting fees from TheravanceBiopharma; and stock options from VentyxBiopharma.
VJ: has received fees or grant and/or research support and/or served as a consultant and/or speaker for: AbbVie, Alimentiv, ArenaPharmaceuticals, AsahiKaseiPharma, AsierisPharmaceuticals, AstraZeneca, BristolMyersSquibb, Celltrion, EliLillyandCompany, FerringPharmaceuticals, FlagshipPioneering, FreseniusKabi, GalapagosNV, Genentech, GileadSciences, GlaxoSmithKline, Janssen, Merck, Metacrine, Mylan, PandionTherapeutics, Pendopharm, Pfizer, PrometheusTherapeuticsandDiagnostics, ProtagonistTherapeutics, ReistoneBiopharma, Roche, Sandoz, SecondGenome, SorrisoPharmaceuticals, Takeda, Teva, Topivert, VentyxBiosciences, and VividionTherapeutics
ST: has received grants from: AbbVie, BUHLMANNDiagnostics, ECCO, EliLillyandCompany, FerringPharmaceuticals, InternationalOrganizationfortheStudyofInflammatoryBowelDisease, Janssen, MerckSharp&Dohme, NormanCollisonFoundation, Pfizer, Procter&Gamble, Schering-Plough, Takeda, UCBPharma, ViforPharma, and WarnerChilcott; and reports other disclosures from: AbacusPharma, AbbVie, ActialFarmaceutica, ai4gi, Alcimed, Allergan, Amgen, Aptel, ArenaPharmaceuticals, AsahiKaseiPharma, AspenPharmacare, Astellas, AstraZeneca, AtlanticPharmaceuticals, Barco, BiocareMedical, Biogen, BL Pharma, BoehringerIngelheim, BristolMyersSquibb, BUHLMANNDiagnostics, CalcicoTherapeutics, Celgene, Cellerix, CerimonPharmaceuticals, ChemoCentryx, Chiesi, Cisbio, Comcast, CoronadoBiosciences, CosmoPharmaceuticals, Dr.FalkPharma, DucentisBioTherapeutics, Dynavax Technologies, ElanPharma, EliLillyandCompany, Enterome, Equillium, FerringPharmaceuticals, GalapagosNV, Genentech/Roche, Genzyme, GileadSciences, GlaxoSmithKline, GlenmarkPharmaceuticals, Grünenthal,
GWPharmaceuticals, Immunocore, IndigoBiosciences, Janssen, LexiconPharmaceuticals, Medarex, MedTrix, Merck, MerrimackPharmaceuticals, MestagTherapeutics, MillenniumPharmaceuticals, Neovacs, Novartis, NovoNordisk, NPSPharmaceuticals/Nycomed, OceraTherapeutics, OPTIMAPharma, OriginPharma, Otsuka, PalauPharma, PentaxMedical, Pfizer, PharmaVentures, Phesi, PhillipsPharmaGroup, Procter&Gamble, Pronota, Proximagen, ResolutePharma, RobartsClinicalTrials, Sandoz, Santarus, SatisfaiHealth, SensyneHealth, Shire, SigmoidPharma, SorrisoPharmaceuticals, Souffinez, SynDermix, Synthon, Takeda, TheravanceBiopharma, TiGenix, TillottsPharmaAG, Topivert, TrinoTherapeutics with WellcomeTrust, TxCellSA, UCBPharma, VertexPharma, VHsquared, ViforPharma, WarnerChilcott, and ZeriaPharmaceutical
MCha: has served as a speaker, as a consultant, or has received research or education funding from MSD, AbbVie, Hospira, Pfizer, Takeda, Janssen, Ferring, ShirePharmaceuticals, DrFalkPharma, TillottsPharma, Biogen, Gilead, and EliLilly
LP-B: Reports the following: personal fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, BoerhingerIngelheim, Pfizer, IndexPharmaceuticals, Sandoz, Celgene, Biogen, SamsungBioepis, Alma, Sterna, Nestle, Inotrem, Enterome, Allergan, MSD, Roche, Arena, Gilead, Hikma, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, FreseniusKabi, OppilanPharma, SublimityTherapeutics, AppliedMolecularTransport, OSEImmunotherapeutics, Enthera, and Theravance; grants from Abbvie, MSD, and Takeda; and stock options from CTMA
M-HC: provided educational activities for AbbVie, ChinaMedicalSystem, IPSEN, Janssen, and Takeda; served on an advisory board for Boehringer Ingelheim and Janssen; and has support for clinical research from Janssen and Takeda.
MD: has received honoraria as a consultant for: AbbVie, ArenaPharmaceuticals, BoehringerIngelheim, BristolMyersSquibb, Celgene, EliLillyandCompany, F.Hoffmann-LaRoche, Genentech, GileadSciences, Janssen, Pfizer, PrometheusTherapeuticsandDiagnostics, Takeda, and UCBPharma; has been contracted for research by: AbbVie, Janssen, Pfizer, and PrometheusBiosciences; has stock interest in: TrellusHealth; and has received licensing fees from: Takeda;
MF: has received fees for grants and/or contracts from: AbbVie, Amgen, Biogen, JanssenCilag, Pfizer, Takeda, and Viatris; consulting fees from: AbbVie, BoehringerIngelheim, Celltrion, Lilly, JanssenCilag, Medtronic, MerckSharp&Dohme, Pfizer, Regeneron, Sandoz, Takeda, and ThermoFisherScientific; lecture fees or honoraria from: AbbVie, Amgen, Biogen, BoehringerIngelheim, Celltrion, Dr.FalkPharma, Lilly, FerringPharmaceuticals, Janssen, Lamepro, Medtronic, MerckSharp&Dohme, Mylan, Pfizer, SamsungBioepis, Sandoz, Takeda, and ThermoFisher; support to attend meetings from: AbbVie, BoehringerIngelheim, Celltrion, Dr.FalkPharma, Janssen, Pfizer, and Takeda; and data safety monitoring fees from: AbbVie, BoehringerIngelheim, Celltrion, Lilly, Janssen, Medtronic, MerckSharp&Dohme, Pfizer, Sandoz, Takeda, and ThermoFisherScientific
SS: has been a consultant for AbbVie, Amgen, ArenaPharmaceuticals, BristolMyersSquibb, BoehringerIngelheim, Celltrion, DrFalkPharma, Ferring, Fresenius, Galapagos, Genentech, GSK, Gilead, I-MABBiopharma, Janssen, Lilly, Merck, Novartis-Sandoz, Pfizer, Protagonist, Takeda, and Theravance.
KM, AV, GY, MP, RM: Employees and shareholders of EliLillyandCompany
SG: has received research grants and consultancy from: EliLillyandCompany; served on steering committees for: AbbVie and BristolMyersSquibb; received consultancy fees from: AbbVie, Celltrion, FerringPharmaceuticals, GalapagosNV, Janssen, Pfizer, and Takeda.

DISEASE CHARACTERISTICS ASSOCIATED WITH BOWEL URGENCY IN CROHN’S DISEASE; RESULTS FROM THE PHASE 3 VIVID-1 TRIAL

Geert R. D'Haens 1, Bruce E. Sands 2, Vipul Jairath 3, Simon Travis 4, María Chaparro 5, Laurent Peyrin-Biroulet 6, Minhu Chen 7, Marla C. Dubinsky 8, Marc Ferrante 9, Stefan Schreiber 10, Kim McGinnis 11, Aisha Vadhariya 11, Guanglei Yu 11, Marijana Protic 11, Richard Moses 11, Subrata Ghosh 12

1 AMC Amsterdam Inflammatory Bowel Disease Centre - Academic Medical Center, AMC Amsterdam Inflammator, Amsterdam, Netherlands

2 Icahn School of Medicine at Mount Sinai, New York, United States

3 Western University & London Health Sciences Centre, London, Canada

4 University of Oxford, Oxford, United Kingdom

5 Hospital Universitario de La Princesa, Madrid, Spain

6 Inserm U1256, Nancy University Hospital, Vandoeuvre-les-Nancy, France

7 First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

8 Mount Sinai Hospital, Mount Sinai, New York City, United States

9 University Hospitals Leuven, Leuven, Belgium

10 University Hospital Schleswig-Holstein, Kiel, Germany

11 Eli Lilly and Company, Indianapolis, United States

12 University College Cork, Cork, Ireland

Conference

UEG Week Vienna 2024

Topics

IBD

Submission format

Abstract

Session

IBD (Posters)

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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Introduction

Long-term data on bowel urgency (BU) in Crohn’s disease (CD) are limited, and the associations with other efficacy outcomes are not well studied.

Aims & Methods

Our aims were to examine the long-term efficacy of mirikizumab (MIRI) on BU remission and the associations between BU remission and clinical remission, endoscopic remission, and patient-reported outcomes (PRO) improvement at week (W) 104 in patients with moderately to severely active CD who were randomized to MIRI in the Phase 3 study VIVID-1 and continued into the long-term extension study VIVID-2. In VIVID-1, the MIRI group received induction with 900 mg intravenously (IV) at W0, W4, and W8, then 300 mg subcutaneously (SC) every 4W. W52 endoscopic responders (≥50% reduction from baseline in Simple Endoscopic Score for CD [SES-CD]) continued MIRI SC dosing in VIVID-2. Endoscopic non-responders received reinduction with MIRI IV (3x Q4W) at the start of VIVID-2 followed by SC dosing (IV-SC) as described. Patients that had an Urgency Numeric Rating Scale (UNRS) ≥3 (least to worst range 0-10) at baseline were included in these analyses. BU remission was defined as an UNRS score of ≤2. Associations between BU remission with clinical remission by Crohn’s Disease Activity Index (CDAI), endoscopic remission, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (range 0-52, higher is better), and Inflammatory Bowel Disease Questionnaire (IBDQ) remission, were assessed at W104, within the VIVID-1 W52 endoscopic response subgroups as well as the MIRI total group. Discontinuations or missing data were handled using modified non-responder imputation (mNRI) for categorical data. Missing values were imputed by multiple imputation and modified baseline observation carried forward for FACIT-Fatigue change from baseline.

