Introduction

Mirikizumab (miri) is an anti-IL23p19 antibody that has shown efficacy in Crohn’s disease (CD). We have previously shown that miri improves health-related quality of life (HRQoL) by 12 weeks as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) in a Phase 2, multicenter, randomized, double-blind, placebo (PBO)-controlled study (NCT02891226) conducted in patients (pts) with moderately-to-severely active CD. This analysis assesses IBDQ scores through Week 104 (W104).

Aims & Methods

At baseline, pts (N=191) were randomized 2:1:1:2 allocation amongst 4 treatment arms (PBO, and 200, 600, 1000mg miri, respectively, administered intravenously (IV) every 4 weeks (Q4W) at Weeks 0, 4, and 8). Pts who received miri and achieved ≥1 point improvement at W12 in Simple Endoscopic Score for Crohn’s Disease (SES-CD) were re-randomized 1:1 into double-blind maintenance to either continue IV treatment assignment Q4W (combined arms of 200, 600, and 1000mg miri IV treatment; IV-C; N=41) or to 300mg miri subcutaneous (SC; N=46) Q4W up to W52. Subjects who had clinical benefit from the maintenance period received 300mg SC Q4W from W52 to W104. For analysis purposes, all IV and all SC arms were pooled. IBDQ score change from baseline (BL), IBDQ response (improvement ≥16 points), and IBDQ remission (score ≥170 points) were assessed up to W104 in pts who achieved endoscopic improvement at W12. IBDQ scores, domain scores (bowel symptoms, systemic symptoms, emotional function, social function), response, and remission were analyzed by descriptive statistics. For IBDQ response and remission, missing data were imputed as nonresponse (NRI).

Results

Out of the 127 pts randomized to miri for induction, 68.5% (87/127) achieved endoscopic improvement at W12 and were rerandomized into maintenance. Among the W12 miri induction endoscopic improvers, IBDQ response rates at W52 were 75.6% (31/41) and 80.4% (37/46) and IBDQ remission rates were 65.9% (27/41) and 67.4% (31/46) in the IV-C and SC groups, respectively. Of the W12 endoscopic improvers, 74 finished W52 in the maintenance and entered period 3 (W52-W104) where 68 went on to complete treatment through W104. At W104, the IBDQ response rates were 81.8% (27/33) and 78.0% (32/41) and IBDQ remission rates were 69.7% (23/33) and 56.1% (23/41) in the IV-C and SC groups, respectively. W52 and W104 IBDQ outcomes and domain scores are reported in Table 1.

Table 1. Week 52 and Week 104 Safety and Efficacy Results in Week 12 endoscopic improvers.

Table 1	Week 12 Endoscopic Improverse
	Week 52	Week 104	Week 52	Week 104
	Miri IV-C N=41	Miri IV-C N=33	Miri SC N=46	Miri SC N=41
Total IBDQ scorea, mean (SD)	188.5 (26.6)	187.4 (21.8)	180.8 (25.4)	173.7 (32.1)
IBDQ responseb, n (%)	31 (75.6)	27 (81.8)	37 (80.4)	32 (78.0)
IBDQ remissionc, n (%)	27 (65.9)	23 (69.7)	31 (67.4)	23 (56.1)
IBDQ score change from baseline a, d mean	64.3	67.1	66.4	57.9
IBDQ Domain Scores a, mean (SD) Bowel Symptoms Systemic Symptoms Emotional Function Social Function	58.6 (8.8) 27.7(5.4) 70.5 (11.1) 31.8 (3.9)	58.8 (6.5) 26.8 (5.1) 70.0 (9.9) 31.8 (3.4)	57.3 (8.0) 25.8 (5.4) 67.1 (11.0) 30.6 (4.2)	54.3 (9.8) 24.7 (6.6) 65.0 (13.1) 29.7 (5.3)
aMean and (SD) for scores and changes in scores do not utilize imputation and therefore are based on patients with observed data at the indicated timepoint (IV week 52 N=35; IV week 104 N=29; SC week 52 N=41; SC week 104 N=33); bIBDQ response: ≥16-point improvement in IBDQ score; cIBDQ remission: total IBDQ score ≥170; dchange from baseline; e Endoscopic improvement: ≥1 point improvement in SES-CD at Week 12. Abbreviations: IBDQ = Inflammatory Bowel Disease Questionnaire; IV-C = Intravenous arms combined; SC = subcutaneous; SD = standard deviation

Conclusion

Treatment with miri produced clinically meaningful improvement in HRQoL as measured by IBDQ at W52 and W104 in pts who achieved endoscopic improvement after miri induction with moderately-to-severely active CD.