Results

Over 50% of the MIRI total group, 56% of MIRI W52 endoscopic responders, and 43% of the MIRI W52 endoscopic non-responders achieved BU remission at W104. In the MIRI total group, a significantly higher percentage of patients achieved clinical remission, endoscopic remission and IBDQ remission at W104 in the BU remission group compared to those without BU remission. The improvement in fatigue by FACIT-Fatigue score was significantly more in the group with BU remission versus those without BU remission (p<0.0001). In both MIRI W52 endoscopic responders and non-responders, patients who achieved BU remission at W104, compared to those who did not, achieved significantly higher rates of clinical remission, greater improvements in FACIT-Fatigue, and higher rates of quality of life improvement measured by IBDQ remission (Table 1).

Table 1

Endpoint at W104	MIRI Total N=405			MIRI W52 endoscopic responders N=236			MIRI W52 endoscopic non-responders N=169
	With BU Remission (51%)	Without BU Remission (49%)	p-value	With BU Remission (56%)	Without BU Remission (44%)	p-value	With BU Remission (43%)	Without BU Remission (57%)	p-value
Clinical remission by CDAI, %	96%	48%	<0.0001	98%	54%	<0.0001	93%	41%	<0.0001
Endoscopic remission, %	34%	21%	0.018	49%	35%	0.058	10%	5%	0.219
FACIT-Fatigue CFBL, mean (SD)	12.2 (1.0)	5.9 (0.9)	<0.0001	12.3 (1.2)	6.1 (1.3)	0.001	12.2 (1.5)	5.7 (1.2)	0.002
IBDQ remission, %	87%	43%	<0.0001	89%	45%	<0.0001	82%	40%	<0.0001
Footnote: P-values for all binary outcomes are from CMH test adjusted by biologic-failed status (yes/no), baseline SES-CD total scores (<12, ≥12), either baseline SF ≥7 and/or baseline AP ≥2.5 (yes or unknown/no). P-values for FACIT-Fatigue are from t-test. mNRI was applied to all binary outcomes and BU remission. Multiple Imputation was applied to FACIT-Fatigue after mBOCF was applied. IBDQ remission is based on patients with baseline IBDQ<170. Clinical remission by CDAI is defined as CDAI total score <150. Endoscopic remission is defined as SES-CD ≤4 and ≥2-point reduction from baseline, and no subscore >1. Abbreviations: AP= abdominal pain; BU= bowel urgency; CDAI= Crohn’s disease activity index; CI=confidence interval; CFBL = change from baseline; CMH= Cochran Mantel Haenszel; mBOCF= Modified Baseline Observation Carried Forward; MIRI = mirikizumab; mNRI = modified nonresponder imputation; N = number of patients in the analysis population; FACIT= Functional Assessment of Chronic Illness Therapy; IBDQ = Inflammatory Bowel Disease Questionnaire; SD= standard deviation; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF= stool frequency; W=week

Conclusion

Over 50% of patients with CD achieved BU remission at 2 years of treatment with MIRI. These results highlight that the achievement of BU remission corresponded with improvements to outcomes important to patients with CD, underscoring the importance of long-term management of BU in improving overall patient outcomes.

Disclosure

SRV: has received consulting fees, speaker’s honoraria and unrestricted research grants from Abbott, Alfasigma, Amgen, Arenapharm, BMS, Falk Pharma GmbH, Ferring Pharmaceuticals, Gilead, iQuone, Janssen, MSD, Permamed, Pfizer, Sanofi-Aventis, Schwabe Pharma, Takeda, Tillotts, UCB and Vifor
DTR: receives grants or contracts from Takeda, and discloses consultancy fees with AbbVie, Altrubio, Apex, Avalo Therapeutics, Bristol Myers Squibb, Buhlmann Diagnostics Corp, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Janssen Pharmaceuticals, Lilly, Pfizer, Samsung Neurologica, and Takeda. He serves on the Board of Directors for Cornerstones Health.
JW, GY, AV, REM, and RRH: Employees and stockholders of Eli Lilly.
GD-H: Has received research grants from: Alimentiv BV, Bristol Myers Squibb, Eli Lilly and Company, Pfizer, and Takeda; and consulting fees from: AbbVie, Alimentiv, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, GSK, Merck Sharp & Dohme, Pfizer, Sorriso Pharmaceuticals, Takeda, Tillotts Pharma AG, and Ventyx Biosciences
ST: has received grants from: AbbVie, BUHLMANN Diagnostics, ECCO, Eli Lilly and Company, Ferring Pharmaceuticals, International Organization for the Study of Inflammatory Bowel Disease, Janssen, Merck Sharp & Dohme, Norman Collison Foundation, Pfizer, Procter & Gamble, Schering-Plough, Takeda, UCB Pharma, Vifor Pharma, and Warner Chilcott; and reports other disclosures from: Abacus Pharma, AbbVie, Actial Farmaceutica, ai4gi, Alcimed, Allergan, Amgen, Aptel, Arena Pharmaceuticals, Asahi Kasei Pharma, Aspen Pharmacare, Astellas, AstraZeneca, Atlantic Pharmaceuticals, Barco, Biocare Medical, Biogen, BL Pharma, Boehringer Ingelheim, Bristol Myers Squibb, BUHLMANN Diagnostics, Calcico Therapeutics, Celgene, Cellerix, Cerimon Pharmaceuticals, ChemoCentryx, Chiesi, Cisbio, Comcast, Coronado Biosciences, Cosmo Pharmaceuticals, Dr. Falk Pharma, Ducentis BioTherapeutics, Dynavax Technologies, Elan Pharma, Eli Lilly and Company, Enterome, Equillium, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Genzyme, Gilead Sciences, GlaxoSmithKline, Glenmark Pharmaceuticals, Grünenthal, GW Pharmaceuticals, Immunocore, Indigo Biosciences, Janssen, Lexicon Pharmaceuticals, Medarex, MedTrix, Merck, Merrimack Pharmaceuticals, Mestag Therapeutics, Millennium Pharmaceuticals, Neovacs, Novartis, Novo Nordisk, NPS Pharmaceuticals/Nycomed, Ocera Therapeutics, OPTIMA Pharma, Origin Pharma, Otsuka, Palau Pharma, Pentax Medical, Pfizer, PharmaVentures, Phesi, Phillips Pharma Group, Procter & Gamble, Pronota, Proximagen, Resolute Pharma, Robarts Clinical Trials, Sandoz, Santarus, Satisfai Health, Sensyne Health, Shire, Sigmoid Pharma, Sorriso Pharmaceuticals, Souffinez, SynDermix, Synthon, Takeda, Theravance Biopharma, TiGenix, Tillotts Pharma AG, Topivert, Trino Therapeutics with Wellcome Trust, TxCell SA, UCB Pharma, Vertex Pharma, VHsquared, Vifor Pharma, Warner Chilcott, and Zeria Pharmaceutical
AW: reports consulting and/or speaking fees from Abbvie, Bristol-Myers Squibb, Ferring, Galapagos, Janssen, Pfizer, and Takeda.

MIRIKIZUMAB LONG-TERM IMPACT ON BOWEL URGENCY IN CROHN’S DISEASE AND ITS ASSOCIATION WITH CLINICAL AND OTHER EFFICACY OUTCOMES: RESULTS FROM THE VIVID-2 OPEN-LABEL EXTENSION STUDY

Stephan Vavricka 1, David T. Rubin 2, Jianmin Wu 3, Guanglei Yu 3, Aisha Vadhariya 3, Richard Moses 3, REBECCA HOZAK 3, Geert R. D'Haens 4, Simon Travis 5, Alissa Walsh 6

1 University Hospital Zurich - Gastroenterology and Hepatology, University Hospital Zurich; Zurich/CH, Zurich, Switzerland

2 University of Chicago Medicine, Chicago, United States

3 Eli Lilly and Company, Indianapolis, United States

4 AMC Amsterdam Inflammatory Bowel Disease Centre - Academic Medical Center, AMC Amsterdam Inflammator, Amsterdam, Netherlands

5 Kennedy Institute, Oxford, United Kingdom

6 John Radcliffe Hospital, Oxford, Oxford, United Kingdom

Conference

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

New treatments on the horizon for Crohn's disease (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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IMPROVEMENT IN FATIGUE WITH MIRIKIZUMAB THERAPY AND ASSOCIATIONS WITH CLINICAL OUTCOMES IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE: RESULTS FROM THE PHASE 3 VIVID-1 STUDY

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Introduction

Fatigue is a debilitating, multifactorial symptom experienced by many patients with Crohn’s disease (CD).¹ Mirikizumab (MIRI), an anti-interleukin-23p19 antibody, demonstrated significant improvement in fatigue in patients with moderately to severely active CD in the Phase 2 AMAG² and Phase 3 VIVID-1³ studies.

Aims & Methods

This analysis examines the association of changes in clinical, endoscopic (endo) and selected patient-reported outcomes with changes in fatigue in MIRI-treated patients in the VIVID-1 study. Co primary and gated secondary outcomes, including comparisons with ustekinumab, have been presented elsewhere^4,5Adult patients (N=1065) with moderately to severely active CD were randomized 6:3:2 to MIRI, ustekinumab or placebo. MIRI was given every 4 weeks (W) as 900 mg intravenous at W0, W4, and W8, then 300 mg subcutaneous from W12 to W52. Fatigue was assessed via the validated Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire (scale from 0-52, higher scores indicating less fatigue⁶ andat least 6-point increase identified as a clinically meaningful within-patient change). Achievement of ≥6-point increase in FACIT-F at W52 was reported among those with and without clinical remission by Crohn’s Disease Activity Index (CDAI), endo response, endo remission, and Urgency Numeric Rating Scale (NRS) ≤2 at W52. For stool frequency (SF), abdominal pain (AP), fecal calprotectin (FCP), and C-reactive protein (CRP), the association of the change from baseline (CFB) at W52 vs. the CFB in FACIT-F at W52 was assessed by the Pearson correlation coefficient.

Results

At W52, 50.9% (268/527) of MIRI-treated patients achieved FACIT-F ≥6-point increase from baseline. Greater proportions of patients who achieved clinical and endo outcomes had ≥6-point increase in FACIT-F (p<0.05) vs. those who did not achieve the outcome (Table). There was weak/moderate correlation between CFB at W52 in AP, SF and log-transformed FCP and CRP, and the CFB in FACIT-F at W52 (Table).

Table: W52 FACIT-F, A: ≥6-pt Increase From BL by Outcomes at W52 and B: CFB Correlation With CFB at W52 in Outcomes

A. W52 FACIT-F ≥6-point Increase From BL by Outcome at W52^a, NRI	Outcome Achieved n/N (%) (95% CI)^b	Outcome NOT Achieved n/N (%) (95% CI)^b	Risk Difference (95% CI)^b	p-Value^c
Clinical remission by CDAI^d	185/280 (66.1) (60.5-71.6)	83/247 (33.6) (27.7-39.5)	32.5 (24.4-40.6)	<0.0001
Endo response^e	154/256 (60.2) (54.2-66.2)	114/271 (42.1) (36.2-47.9)	18.1 (9.7-26.5)	<0.0001
Endo remission^f	59/96 (61.5) (51.7-71.2)	209/431 (48.5) (43.8-53.2)	13.0 (2.1-23.8)	0.0216
Urgency NRS ≤2^g	127/188 (67.6) (60.9-74.2)	127/311 (40.8) (35.4-46.3)	26.7 (18.1-35.4)	<0.0001
B. CFB in FACIT-F vs. CFB in Outcomes at W52	N	Pearson Correlation Coefficient	95% CI^h	p-Value
CFB in AP score	574	-0.379	-0.447 to -0.306	<0.0001
CFB in SF score	572	-0.306	-0.378 to -0.230	<0.0001
CFB in log-transformed FCP	461	-0.112	-0.201 to -0.020	0.0166
CFB in log-transformed CRP	576	-0.208	-0.285 to -0.128	<0.0001

^aMIRI-treated patients with baseline (BL) FACIT-F score ≤46 points; ^bConfidence interval (CI) constructed using asymptotic method without continuity correction; ^cChi Square test; ^dCDAI <150; ^eSimple Endoscopic Score for CD (SES-CD) Total Score ≥50% improvement from BL; ^fSES-CD Total Score ≤4, ≥2-point reduction from BL and no subscore >1; ^gIn those with BL Urgency NRS ≥3; ^hPearson correlation with Fisher’s z-transformation. A negative correlation indicates an improvement in outcome is associated with an improvement in FACIT-F. Correlation strength defined as: >0.5=strong, 0.3 to ≤0.5=moderate, 0.1 to <0.3=weak, <0.1=insubstantial⁷
NRI=nonresponder imputation.

Conclusion

In patients with moderately to severely active CD treated with MIRI, improvements in clinical, endoscopic, and selected patient-reported outcomes were associated with clinically meaningful improvements in fatigue at W52.

References

D’Silva A, et al. Clin Gastroenterol Hepatol. 2022;20:995-1009.
Regueiro MD, et al. Am J Gastroenterol. 2023;118:S816.
Travis S, et al. J Crohn's Colitis.2024;18:i21–i23.
Ferrante M, et al. J Crohn's Colitis. 2024;18:S1 i7–i9.
Jairath V, et al. J Crohn's Colitis. 2024;18:i62–i64.
Tinsley A, et al. Aliment Pharmacol Ther. 2011;34:1328-36.
Cohen J. Statistical Power Analysis for the Behavioural Sciences, 1988, Routledge.

Disclosure

P. Bossuyt has received financial support for research from: AbbVie, Amgen, Janssen, Pfizer, and Viatris; lecture fees from: AbbVie, Bristol Myers Squibb, CAG, Celltrion, Eli Lilly and Company, EPGS, Galapagos NV, Globalport, Janssen, Materia Prima, Pentax, Scope, and Takeda; and advisory board fees from: AbbVie, Bristol Myers Squibb, Celltrion, CIRC, Dr. Falk Pharma Benelux, Eli Lilly and Company, Galapagos NV, Janssen, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros; M. Regueiro has served as an advisor and/or consultant for: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Genentech, Gilead Sciences, Janssen, Organon, Pfizer, Prometheus Therapeutics and Diagnostics, Salix Pharmaceuticals, Takeda, and UCB Pharma; M. Fischer has received consulting fees from: AbbVie, Bristol Myers Squibb, Eli Lilly and Company, Ferring Pharmaceuticals, Janssen, Pfizer, Rebiotix, Scioto Biosciences, and Seres Therapeutics; K. Traxler, G. Yu, M. Protic, K. Tsilkos, and A. Vadhariya are employees and shareholders of: Eli Lilly and Company; T. Hisamatsu has received lecture fees from: AbbVie, EA Pharma, Gilead Sciences, Janssen Pharmaceutical K.K., JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda; has received honoraria as an advisory board member or consultant for: AbbVie, Brystol Myers Squibb, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Pfizer, and Takeda; and has received pharmaceutical/research grants from: AbbVie, Boston Scientific, Daiichi Sankyo, EA Pharma, Kissei Pharmaceutical, JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nichi-lko Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical; P. Juillerat has received fees for lectures and consulting/advisory board from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly and Company, Ferring Pharmaceuticals, Gilead Sciences, Janssen, Merck Sharp & Dohme, Pfizer, Pierre Fabre, Sandoz, Takeda, Tillotts Pharma AG, and UCB Pharma

IMPROVEMENT IN FATIGUE WITH MIRIKIZUMAB THERAPY AND ASSOCIATIONS WITH CLINICAL OUTCOMES IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE: RESULTS FROM THE PHASE 3 VIVID-1 STUDY

Peter Bossuyt 1, Miguel Regueiro 2, Monika Fischer 3, Kristina Traxler 4, Guanglei Yu 4, Marijana Protic 4, Konstantinos Tsilkos 4, Aisha Vadhariya 4, Tadakazu Hisamatsu 5, Pascal Juillerat 6

1 Imelda General Hospital, Bonheiden, Belgium

2 Cleveland Clinic, Cleveland, United States

3 IUPUI, Indianapolis, United States

4 Eli Lilly and Company, Indianapolis, United States

5 Kyorin University School of Medicine, Tokyo, Japan

6 Intesto Crohn's and Colitis Center, Bern and Fribourg, Switzerland

Event

UEG Week Vienna 2024

Topics

Histopathology IBD Mechanisms & Personalised Medicine

Submission format

Abstract

Session

Ameliorating acute disease through novel treatment in IBD: Part 2

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

UEG Poster

Standard Poster

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Introduction

Bowel urgency (BU), the sudden or immediate need to have a bowel movement, is an impactful symptom of Crohn’s disease (CD) that varies in intensity¹. We report the efficacy of the IL-23 p19 inhibitor, mirikizumab (miri) in improving BU among patients with moderately-to-severely active CD from the phase 3 VIVID-1 trial (NCT03926130). VIVID-1 co-primary and gated endpoints, including comparison with ustekinumab, are already reported².

Aims & Methods

Adult patients (N=1065) were randomised to placebo (PBO) or miri 900mg intravenously at weeks (W) 0, 4, and 8, then 300mg subcutaneously every 4 weeks (Q4W) from W12 to W52. At W12, PBO responders continued PBO to W52, non-responders received the blinded miri regimen per protocol. BU was assessed at W12 and W52 using the Urgency Numeric Rating Scale (UNRS)³. We evaluated the proportion of patients with baseline (BL) UNRS ≥3 and ≥6 who achieved BU Clinically Meaningful Improvement (CMI; >3 change in UNRS) and BU remission (UNRS ≤2). Treatment comparisons used Cochran-Mantel-Haenszel tests with non-responder imputation for missing values.

Results

Study population: 55.1% male. Mean (SD) age 36.2 (13.0) years. Disease duration 7.4 (7.9) years. At BL, median (Q1, Q3) UNRS 6.9 (5.2, 8.1), 94.5% patients achieved UNRS ≥3 and 66.0% patients achieved ≥6. In patients with BL UNRS ≥3, nominally significantly higher proportions of miri versus PBO patients achieved BU CMI and BU remission at both W12 and W52 (Table). A nominally significantly greater proportion of miri-treated patients achieved W52 BU CMI-composite and BU remission-composite (Table). Similar results were seen with BL UNRS ≥6.

		W12 PBO	W12 Miri	W12 p-value	W12 95% CI	W52 PBO	W52 Miri	W52 p-value	W52 95% CI
	UNRS^a CFB (LSM ±SE)	-1.58 (0.168)	-2.44 (0.099)	0.00011	-1.24, -0.48	-1.23 (0.180)	-3.24 (0.106)	<0.0001	-2.42, -1.60
Patients with BL UNRS ≥3	BU CMI-TT	50/186 (26.9)	227/547 (41.5)	0.0004	6.7, 22.0	38/186 (20.4)	301/547 (55.0)	<0.0001	28.0, 42.1
	BU CMI-composite^b					38/186 (20.4)	251/547 (45.9)	<0.0001	18.5, 32.8
	BU Remission^c-TT	29/186 (15.6)	134/547 (24.5)	0.01	2.3, 15.0	21/186 (11.3)	209/547 (38.2)	<0.0001	21.0, 33.2
	BU Remission-composite					21/186 (11.3)	180/547 (32.9)	<0.0001	15.7, 27.8
Patients with BL UNRS ≥6	BU CMI-TT	38/137 (27.7)	180/376 (47.9)	0.0001	9.8, 28.2	31/137 (22.6)	229/376 (60.9)	<0.0001	30.1, 47.3
	BU CMI-composite					31/137 (22.6)	188/376 (50.0)	<0.0001	18.4, 36.0
	BU Remission-TT	11/137 (8.0)	70/376 (18.6)	0.007	3.8, 15.8	13/137 (9.5)	126/376 (33.5)	<0.0001	17.1, 31.1
	BU Remission-composite					13/137 (9.5)	111/376 (29.5)	0.0002	13.2, 27.0

PBO, N=199; Miri, N=579. Data are N (%) unless otherwise stated. ^aUNRS scale: 0 (no urgency)-10 (worst possible urgency)³.^bComposite=Clinical response by PRO (2 of the patient-reported items of the CDAI, AP and SF) at W12 and W52 parameter (CMI or Remission). ^cBU remission=no to minimal BU (UNRS≤2). Treatment comparison: CFB used a mixed model for repeated measures model containing treatment, BL value, visit, stratification factors and interaction of BL value by visit and treatment by visit. Response rates usedCochran-Mantel-Haenszel tests with non-responder imputation. AP=abdominal pain; BL=baseline; CFB=change from BL; CI=confidence interval; CMI=clinically meaningful improvement; LSM=least squares mean; PBO=placebo; PRO=Patient Reported Outcome; SD=standard deviation; SE=standard error; SF=stool frequency; TT=treat-through; UNRS=Urgency Numeric Rating Scale; W=week.