Disclosure

Bruce E Sands: Received fees for consulting and speaking from Abivax, Bristol Myers Squibb, Janssen, Lilly Pfizer, and Takeda; for consulting from AbbVie; Adiso Therapeutics; Alimentiv; Amgen; Arena Pharmaceuticals; Artizan Biosciences; Artugen Therapeutics; AstraZeneca; Bacainn Therapeutics; Boehringer-Ingelheim; Boston Pharmaceuticals; Calibr; Celltrion Healthcare; ClostraBio; Cytoki Pharma; Connect Biopharma; Entera; Evommune; Fresenius Kabi; Galapagos; Genentech; Gilead Sciences; GlaxoSmithKline; Gossamer Bio; Imhotex; Immunic; Index Pharmaceuticals; Inotrem; Innovation Therapeutics; Ironwood Pharmaceuticals; Kaleido; Kallyope; MiroBio; Morphic Therapeutics; MRM Health; OSE Immunotherapeutics; Progenity; Prometheus Biosciences; Protagonist Therapeutics; Q32 Bio; Redhill Biopharma; Sun Pharma; Surrozen; Synlogic; Target RWE; Teva; Theravance Biopharma; TLL Pharmaceutical; USWM Enterprises; VielaBio: VTA Labs; and personal fees and stock options for consulting from Ventyx Biosciences.
Vipul Jairath: Consulting/advisory board fees: AbbVie, Alimentiv Inc, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, Second Genome, Sorriso pharmaceuticals, Takeda, Teva, Topivert, Ventyx, Vividion; speaker’s fees: Abbvie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, Fresenius Kabi
Brian G Feagan: Consultant for AbbVie, AbolerIS, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport Inc, Arena Pharma, Avoro Capital Advisors, Atomwise,, BioJamp, Biora Therapeutics, Boehringer-Ingelheim, Boxer, Celsius Therapeutics,Celgene/BMS, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium,, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer Pharma, GSK, Hinge Bio, Hot Spot Therapeutics, Index Pharma, Imhotex, Immunic Therapeutics, JAKAcademy, Janssen, Japan Tobacco Inc., Kaleido Biosciences, Landos Biopharma, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic Therapeutics, Mylan, OM Pharma, Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus Therapeutics and Diagnostics, Play to Know AG, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen Inc., Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHSquared Ltd., Viatris, Ysios, Ysopia, Zealand Pharma. Speakers bureau for AbbVie, Janssen, Takeda. Member, Scientific Advisory Board, DSMB: AbbVie, Amgen, AMT, AnaptysBio, Boehringer-Ingelheim, Celgene/BMS Eli Lilly, Genentech/Roche, Janssen, MiroBio, Origo BioPharma, Pfizer, Prometheus, REDX Pharma, Sanofi, Takeda,Tillotts Pharma, Teva, Progenity, Index, Ecor1Capital, Morphic, GSK, Axio Research. Stock Shareholder: Gossamer Pharma. Other: Employee, Western University, Senior Scientific Director, Alimentiv Inc.
Alessandro Armuzzi: Consulting/advisory board fees: AbbVie, Allergan, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda; speaker’s fees: AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Tigenix; research grants: MSD, Takeda, Pfizer, Biogen
Peter Bossuyt: Received financial support for research from Abbvie, Amgen, Celltrion, Mylan, Pfizer and Takeda; lecture fees from AbbVie, Celltrion, Janssen, Lilly and Takeda; advisory board fees from Abbvie, Arena pharmaceuticals, BMS, Celltrion, Dr Falk, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda and Tetrameros.
Theresa Hunter Gibble, Zhantao Lin, Kristina Traxler, Marijana Protic, and Rebecca Hozak: employees and shareholders of Eli Lilly and Company.