Conclusion

BU is one of the most unrecognised symptoms in patients with CD. Patients enrolled in VIVID-1 had high BU scores at BL. Compared to PBO-treated pts, miri-treated pts achieved nominally significantly higher rates of BU CMI and remission at W12 and W52.

References

1. Dulai PS, et al. Aliment Pharmacol Ther 2020; 51(11): 1047-66.
2. Ferrante, M et al. (2024). Journal of Crohn's and Colitis, 18(Supplement_1), i7-i9.
3. Dubinsky MC, et al.. Qual Life Res 2023; 32(12): 3403-15.

Disclosure

VP consulting/advisory board fees from AbbVie, Alimentiv Inc., Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, SCOPE, Second Genome, Sorriso, Takeda, TD Securities, Teva, Topivert, Ventyx, and Vividion; speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, and Fresenius Kabi.
BES consulting fees from Abbvie, Alimentiv, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Boehringer IngelheSim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Morphic Therapeutics, MRM Health, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Target RWE,Teva, TLL Pharmaceutical, and Ventyx Biosciences; consulting/speaking fees from Abivax; consulting/speaking fees/other support from Lilly, Bristol Myers Squibb, Janssen, Pfizer, and Takeda; research grants and consulting fees from Theravance Biopharma; stock options from Ventyx Biopharma.
MC speaker, consultant, or has received research/education funding from MSD, AbbVie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr Falk Pharma, Tillotts Pharma, Biogen, Gilead, and Lilly.
MChen provided educational activities for AbbVie, China Medical System, IPSEN, Janssen, and Takeda; advisory board for Boehringer Ingelheim and Janssen; support for clinical research from Janssen and Takeda.
GD’H adviser and/or speaker for Abbvie, Alimentiv, Amgen, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Ferring, Lilly, Engene, Galapagos, Glaxo Smith Kline, Immunic, Index Pharmaceuticals, Johnson and Johnson, Merck, Polpharm, Prometheus biosciences, Prometheus Laboratories, Procise diagnostics, Protagonist, Sandoz, Takeda, Tillotts, and Ventyx.
MD consultant for AbbVie, Arena, Astra Zeneca, Boehringer Ingelheim, Celgene, Lilly, Gilead, Janssen, Merck, Pfizer, Prometheus Laboratories, Takeda, and UCB; research grants from Janssen, AbbVie, and Prometheus Laboratories.
MF research grants from AbbVie, Biogen, EG, Janssen, Pfizer, Takeda, and Viatris; consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Lilly, Janssen-Cilag, MRM Health, MSD, Pfizer, Takeda, and ThermoFisher; speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Falk, Ferring, Janssen-Cilag, MSD, Pfizer, Takeda, Truvion Healthcare, and Viatris.
LP-B personal fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSE Immunotherapeutics, Enthera, Theravance, Pandion Therapeutics, Gossamer Bio, Viatris, and Thermo Fisher Scientific; grants from AbbVie, MSD, Takeda, and Fresenius Kabi; holds stock options in Clinical Trials Mobile Application.
SS consultant/speaker fees from AbbVie, Allergosan, Amgen, Arena, BMS, Celltrion, Falk Pharma, Ferring, Galapagos, Gilead, Genentech (Roche), GSK, IMAB, Janssen, Lilly, MSD, Pfizer, Shire, Takeda, and Ventyx.
ST consultancy from Biogen, Bristol-Myers Squibb, Celgene, ChemoCentryx, Cosmo, Enterome, Ferring, Giuliani, GlaxoSmithKline, Genentech, Immunocore, Immunometabolism, Janssen, Lilly, MSD, Merck, Neovacks, Novonordisk, Novartis, NPS Pharmaceuticals, Pfizer, Proximagen, Receptos, Roche, Shire, Sigmoid Pharma, Takeda, Topivert, UCB, VHsquared, Vifor, Zeria, Sensyne, Satisfai, Bioclinica, Equillium, Mestag, Sorriso, Protagonist; research support from AbbVie, the International Organization for the Study of Inflammatory Bowel Diseases, Lilly, UCB, Vifor, Norman Collisson Foundation, Pfizer, UK–India Education and Research Initiative, ECCO Health Care, the Helmsley Trust; honoraria from AbbVie, Amgen, Biogen, Ferring, Takeda, Lilly; travel expenses covered or reimbursed from AbbVie, Lilly, Johnson & Johnson, Pfizer, Takeda, Ferring, Amgen, and Biogen.
HC, ZL, RM, MP, AV and KT are employees and stockholders of Lilly.
SG speaking commitments with AbbVie, Takeda, Janssen, Pfizer, Gilead, Galapagos, Ferring, Lilly and Company, and Celltrion; drug monitoring committees with Janssen; advisory committees with Janssen, AbbVie, Takeda, Gilead, Galapagos, Lilly, Pfizer, Celltrion, and Ferring; steering committees with Janssen, Bristol Myers Squibb, and AbbVie.

MIRIKIZUMAB EFFECT ON BOWEL URGENCY RESOLUTION IN A RANDOMISED CONTROLLED PHASE 3 TRIAL OF PARTICIPANTS WITH CROHN’S DISEASE

Vipul Jairath 1, Bruce E. Sands 2, María Chaparro 3, Minhu Chen 4, Geert R. D'Haens 5, Marla C. Dubinsky 6, Marc Ferrante 7, Laurent Peyrin-Biroulet 8, Stefan Schreiber 9, Simon Travis 10, Hilde Carlier 11, Zhantao Lin 11, Richard Moses 11, Marijana Protic 11, Aisha Vadhariya 11, Konstantinos Tsilkos 11, Subrata Ghosh 12

1 Western University, London, Canada

2 Icahn School of Medicine at Mount Sinai, New York, United States

3 Hospital Universitario de La Princesa, Madrid, Spain

4 First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

5 AMC Amsterdam Inflammatory Bowel Disease Centre - Academic Medical Center, AMC Amsterdam Inflammator, Amsterdam, Netherlands

6 Mount Sinai Hospital, Mount Sinai, New York City, United States

7 University Hospitals Leuven, Leuven, Belgium

8 Nancy University Hospital, Vandoeuvre-les-Nancy, France

9 Kiel University, Kiel, Germany

10 University of Oxford, Oxford, United Kingdom

11 Eli Lilly and Company, Indianapolis, United States

12 University College Cork, Cork, Ireland

Conference

UEG Week Vienna 2024

Topics

IBD

Submission format

Abstract

Session

IBD (Posters)

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

UEG Presentation

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ETRASIMOD FOR MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE: RESULTS FROM THE EXTENSION PERIOD OF A PHASE 2 STUDY

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Introduction

Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate_1,4,5 receptor modulator. Within the phase 2/3 CULTIVATE trial (NCT04173273), we report extension data on the efficacy, safety and tolerability of etrasimod in patients with moderately to severely active Crohn’s disease (CD) from substudy A, a phase 2, randomised, double-blind study.

Aims & Methods

Adults (18–80 years) who completed the 14-week induction phase (data reported previously¹) were eligible for the 52-week extension period. Patients receiving etrasimod 3 mg during induction continued this treatment within the extension period, regardless of response. Etrasimod 2 mg responders at Week 14 continued treatment during the extension period, while nonresponders were re‑randomised (1:1) to etrasimod 2 or 3 mg. Two analyses were performed based on two approaches for patients entering extension: treat-through (TT; outcomes reported for all randomised patients regardless of Week 14 response) and responders only (RO; outcomes reported for Week 14 responders only). Both used non‑responder imputation. The primary endpoint was the achievement of endoscopic response (defined by endoscopic remission or ≥50% decrease in Simple Endoscopic Score in Crohn’s Disease) at Week 52; other endpoints included the achievement of clinical remission based on Crohn’s Disease Activity Index (CDAI; <150) and based on PRO2 (<8) at Week 52 (Table). Treatment-emergent adverse events (TEAEs) were reported for the safety set (all randomised patients who received ≥1 dose).

Results

In total, 65 patients (safety set) were enrolled in the extension period with 38 completing the study; patient demographics and baseline characteristics are shown in the Table. For the TT analysis, 14.3% and 19.5% of patients receiving 2 mg or 3 mg etrasimod, respectively, achieved endoscopic response, 28.6% and 34.1% achieved CDAI remission, and 19.0% and 36.6% achieved PRO2 remission at Week 52 (Table). Among Week 14 responders (RO), 23.1% and 33.3% of patients receiving 2 mg or 3 mg etrasimod, respectively, achieved endoscopic response, 46.2% and 54.2% achieved CDAI remission, and 30.8% and 58.3% achieved PRO2 remission at Week 52 (Table). Most TEAEs were mild or moderate. Nine TEAEs led to discontinuation; one was deemed treatment-related (Table). No deaths or TEAEs of macular oedema or malignancies were reported.

Table. Baseline demographics and clinical characteristics of patients entering the extension period, proportions of patients achieving efficacy endpoints at Week 52 and summary of safety data
	Etrasimod 2 mg QD (N=28)	Etrasimod 3 mg QD (N=37)
Demographics and baseline clinical characteristics (extension period)
Age, mean (SD), years Sex, female (%) Extent of disease (%) Ileal disease Colonic disease Ileocolonic disease Baseline CDAI, mean (SD) Baseline SES-CD, mean (SD) Baseline systemic corticosteroids (%) Prior use of thiopurines/methotrexate^a (%) Number of prior biologics^a (%) 0 1 2 ≥3	41.8 (12.8) 53.6 17.9 39.3 42.9 338.6 (81.2) 12.3 (7.3) 39.3 46.4 50.0 21.4 10.7 17.9	41.6 (14.2) 43.2 24.3 21.6 54.1 315.7 (61.5) 10.7 (5.9) 35.1 56.8 40.5 18.9 13.5 27.0
Efficacy endpoints at Week 52
Endoscopic response^b [n/N (%)] Treat-through^c Responders only^d Clinical remission CDAI^e [n/N (%)] Treat-through^c Responders only^d Clinical remission PRO2^f [n/N (%)] Treat-through^c Responders only^d	14.3 (6 / 42) 23.1 (6 / 26) 28.6 (12 / 42) 46.2 (12 / 26) 19.0 (8 / 42) 30.8 (8 / 26)	19.5 (8 / 41) 33.3 (8 / 24) 34.1 (14 / 41) 54.2 (13 / 24) 36.6 (15 / 41) 58.3 (14 / 24)
Summary of safety (extension period)
Any TEAE [n (%)] Any serious TEAE [n (%)] TEAEs leading to study treatment discontinuation [n (%)] TEAEs leading to death [n (%)] Most frequently reported TEAEs^h [n (%)] CD (worsening of/flare) Headache Arthralgia COVID-19 TEAEs of special interestⁱ [n (%)] Severe infections (CTCAE ≥3) [n (%)] Opportunistic infections [n (%)] Ophthalmic herpes zoster^l Macular oedema [n (%)] Cardiovascular events [n (%)] 1^st degree AV block 2^nd degree AV block, Mobitz type I^m Bradycardiaⁿ Hypertension	22 (78.6) 4 (14.3) 3 (10.7) 0 7 (25.0) 3 (10.7) 3 (10.7) 3 (10.7) 1 (3.6)^j 0 0 0 0 1 (3.6) 0	33 (89.2) 7 (18.9) 6 (16.2)^g 0 8 (21.6) 6 (16.2) 5 (13.5) 9 (24.3) 2 (5.4)^k 1 (2.7) 0 2 (5.4) 0 0 1 (2.7)
^aThiopurines/methotrexate and biologics were discontinued prior to randomisation. ^bEndoscopic response defined as endoscopic remission [SES-CD ≤4 and ≥2-point reduction from baseline with no subscore >1] or ≥50% decrease in SES-CD. ^cAll randomised patients at baseline who received ≥1 dose of etrasimod (N=42 in the etrasimod 2 mg group; N=41 in the etrasimod 3 mg group). ^dAll patients who were responders^o at Week 14 (N=26 in the etrasimod 2 mg group; N=24 in the etrasimod 3 mg group). ^eCDAI remission defined as CDAI <150. ^fPRO2 remission defined as a PRO score <8. ^gOne patient discontinued due to TEAE, which was deemed by the investigator as related to etrasimod 3 mg. All other TEAEs that led to discontinuation were related to CD. ^hOccurred in >10% of patients in both etrasimod 2 mg and 3 mg groups. ⁱDefined as a subset of TEAEs that met the criteria of the sponsor’s medical review, and include cardiovascular events, macular oedema and infections. ^jOne event of severe COVID-19. ^kOne event of severe COVID-19 and one event of severe anal abscess. ^lEvent had onset 10 days after the patient had discontinued etrasimod treatment and had started on monoclonal antibody treatment combined with prednisone for worsening CD. The event was assessed as unrelated to study treatment by the investigator. ^mNo TEAEs of 2^nd degree AV block, Mobitz type II or higher were reported. ⁿEvent was non-serious (Grade 1) and did not require intervention. ^oResponders were required to achieve clinical response CDAI (clinical remission CDAI or ≥100-point decrease from baseline in CDAI) or endoscopic response. AV, atrioventricular; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; COVID-19, coronavirus disease 2019; CTCAE, Common Terminology Criteria For Adverse Events; N, number of patients in group; n, number of patients; PRO, patient-reported outcome; PRO2, patient-reported outcome 2; QD, once daily; SD, standard deviation; SES-CD, Simple Endoscopic Score in Crohn’s Disease; TEAE, treatment-emergent adverse event.

Conclusion

Both etrasimod doses remained well tolerated with no new safety signals. This non-placebo-controlled study suggests that etrasimod may be effective in moderately to severely active CD, with higher efficacy at the 3 mg dose. Placebo-controlled studies are ongoing.

References

1. D’Haens G et al. J Crohns Colitis 2023; 17: i764–i765.

Disclosure

GD, Advisor: AbbVie, Alimentiv, AstraZeneca, BI, BMS, Celltrion, Cosmo, Lilly, Galapagos, GSK, J&J, Pfizer, Polpharma, Prometheus, Takeda, Tillotts, and Ventyx. Speaker fees: AbbVie, BI, Celltrion, Lilly, J&J, Pfizer, Takeda, and Tillotts; MCD, Consulting fees: AbbVie, Abivax, Arena, AstraZeneca, BMS, Lilly, Galapagos, Genentech, Gilead, Janssen, Merck, Pfizer, Prometheus, Prometheus Laboratories, Sphyre, Takeda, and UCB. Shareholder/Royalties: Trellus Health. Directorship/Ownership interest: Trellus Health. LPB, Consulting fees: AbbVie, Abivax, Alimentiv, Alma Bio, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC, IAG Image Analysis, Index, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fisher, Tigenix, Tillotts, Viatris, Vifor, Vectivbio, Ventyx, and Ysopia. Grants: Celltrion, Fresenius Kabi, and Takeda. Lecture/speaker bureau: AbbVie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genetech, Gilead, Janssen, Lilly, Medac, MSD, Pfizer, Sandoz, Takeda, Tillotts, Viatris, and Vifor; SD, Lecture/speaker fees: AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda. Consulting/advisory fees: AbbVie, Allergan, Amgen, AstraZeneca, Biogen, BI, Celgene, Celltrion, Ferring, Gilead, Hospira, Janssen, J&J, MSD, Mundi, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB, and Vifor. Directorship/Ownership: Gastroenterology and Endoscopy. BES, Consulting fees: AbbVie, Abivax, Adiso, Agomab, Alimentiv, Amgen, AnaptysBio, Arena, Artugen, AstraZeneca, Biora, BI, Boston, BMS, Calibr, Celgene, Celltrion, ClostraBio, Enthera, Equillium, Evommune, Ferring, Fresenius Kabi, Fzata, Galapagos, Genentech/Roche, Gilead, GSK, Gossamer Bio, Index, Innovation, Janssen, Kaleido, Kallyope, Lilly, Merck, Mobius Care, Morphic, MRM Health, Nexus, Nimbus Discovery, Odyssey, Palisade Bio, Pfizer, Progenity, Prometheus, Prometheus Laboratories, Protagonist, Q32 Bio, Rasayana, Sun, Surrozen, Takeda, Target RWE, Teva, Theravance, TLL, TR1X, Union, and Ventyx. Speaking fees: AbbVie, Abivax, BMS, Janssen, Lilly, Pfizer, and Takeda. Research grants: BMS, Janssen, Pfizer, and Takeda. Stock and Stock options: Ventyx. Other support: Abivax, BMS, Lilly, Janssen, Pfizer, and Takeda. AY, Consulting fees: AbbVie, Arena, BMS, Pfizer, and Takeda. Lecture fees: AbbVie and BMS. MVC, Grant support: BMS, Janssen, Pfizer, and Novartis. Consulting fees: AbbVie, Arena, BMS, Celltrion, Fresenius Kabi, Janssen, Lilly, Medtronic, Pfizer, Prometheus, and Takeda. Speaker fees: AbbVie, BMS, Janssen, Lilly, Medtronic, Pfizer, and Takeda. IM, DB, AM, MK, LVC, GG, HT, CS, Shareholder and employee: Pfizer; LVC Shareholder and employee: BMS; SS, Lecture/speaker fees: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Falk, Fresenius, Janssen, MSD, Pfizer, and Takeda. Consulting/advisory fees: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Falk, Fresenius, Gilead, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Takeda, Theravance, and Ventyx. BF, Senior Scientific Director: Alimentiv. Speaker fees: AbbVie, Janssen, and Takeda. Consulting/advisory board: AbbVie, AbolerIS, AgomAB, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Atomwise, Avoro Capital Advisors, BioJamp, Biora, BI, Boxer, Celgene/BMS, Celsius, Connect, Cytoki, Disc Medicine, Duality, EcoR1, Lilly, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer, GSK, Hinge Bio, Hot Spot, Index, Imhotex, Immunic, JAKAcademy, Janssen, Japan Tobacco, Kaleido, Landos, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic, Mylan, OM, Origo, Orphagen, Pandion, Pendopharm, Pfizer, Play to Know AG, Progenity, Prometheus and Diagnostics, Protagonist, PTM, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres, Silverback, Surrozen, Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx, VHSquared Ltd, Viatris, Ysios, Ysopia, and Zealand. Shareholder: Gossamer; SV, Lecture/speaker fees: AbbVie, Dr. Falk, Ferring, Galapagos, Hospira, Janssen, MSD, Takeda, and Tillotts. Consulting/advisory fees: AbbVie, AbolerIS, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, BI, Celgene, CVasThera, Dr Falk, Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, J&J, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundi, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts AG, and Zealand. Grant/research support: AbbVie, Galapagos, Janssen, MSD, Pfizer, and Takeda.

ETRASIMOD FOR MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE: RESULTS FROM THE EXTENSION PERIOD OF A PHASE 2 STUDY

Geert R. D'Haens 1, Marla C. Dubinsky 2, Laurent Peyrin-Biroulet 3, Silvio Danese 4, Bruce E. Sands 2, Andres Yarur 5, Michael Chiorean 6, Irene Modesto 7, Diogo Branquinho 7, Aoibhinn McDonnell 8, Maria Kudela 9, Leonel Villa-Caballero 10, Guibao Gu 10, Huaming Tan 11, Chinyu Su 12, Stefan Schreiber 13, Brian G. Feagan 14, Severine Vermeire 15

1 Amsterdam University Medical Centers, Amsterdam, Netherlands

2 Icahn School of Medicine at Mount Sinai, New York, United States

3 Nancy University Hospital, F-54500 Vandœuvre-lès-Nancy, France|||University of Lorraine, F-54000 Nancy, France|||Nancy University Hospital, F-54500 Vandœuvre-lès-Nancy, France|||Nancy University Hospital, F-54500 Vandœuvre-lès-Nancy, France|||Paris IBD Ce

4 IRCCS San Raffaele Hospital and Vita Salute San Raffaele University, Milan, Italy

5 Cedars-Sinai Medical Center, Los Angeles, United States

6 Swedish Medical Center, Seattle, United States

7 Pfizer Inc, New York, United States

8 Pfizer Ltd, Sandwich, United Kingdom

9 Pfizer Inc, Cambridge, United States

10 Pfizer Inc, La Jolla, United States

11 Pfizer Inc, Groton, United States

12 Pfizer Inc, Collegeville, United States

13 University Hospital Schleswig-Holstein, Kiel University, Kiel, Germany

14 Western University, London, Canada|||Alimentiv Inc, London, Canada

15 University Hospitals Leuven, Leuven, Belgium

Event

UEG Week Vienna 2024

Topics

IBD Mechanisms & Personalised Medicine Paediatrics

Submission format

Late-Breaking Abstract

Session

Crohn’s disease hot of the press: Late-breaking abstracts

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

UEG Presentation

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RISANKIZUMAB VERSUS USTEKINUMAB FOR PATIENTS WITH MODERATE TO SEVERE CROHN'S DISEASE: RESULTS FROM THE PHASE 3B SEQUENCE STUDY

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Introduction

Inhibition of interleukin (IL)-23 has been demonstrated as a safe and effective mechanism of action for treating various chronic inflammatory diseases, including Crohn's disease (CD). The phase 3b SEQUENCE study directly compared the efficacy and safety of risankizumab (RZB), a selective IL-23 p19 subunit inhibitor, and ustekinumab (UST), an IL-12/IL-23 p40 subunit inhibitor, in patients (pts) with moderate to severe CD.