Introduction

Most clinical trials of systemic ulcerative colitis (UC) therapies exclude patients (pts) with isolated proctitis, who are considered a more treatment-refractory population, creating a need for clinical evidence. Etrasimod is an investigational, oral, once-daily, selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator in development for the treatment of moderately to severely active UC. The phase 3 etrasimod ELEVATE UC trials included pts with isolated proctitis (< 10 cm rectal involvement), provided they met all other eligibility criteria.¹

Aims & Methods

This post hoc analysis assessed predefined efficacy and safety outcomes in subgroups of pts with isolated proctitis and more extensive colitis (proctosigmoiditis/left-sided colitis/pancolitis). In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), pts (aged 16–80 years) with moderately to severely active UC were randomised 2:1 to etrasimod 2 mg once daily or placebo. ELEVATE UC 52 comprised a 12-week (wk) induction period followed by a 40-wk maintenance period with a treat-through design. ELEVATE UC 12 comprised a 12-wk induction period. Clinical endpoints were assessed in pts with isolated proctitis (data pooled from both trials) and in pts with more extensive colitis (individual trial data). Sustained and corticosteroid-free clinical remission were assessed at Wk 52 (ELEVATE UC 52 only). Bowel urgency Numeric Rating Scale (NRS) was assessed at Wks 12 and 52. Safety was assessed up to Wk 52.

Results

This analysis included 64 (pooled; Wk 12) and 36 (ELEVATE UC 52; Wk 52) pts with isolated proctitis, and 397 (ELEVATE UC 52; Wks 12 and 52) and 326 (ELEVATE UC 12; Wk 12) pts with more extensive colitis. Similar proportions of pts with isolated proctitis achieved the predefined efficacy endpoints vs those with more extensive colitis (Table). Pts with isolated proctitis receiving etrasimod had similar improvements in urgency NRS scores vs those with more extensive colitis (mean change from baseline: Wk 12, -2.8 vs -2.9 [both trials]; Wk 52, -5.0 vs -4.1). Safety in pts with isolated proctitis was generally similar to that in the overall trial population.¹