Aims & Methods

SEQUENCE, an open-label, multicenter, randomized, efficacy assessment-blinded study, enrolled pts who previously failed ≥1 anti-TNF therapies and had a CD Activity Index score of 220-450, Simple Endoscopic Score for CD ≥6 for ileocolonic or colonic disease (≥4 for isolated ileal disease) excluding the presence of narrowing component, plus an average (avg) daily stool frequency ≥4 and/or avg daily abdominal pain score ≥2. In Part 1 of the trial, described herein, pts were randomized 1:1 to receive RZB (600 mg IV induction dosing at baseline [BL], weeks [wks] 4 and 8, followed by 360 mg SC maintenance dosing every 8 wks [Q8w] starting at wk12) or UST (a single weight-based IV induction dose, followed by 90 mg SC maintenance dosing Q8w starting at wk8) over a period of 48 wks.¹ Randomization was stratified by number of anti-TNF therapies failed (1, >1) and steroid use at BL (Y, N). A mandatory steroid taper started at wk2. Two primary endpoints were clinical remission at wk24 (non-inferiority of RZB vs UST in 50% of planned subjects) and endoscopic remission at wk48 (superiority of RZB vs UST). Ranked secondary endpoints included clinical remission at wk48, endoscopic response at wks 48 and 24, steroid-free (SF) endoscopic remission at wk48, and SF clinical remission at wk48 (all tested for superiority of RZB vs UST). Safety was assessed throughout the trial.

Results

Variable	RZB N=255 n/N (%)	UST N=265 n/N (%)	Treatment Difference RZB – UST % [95% CI]
Primary^a 1. Clinical remission at wk 24 (ITT-1H^b) 2. Endoscopic remission at wk 48 (ITT-1^d) Ranked Secondary^a,d 1. Clinical remission at wk 48 2. Endoscopic response at wk 48 3. Endoscopic response at wk 24 4. Steroid-free endoscopic remission at wk 48 5. Steroid-free clinical remission at wk 48	75/128 (58.6%) 81/255 (31.8%) 155/255 (60.8%) 115/255 (45.1%) 115/255 (45.2%) 80/255 (31.4%) 155/255 (60.8%)	54/137 (39.5%) 43/265 (16.2%) 108/265 (40.8%) 58/265 (21.9%) 70/265 (26.4%) 41/265 (15.5%) 107/265 (40.4%)	Non-inferiority^c met; 18.4 [6.6, 30.3] 15.6 [8.4, 22.9], P<0.0001 19.7 [11.3, 28.1], P<0.0001 23.3 [15.4, 31.2], P<0.0001 18.9 [10.9, 26.9], P<0.0001 15.9 [8.8, 23.1], P<0.0001 20.1 [11.7, 28.4], P<0.0001
Treatment Emergent Adverse Events (AEs)^e	RZB N=262 PYs = 257.6 Events (E/100PYs)^f	UST N=265 PYs = 269.9 Events (E/100PYs)^f	Treatment Difference RZB – UST % [95% CI]
All TEAEs Investigator-defined drug-related AE^g,h Severe AE Serious AE AEs leading to study drug discontinuation Death Adverse Events of Special Interest Adjudicated MACE/Extended MACEⁱ Serious infections Active tuberculosis Opportunistic infections excluding tuberculosis and herpes zoster^j Herpes zoster Malignant tumours^k Non-melanoma skin cancer (NMSC) Malignancies excluding NMSC Hypersensitivity Serious hypersensitivity Adjudicated anaphylactic reaction Hepatic events Injection site reactions	879 (341.2) 167 (64.8) 60 (23.3) 36 (14.0) 10 (3.9) 0 0 10 (3.9) 0 1 (0.4) 1 (0.4) 1 (0.4) 1 (0.4) 0 37 (14.4) 0 0 26 (10.1) 5 (1.9)	763 (282.7) 111 (41.1) 82 (30.4) 64 (23.7) 14 (5.2) 0 1 (0.4) 14 (5.2) 0 0 1 (0.4) 1 (0.4) 0 1 (0.4) 32 (11.9) 0 0 23 (8.5)i 8 (3.0)	58.5 (28.3, 88.7) 23.7 (11.2, 36.2) -7.1 (-15.9, 1.7) -9.7 (-17.1, -2.4) -1.3 (-4.9, 2.3) 0 -0.4 (-1.1, 0.4) -1.3 (-4.9, 2.3) 0 0.4 (-0.4, 1.1) 0.0 (-1.0, 1.1) 0.0 (-1.0, 1.1) 0.4 (-0.4, 1.1) -0.4 (-1.1, 0.4) 2.5 (-3.7, 8.7) 0 0 1.6 (-3.6, 6.8) -1.0 (-3.7, 1.6)
AE – adverse event; BL - baseline; CD – Crohn’s disease; CDAI – CD activity index; ITT – intention to treat; RZB - risankizumab; PY, patient years; SES-CD, simple endoscopic score for CD; TEAE – treatment emergent AE; UST – ustekinumab; wk, week Clinical remission – CDAI < 150 Endoscopic remission - SES-CD ≤ 4 and at least a 2-point reduction versus BL and no sub score greater than 1 in any individual variable, as scored by a central reviewer blinded to treatment allocation Endoscopic response - decrease in SES-CD > 50% from BL (or for pts with isolated ileal disease and a BL SES-CD of 4, at least a 2-point reduction from BL), as scored by central reviewer Steroid-free endoscopic remission - endoscopic remission and not receiving steroids at the corresponding visit Steroid-free clinical remission - clinical remission and not receiving steroids at the corresponding visit *SEQUENCE Part 1 compared the efficacy and safety of RZB versus UST over 48 wks, while Part 2 is an ongoing open-label long-term extension to evaluate the long-term safety of RZB in pts who received RZB in Part 1 and completed wk48 visit. ^aCategorical variables were analyzed using Cochran-Mantel-Haenszel (CMH) test. For both the primary and secondary endpoints, the non-responder imputation while incorporating multiple imputation to handle missing data (due to COVID-19 or geopolitical conflict) was used. Primary and secondary endpoints were tested sequentially in the order specified using the CMH risk difference estimate test stratified by the number of failed anti-TNF therapies (1, > 1) and steroid use at baseline (yes, no). ^bITT1H population is a subset of ITT-1 population and includes approximately 50% of ITT1 subjects who have opportunity to reach wk24 by the time of the primary analysis of CDAI clinical remission at wk24; non-inferiority of RZB vs. UST ^cNon-inferiority test: If the lower limit of 95% confidence interval based on the CMH estimation for the risk difference between RZB and UST groups (RZB – UST) was greater than the negative of 10% noninferiority margin, then noninferiority was demonstrated for clinical remission at wk24. If non-inferiority was demonstrated for clinical remission (CDAI) at Week 24, the superiority for the endoscopic remission at Week 48 was subsequentially tested at two-sided significance level of 0.05 using the CMH test. ^dIntent-to-treat-1 (ITT-1) population included all randomized subjects who were randomized to RZB with the selected RZB dose (RZB 600 mg IV followed by RZB 360 mg SC) or UST and who received at least 1 dose of study drug during Part 1 of the study; superiority of RZB vs. UST ^eTEAEs are events that begin either on or after the first dose of UST or RZB in Part 1 and until the first dose of study drug (RZB) in Part 2 if the pt is enrolled into the Part 2 or within 140 days after the last dose administration of the study drugs (UST or RZB) in Part 1 if the pt does not participate in Part 2. Only safety data obtained before 12JUL2023 or Week 52 dosing date (the first dose date of Part 2), whichever occurred earlier, are reported here. ^fSA1 population includes all pts who received at least 1 dose of study drug during Part 1 of the study. ^gAs assessed by investigator ^hRZB related: 3 patients with SAEs related to RZB (anal fistula, anal abscess, campylobacter, cystitis, localized infection, genital fistula); 8 patients with SAEs related to UST (abdominal pain, anal fistula, CD, ileal stenosis, vomiting) ⁱMACE: Major Adverse Cardiovascular Events, defined as cardiovascular death or death due to stroke, non-fatal myocardial infarction, and non-fatal stroke; extended MACE defined as MACE with hospitalization for unstable angina and coronary revascularization procedures ^jOpportunistic infection: RZB, oesophageal candidiasis ^kMalignant tumor: RZB, squamous cell carcinoma of skin; UST, anal squamous cell carcinoma ⁱOne case of potential Hy’s Law in the UST treatment group

In total, 520 pts were randomized and assessed for efficacy: RZB (N=255) and UST (N=265). The proportion of pts who completed the study was numerically higher with RZB (89.4%) vs UST (74.0%). The two primary endpoints of the study were met. At wk24, in half of the patients enrolled, clinical remission rates were 58.6% (75/128) for RZB and 39.5% (54/137) for UST (Δ18.4 [6.6-30.3], non-inferiority met with the pre-defined margin of 10%) (Table). At wk48, endoscopic remission rates were 31.8% (81/255) for RZB and 16.2% (43/265) for UST (Δ15.6% [8.4-22.9], P<0.0001 for superiority). RZB was superior to UST for all secondary endpoints (all P<0.0001). Exposure adjusted adverse event (AE) rates (Events [E/100PYs]) were comparable between RZB (879 [341.2]) and UST (763 [282.7]). Rates of serious AEs and AEs leading to study drug discontinuation were numerically higher with UST than RZB (Table). Rates of serious infections and hepatic events were similar between treatment groups, with no serious hepatic events with RZB. Two cases of malignancy were reported (one in each treatment arm). There was one event of adjudicated MACE with UST. There were no deaths.

Conclusion

In pts with moderate to severe CD who failed anti-TNF therapy, RZB demonstrated non-inferiority to UST in achieving wk24 clinical remission, superiority in achieving wk48 endoscopic remission, and superiority for achieving all secondary endpoints. The safety profiles of RZB and UST were consistent with previously published results.

References

1. Stelara Label [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125261s161lbl.pdf

Disclosure

Laurent Peyrin-Biroulet: Fees: Galapagos, AbbVie, Janssen, Genentech, Alimentiv, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index, Sandoz, Celgene, Biogen, SamsungBioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSEImmunotherapeutics, Enthera, Theravance, Pandion, Gossamer, Viatris, ThermoFisher, ONOPharma, Mopac, Cytoki, Morphic, Prometheus, Applied MolecularTransport; J. Casey Chapman: Consultant: AbbVie, Medtronic; Advisory Board: AbbVie, Pfizer, Takeda; Speaker: AbbVie, BMS, Janssen, Pfizer, Takeda; Jean-Frederic Colombel: Grants: AbbVie, Janssen, Takeda, BMS; Speaking fees: AbbVie, Takeda; Consultant: AbbVie, Amgen, AnaptysBio, Allergan, Arena, BI, BMS, Celgene, Celltrion, Lilly, Ferring, Galmed, GSK, Genentech (Roche), Janssen, Kaleido, Immunic, IterativeScopes, Merck, Landos, Microba Life Science, Novartis, Otsuka, Pfizer, ProtagonistTherapeutics, Sanofi, Takeda, TiGenix, Vifor; Stock options: IntestinalBiotechDevelopment; Flavio Caprioli: Consultant: AbbVie, MSD, Takeda, Janssen, Roche, Celgene, BMS, Galapagos, Gllead, Pfizer, Mundipharma, Galapagos, Biogen; Speaker: AbbVie, Ferring, Takeda, AllergyTherapeutics, Janssen, Pfizer, Biogen; Research grants: Giuliani, Sofar, MSD, Takeda, AbbVie; Geert D’Haens: Advisor: AbbVie, Ablynx, ActiveBiotechAB, AgomabTherapeutics, Alimentiv, Allergan, Alphabiomics, Amakem, Amgen, AMPharma, AppliedMolecularTherapeutics, Arena, AstraZeneca, Biogen, BMS, BI, Celltrion, DSMPharma; Echo, Engene, Exeliom, Ferring, Dr Falk, Galapagos, Genentech/Roche, Gilead, GSK, Gossamerbio, Immunic, J&J, Kintai, Lilly, Lument, Lycera, Medtronic, MSD, MitsubishiTanabe, NovoNordisk, Otsuka, Pfizer, Photopill, ProciseDx, Prodigest, Progenity, Prometheus/Nestlé, Protagonist, RedHill, SamsungBioepis, Sandoz, Seres, Setpoint, Shire, Takeda, Teva, Tillotts, Topivert, Versant, Vifor. Marc Ferrante: Grants: AbbVie, Amgen, Biogen, EG, Janssen, Pfizer, Takeda, Viatris; Consultant: AbbVie, Agomab, BI, Celgene, Celltrion, Lilly, Janssen-Cilag, Medtronic, MSD, Pfizer, Regeneron, SamsungBioepis, Sandoz, Takeda, ThermoFisher; Speaker: AbbVie, Amgen, Biogen, BI, Falk, Ferring, Janssen-Cilag, Lamepro, MSD, Pfizer, Sandoz, Takeda, Truvion, Viatris; Stefan Schreiber: Consultant: AbbVie, Amgen, Arena, BMS, BI, Celltrion, Dr Falk, Ferring, Fresenius, Galapagos, Genentech, Gilead, GSK, IMAB-Biopharma, Janssen, Lilly, Merck, Novartis/Sandoz, Pfizer, Protagonist, Takeda, Theravance. Raja Atreya: Speaker, consultant, or grants: AbbVie, Amgen, Arena, Biogen, BI, BMS, Cellgene, Celltrion, DrFalk, Galapagos, Gilead, InDex, Janssen-Cilag, Lilly, MSD, Novartis, Pandion, Pfizer, Roche, SamsungBioepis, Takeda, Viatris; Silvio Danese: Consultant: AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, AthosTherapeutics, Biogen, BI, Celgene, Celltrion, Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, J&J, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB, and Vifor; Lecture fees: Abbvie, Amgen, Dr Falk, Ferring, Gilead, Janssen, Mylan, Pfizer, Takeda. James O. Lindsay: Consultant/advisory board: AbbVie, AtlanticHealthcare, BMS, Celgene, Celltrion, Lilly, Ferring, Galapagos, Gilead, GSK, Janssen, MSD, Napp, Pfizer, Shire, Takeda, Vifor; Speaker fees/sponsorship: AbbVie, Ferring, Janssen, MSD, Napp, Norgine, Pfizer, Shire, Tillotts, Takeda; Grants: AbbVie, Gilead, Pfizer, Shire, Takeda; Peter Bossuyt: Grants: AbbVie, Amgen, Janssen, Mundipharma, Mylan, Pfizer; Speaker: AbbVie, Celltrion, Janssen, Pfizer, Takeda; Advisory Board: AbbVie, Arena, BMS, Hospira, Janssen, Lilly, Merck, Mundipharma, PentaxMedical, Pfizer, PSI CRO, Roche, Sandoz, Takeda; Britta Siegmund: Consultant: AbbVie, Arena, BI, BMS, Celgene, Falk, Galapagos, Janssen, Lilly, Pfizer, Prometheus, Takeda; Speaker’s fees: AbbVie, CEDServiceGmbH, Falk, Ferring, Janssen, Novartis, Pfizer, Takeda; Peter Irving: Grants/ Fees: Janssen, MSD,Takeda; Personal fees: AbbVie, Arena, Dr. Falk, Lilly, Ferring, Genentech, Hospira, Pfizer, Pharmacosmos, SamsungBioepis, Sandoz, Shire, Tillotts, TopiVert, VHsquared, Vifor, WarnerChilcott. Remo Panaccione: Consultant: AbbVie, Abbott, Alimentiv, Amgen, Arena, AstraZeneca, BMS, BI, Celgene, Celltrion, Cosmos, Eisai, Elan, Ferring, Galapagos, Genentech, Gilead, GSK, Janssen, Lilly, Merck, Mylan, Oppilan, Pandion, Pfizer, Progenity, Protagonist, Roche, Sandoz, Satisfai, Schering-Plough, Shire, Sublimity, Theravance, UCB, Takeda; Speaker: AbbVie, Arena, Celgene, Ferring, Gilead, Janssen, Lilly, Merck, Pfizer, Roche, Sandoz, Shire, and Takeda; Grants: AbbVie, Ferring, Janssen, Pfizer, Takeda; Advisory board: AbbVie, Amgen, Arena, BMS, Celgene, Celltrion, Ferring, Galapagos, Genentech, Gilead, GSK, Janssen, Lilly, Merck, Mylan, Oppilan, Pandion, Pfizer, Sandoz, Shire, Sublimity, Takeda, Theravance. Marla Dubinsky: Consultant: AbbVie, Arena, BMS, Celgene, Lilly, Genentech, Gilead, Janssen, Pfizer, Prometheus, Takeda; Founder/shareholder Trellus Health.
Ezequiel Neimark, Kori Wallace, Toni Anschutz, Kristina Kligys, W Rachel Duan, Valerie Pivorunas, Xiu Huang, Sofie Berg, Lei Shu: AbbVie full-time employees; may own AbbVie stock or options.

RISANKIZUMAB VERSUS USTEKINUMAB FOR PATIENTS WITH MODERATE TO SEVERE CROHN'S DISEASE: RESULTS FROM THE PHASE 3B SEQUENCE STUDY

Laurent Peyrin-Biroulet 1, J. Casey Chapman 2, Jean-Frédéric Colombel 3, Flavio Caprioli 4, Geert R. D'Haens 5, Marc Ferrante 6, Stefan Schreiber 7, Raja Atreya 8, Silvio Danese 9, James O. Lindsay 10, Peter Bossuyt 11, Britta Siegmund 12, Peter Irving 13, Remo Panaccione 14, Ezequiel Neimark 15, Kori Wallace 15, Toni Anschutz 15, Kristina Kligys 15, Rachel Duan 16, Valerie Pivorunas 15, Xiu Huang 15, Sofie Berg 15, Lei Shu 15, Marla C. Dubinsky 17

1 Inserm U1256, Nancy University Hospital, Vandoeuvre-les-Nancy, France

2 Crohn's and Colitis Center at the Baton Rouge General, Baton Rouge, United States|||GI Alliance, Baton Rouge, United States|||Louisiana State University Health Sciences Center, Baton Rouge, United States

3 Icahn School of Medicine at Mount Sinai, USA, United States

4 University of Milan, Milano, Italy

5 AMC Amsterdam Inflammatory Bowel Disease Centre - Academic Medical Center, AMC Amsterdam Inflammator, Amsterdam, Netherlands

6 University Hospitals Leuven, Leuven, Belgium

7 University Hospital Schleswig-Holstein, Kiel, Germany

8 University Erlangen-Nuremberg, Erlangen, Germany

9 Vita-Salute San Raffaele University - IRCCS San Raffaele Scientific Institute, Milan, Netherlands

10 Digestive Disorders Clinical Academic Unit, Barts & The London School of Medicine, London, United Kingdom

11 Imelda General Hospital, Bonheiden, Belgium

12 Charité - Universitätsmedizin Berlin, Berlin, Germany

13 Guy´s and St Thomas´ Hospital, London, United Kingdom

14 University of Calgary, Calgary, Canada

15 AbbVie, North Chicago, United States

16 Abbvie, North Chicago, United States

17 Mount Sinai Hospital, Mount Sinai, New York City, United States

Event

UEG Week Copenhagen 2023

Topics

IBD

Submission format

Late-Breaking Abstract

Session

Breakthroughs in IBD treatment and outcomes: Late-breaking abstracts

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

UEG Poster

Standard Poster

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Introduction

Mirikizumab (miri), an anti-IL-23p19 antibody, demonstrated robust efficacy in improving clinical, endoscopic, and inflammatory biomarker endpoints, and an acceptable safety profile for patients with moderately to severely active Crohn’s disease (CD) in the Phase 3 VIVID-1 study. Here, we investigate the onset of symptomatic improvement and the safety of miri as induction therapy through Week 12 (W12) for patients with moderately to severely active CD.