Table. Achievement of prespecified efficacy endpoints among pts with isolated proctitisa and those with more extensive colitis in the etrasimod ELEVATE UC trials (full analysis set)
Endpoint	Pts with isolated proctitis			Pts with more extensive colitis
	ELEVATE UC 12 + ELEVATE UC 52			ELEVATE UC 52			ELEVATE UC 12
Wk 12	PBO, n (%) [N=22]	Etrasimod 2 mg QD, n (%) [N=42]	Percentage difference from PBOb	PBO, n (%) [N=135]	Etrasimod 2 mg QD, n (%) [N=262]	Percentage difference from PBOb	PBO, n (%) [N=103]	Etrasimod 2 mg QD, n (%) [N=223]	Percentage difference from PBOb
Clinical remissionc Clinical responsed Symptomatic remissione Endoscopic improvementf Endoscopic improvement-histological remissiong	3 (13.6) 9 (40.9) 5 (22.7) 5 (22.7) 3 (13.6)	18 (42.9) 30 (71.4) 22 (52.4) 22 (52.4) 16 (38.1)	45.5*** 35.2* 44.2*** 41.3** 40.7**	10 (7.4) 48 (35.6) 30 (22.2) 20 (14.8) 7 (5.2)	68 (26.0) 162 (61.8) 118 (45.0) 93 (35.5) 55 (21.0)	18.5*** 26.0*** 22.7*** 20.6*** 16.0***	16 (15.5) 43 (41.7) 31 (30.1) 21 (20.4) 9 (8.7)	57 (25.6) 141 (63.2) 108 (48.4) 71 (31.8) 36 (16.1)	9.9* 21.0*** 18.0** 11.4* 7.4*
Wk 52, ELEVATE UC 52	PBO, n (%) [N=9]	Etrasimod 2 mg QD, n (%) [N=27]	Percentage difference from PBOb	PBO, n (%) [N=135]	Etrasimod 2 mg QD, n (%) [N=262]	Percentage difference from PBOb	N/A
Clinical remissionc Clinical responsed Symptomatic remissione Endoscopic improvementf Endoscopic improvement-histological remissiong Sustained clinical remissionh Corticosteroid-free clinical remissioni	1 (11.1) 3 (33.3) 1 (11.1) 3 (33.3) 3 (33.3) 1 (11.1) 1 (11.1)	12 (44.4) 15 (55.6) 15 (55.6) 14 (51.9) 8 (29.6) 8 (29.6) 12 (44.4)	44.4*** 32.3 53.6*** 29.5 -2.3 35.7*** 44.4***	10 (7.4) 32 (23.7) 27 (20.0) 16 (11.9) 12 (8.9) 3 (2.2) 9 (6.7)	82 (31.3) 128 (48.9) 112 (42.7) 99 (37.8) 71 (27.1) 46 (17.6) 82 (31.3)	24.0*** 25.2*** 22.8*** 26.0*** 18.4*** 15.5*** 24.8***
*p<0.05; **p<0.01; ***p<0.001 (nominal p values are reported without adjustment for multiple comparisons) aPts with isolated proctitis at baseline (defined as < 10 cm of rectal involvement) met all other eligibility criteria for inclusion (MMS 4–9, ES ≥ 2 [centrally read] and RBS ≥1) bTreatment comparisons and 2-sided p values were obtained using the Cochran–Mantel–Haenszel method within each subgroup, adjusting to study stratification (for pooled data only), naïvety to prior biologic/Janus kinase inhibitor therapy, baseline corticosteroid use and baseline disease activity (MMS 4–6 or 7–9). Difference (%) is for etrasimod minus PBO and is based on estimated common risk difference using Mantel–Haenszel weights cClinical remission was defined as an SFS=0 (or =1 with a ≥ 1-point decrease from baseline), RBS=0 and ES ≤ 1 (excluding friability) dClinical response was defined as a ≥ 2-point and ≥ 30% decrease from baseline in MMS, and a ≥ 1-point decrease from baseline in RBS or an absolute RBS ≤ 1 eSymptomatic remission was defined as an SFS=0 (or =1 with a ≥ 1-point decrease from baseline) and an RBS=0 fEndoscopic improvement was defined as a score of ≤ 1 (excluding friability) gEndoscopic improvement-histologic remission was defined as an ES ≤ 1 (excluding friability) with histologic remission as measured by a Geboes Index score < 2.0 hSustained clinical remission was defined as clinical remission at both Wks 12 and 52 iCorticosteroid-free remission was defined as remission at Wk 52 with no use of corticosteroids for at least the last 12 study wks immediately before Wk 52 ES, endoscopic subscore; MMS, modified Mayo score; N, total number of patients; n, number of patients with evaluable data within each category; N/A, not applicable; PBO, placebo; pt, patient; RBS, rectal bleeding subscore; SFS, stool frequency subscore; QD, once daily; UC, ulcerative colitis; wk, week

Conclusion

Etrasimod treatment had similar efficacy in pts with isolated proctitis and in those with more extensive colitis. Prospective confirmation in larger pt cohorts with isolated proctitis is necessary. Safety was consistent with the overall population.¹