Aims & Methods

In VIVID-1 (NCT03926130), patients (N=1065) had moderately to severely active CD (unweighted daily average stool frequency (SF) ≥4 [loose and watery stools defined as Bristol Stool Scale Category 6 or 7] AND/OR unweighted daily average abdominal pain (AP) ≥2 at baseline) and had prior failure to biologic and/or conventional therapy. Patients were randomized in a 6:3:2 ratio to receive miri (a single 900mg intravenous (IV) dose at W0, W4, and W8 followed by a subcutaneous (SC) dose of 300mg at W12 and then every 4 weeks), ustekinumab (uste) (6mg/kg IV at W0 and SC dose of 90mg at W8 and then every 8 weeks), or placebo (PBO). Results for the co-primary endpoints and major secondary endpoints versus PBO, as well as for the 2 major secondary endpoints versus uste, have been reported previously ^1,2. This analysis focuses on comparisons of clinical response by Patient Reported Outcome (PRO) (defined as at least a 30% decrease in SF and/or AP with neither score worse than baseline), clinical remission by PRO (defined as SF≤3 and not worse than baseline [as per Bristol Stool Scale Category 6 or 7] and AP ≤1 and no worse than baseline), change from baseline (CFB) in SF, and CFB in AP up to W12 in patients who were randomized to miri or PBO.

Results

Baseline characteristics were balanced across the miri (N=579) and PBO (n=199) treatment groups¹. Compared to PBO, a greater proportion of patients on miri achieved clinical response by PRO at W4, 6, 8, and 12, and clinical remission by PRO at W6, 8, and 12. Treatment with miri resulted in significant improvements in SF at W6, 8, and 12, and in AP at W4, 6, 8, and 12 when compared to PBO (Table 1). The overall safety was consistent with the known safety profile of miri. The most common treatment-emergent adverse events (TEAEs) during induction period in miri-treated patients were COVID-19, anaemia and headache. There were lower frequencies of SAEs (miri: 5.9%, PBO: 9.0%) and discontinuations due to adverse events (miri: 2.4%, PBO:4.7%) in miri-treated patients versus PBO. There were no malignancies, no MACEs, no Hy’s law cases or deaths in the miri arm up to W12. One death was reported in the induction period in the PBO group.

	Clinical response by PRO^a n (%)		Clinical remission by PRO^a n (%)		Stool Frequency (CFB)^b LSM (SE)		Abdominal Pain (CFB)^b LSM (SE)
	Miri N=579	PBO N=199	Miri N=579	PBO N=199	Miri N=579	PBO N=199	Miri N=579	PBO N=199
Week 2	224 (38.7)	75 (37.7)	41 (7.1)	10 (5.0)	-1.24 (0.076)	-1.24 (0.129)	-0.38 (0.022)	-0.31 (0.036)
Week 4	308 (53.2)*	87 (43.7)	90 (15.5)	27 (13.6)	-1.74 (0.087)	-1.42 (0.146)	-0.55 (0.026)*	-0.43 (0.043)
Week 6	376 (64.9)***	100 (50.3)	150 (25.9)*	36 (18.1)	-2.20 (0.091)*	-1.81 (0.153)	-0.72 (0.028)***	-0.52 (0.047)
Week 8	404 (69.8)****	101 (50.8)	175 (30.2)**	37 (18.6)	-2.43 (0.096)**	-1.85 (0.162)	-0.80 (0.029)****	-0.56 (0.049)
Week 12	409 (70.6)****	103 (51.8)	216 (37.3)****	44 (22.1)	-2.65 (0.101)****	-1.86 (0.171)	-0.90 (0.031)****	-0.61 (0.052)
Footnotes: ^aNonresponder imputation was used. ^bModified baseline observation carried forward was used. * refers to p < 0.05 significance; refers to p < 0.01 significance; * refers to p < 0.001 significance; **** refers to p < 0.0001 significance Abbreviations: AP=abdominal pain; CDAI= Crohn’s Disease Activity Index; CFB=change from baseline; PRO=Patient Reported Outcome (2 of the patient-reported items of the CDAI, AP and SF); LSM=least square mean; SE=standard error; SF=stool frequency; miri=mirikizumab; PBO=placebo

Conclusion

In patients with moderately to severely active CD, miri induction was associated with higher rates of clinical response and greater improvement in AP as early as W4, and higher rates of clinical remission and greater improvement in SF as early as W6 versus PBO. Increasing treatment effect was observed through W12. The safety of miri induction therapy was consistent with its known favourable safety profile.

References

M Ferrante, S Danese, M Chen, G D'Haens, S Ghosh, T Hisamatsu, V Jairath, J Kierkus, L Peyrin-Biroulet, B Siegmund, S M Bragg, W Crandall, T Hunter Gibble, Z Lin, M Ugolini Lopes, N Morris, H Carlier, B Sands, VIVID Study Group, OP05 Primary efficacy and safety of mirikizumab in moderate to severe Crohn’s Disease: results of the treat-through VIVID 1 study, Journal of Crohn's and Colitis, Volume 18, Issue Supplement_1, January 2024, Pages i7–i9, https://doi.org/10.1093/ecco-jcc/jjad212.0005
V Jairath, B E Sands, P Bossuyt, F Farraye, M Ferrante, T Hisamatsu, A Kaser, J Kierkus, D Laharie, W Reinisch, B Siegmund, S M Bragg, E Hon, Z Lin, M Ugolini Lopes, N Morris, M Protic, S Danese, VIVID Study Group, OP35 Efficacy of mirikizumab in comparison to ustekinumab in patients with moderate to severe Crohn’s disease: Results from the phase 3 VIVID 1 study, Journal of Crohn's and Colitis, Volume 18, Issue Supplement_1, January 2024, Pages i62–i64, https://doi.org/10.1093/ecco-jcc/jjad212.0035

Disclosure

Bruce E Sands: reports consulting fees from Abbvie, Alimentiv , Amgen, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Morphic Therapeutics, MRM Health, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Target RWE,Teva, TLL Pharmaceutical, Ventyx Biosciences; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees and other support from Bristol Myers Squibb, Janssen, Pfizer, Takeda; research grants and consulting fees from Theravance Biopharma; and stock options from Ventyx Biopharma.
Minhu Chen: provided educational activities for AbbVie, China Medical System, IPSEN, Janssen, and Takeda; served on an advisory board for Boehringer Ingelheim and Janssen; and has support for clinical research from Janssen and Takeda.
Silvio Danese: has consulting fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, and Vifor; has lecture fees from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, and Takeda.
Monika Fischer: has served as an Advisor, Review Panel Member, Speakers Bureau, or DSMB for AbbVie, BMS, Lilly, Ferring, Janssen, Pfizer, Rebiotix, Scioto, Seres
Tadakazu Hisamatsu: has joint research agreement from Kissei Pharmaceutical and EA Pharma; has received research grants from AbbVie, Daiichi Sankyo, EA Pharma, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, Boston Scientific, and Zeria Pharmaceutical; and has received consulting and lecture fees from AbbVie, EA Pharma, Gilead Sciences, Janssen Pharmaceuticals, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, Pfizer, Kissei Pharmaceutical, and Takeda.
Sami Hoque: Reports advisory to Eli Lilly and Company and advisory and lecture fees to Tillots.
Laurent Peyrin-Biroulet: Reports the following: personal fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, Boerhinger Ingelheim, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma, Sterna, Nestle, Inotrem, Enterome, Allergan, MSD, Roche, Arena, Gilead, Hikma, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, Oppilan Pharma, Sublimity Therapeutics, Applied Molecular Transport, OSE Immunotherapeutics, Enthera, and Theravance; grants from Abbvie, MSD, and Takeda; and stock options from CTMA
Frank Siebold: has consulting fees from Abbvie, Amgen, BMS, Dr. Falk, Eli Lilly, Geilead, Janssen, Pfizer, Takeda.
Geert D’Haens: has served as adviser and/or speaker for Abbvie, Alimentiv, Amgen, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Ferring, Eli Lilly, Engene, Galapagos, Glaxo Smith Kline, Immunic, Index Pharmaceuticals, Johnson and Johnson, Merck, Polpharm, Prometheus biosciences, Prometheus Laboratories, Procise diagnostics, Protagonist, Sandoz, Takeda, Tillotts, and Ventyx.
Frederick Durand, Emily Hon, Zhantao Lin, Nathan Morris, and Michelle Ugolini Lopes are all Eli Lilly and Company employees and stockholders.

EARLY SYMPTOMATIC IMPROVEMENT WITH MIRIKIZUMAB INDUCTION THERAPY IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE: RESULTS FROM THE PHASE 3 VIVID-1 STUDY

Bruce E. Sands 1, Minhu Chen 2, Silvio Danese 3, Monika Fischer 4, Tadakazu Hisamatsu 5, Sami Hoque 6, Laurent Peyrin-Biroulet 7, Frank Seibold 8, Frederick Durand 9, Zhantao Lin 9, Michelle Ugolini Lopes 9, Nathan Morris 9, Emily Hon 9, Geert R. D'Haens 10

1 Icahn School of Medicine at Mount Sinai, New York, United States

2 The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

3 Vita-Salute San Raffaele University - IRCCS San Raffaele Scientific Institute, Milan, Italy

4 IUPUI, Indianapolis, United States

5 Kyorin University School of Medicine, Tokyo, Japan

6 Barts Health NHS Trust, London, United Kingdom

7 Inserm U1256, Nancy University Hospital, Vandoeuvre-les-Nancy, France

8 Crohn-Colitis Zentrum, Bern, Switzerland

9 Eli Lilly and Company, Indianapolis, United States

10 AMC Amsterdam Inflammatory Bowel Disease Centre - Academic Medical Center, AMC Amsterdam Inflammator, Amsterdam, Netherlands

Conference

UEG Week Vienna 2024

Topics

IBD

Submission format

Abstract

Session

IL-23 inhibitor in UC and Crohn's disease: Part 1 (Posters)

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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