References

1. Sandborn WJ et al. Lancet 2023: Epub ahead of print

Disclosure

LPB: research: Takeda, Fresenius Kabi, Celltrion; consultancy: AbbVie, Alimentiv, Alma, Amgen, Applied MolecularTransport, Arena, Biogen, BMS, Celltrion, CONNECTBiopharm, Cytoki, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer, GSK, HAC, IAG ImageAnalysis, Index, Inotrem, Janssen, Eli Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par'Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, Abivax; speaker: Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Eli Lilly, Gilead, Viatris, Medac, Sanofi; stock: CTMA.
MCD: research: Janssen; consultancy: AbbVie, Arena, BMS, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, Janssen, Pfizer, Prometheus, Takeda, Trellus Health, UCB; shares/royalties: Trellus; directorship/ownership interests: Trellus.
BES: research/grants: Arena, Janssen. Lecture/Speakers Bureau: BMS, Janssen, Lilly, Pfizer, Takeda. Consultancy: AbbVie, Alimentiv, Amgen, Arena, AstraZeneca, Boehringer-Ingelheim, BMS, Celltrion, Fresenius Kabi, Genentech, GSK, Janssen, Lilly, Merck, Pfizer, Prometheus Biosciences, Sun Pharma Global, Takeda Pharmaceuticals International, Teva Branded Pharmaceutical Products R&D. Shareholder/Stock Options: Ventyx Biosciences. Other non-financial support: Janssen, Lilly, Pfizer, Takeda.
JP: personal: AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Galapagos, Genentech/Roche, GSK, Immunic, Janssen, Mirum, Morphic, Nestlé, Origo, Pandion, Pfizer, Progenity, Revolo, Takeda, Theravance, Wassermann; grants: AbbVie, Pfizer.
SS: speaker: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Dr. Falk, Fresenius, Janssen, MSD, Pfizer, Takeda; consultancy/advisory: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Dr. Falk, Fresenius, Gilead, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, Provention, Takeda, Theravance.
WR: speaker: AbbVie, Celltrion, Dr. Falk, Ferring, Janssen, Galapagos, MSD, Roche, Pfizer, Pharmacosmos, Shire, Takeda, Therakos; consultant: AbbVie, Amgen, AOP Orphan, Arena, Astellas, AstraZeneca, Bioclinica, Boehringer Ingelheim, BMS, Calyx, Celgene, Celltrion, Eli Lilly, Dr. Falk, Ferring, Galapagos, Gatehouse, Genentech, Gilead, Grünenthal, ICON, Index, Inova, Janssen, Landos Biopharma, Medahead, MedImmune, Microbiotica, Mitsubishi Tanabe, MSD, Novartis, OMass, Otsuka, Parexel, Periconsulting, Pharmacosmos, Pfizer, Protagonist, Provention, Quell, Sandoz, Seres, Setpointmedical, Sigmoid, Sublimity, Takeda, Teva, Therakos, Theravance, Zealand; advisory board: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Celltrion, Galapagos, Janssen, Mitsubishi Tanabe, MSD, Pharmacosmos, Pfizer, Sandoz, Takeda; research: AbbVie, Janssen, MSD, Sandoz, Sanofi, Takeda.
BGF: consultant/advisory: AbbVie, AbolerIS, AgomAB, AllianThera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Avoro Capital, Atomwise, BIOJAMP, Biora, Boehringer Ingelheim, Boxer, Celsius, BMS, Connect, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, FirstWord, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer, GSK, Hinge, HotSpot, InDex, Imhotex, Immunic, JAK, Janssen, Japan Tobacco, Kaleido, Landos, Leadiant, L.E.K., Lenczner Slaght, LifeSci, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic, Mylan, OM, Origo, Orphagen, Pandion, Pendopharm, Pfizer, Prometheus, Diagnostics, Play to Know AG, Progenity, Protagonist, PTM, Q32, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres, Silverback, Surrozen, Takeda, Teva, Thelium, TiGenix, Tillotts, Ventyx, VHSquared, Viatris, Ysios, YSOPIA, Zealand; speaker: AbbVie, Janssen, Takeda; Alimentiv Senior Scientific Director, provides central reading services; not a company employee, no equity stake; shareholder: Gossamer.
SD: consultancy/advisory: AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead, Hospira, Janssen, J&J, MSD, Mundipharma, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB Vifor; speaker: AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, Takeda; directorship/ownership interests: Gastroenterology and Endoscopy.
AJY: consultancy: Pfizer, Arena, Takeda, BMS; speaker: BMS.
GD’H: advisor: AbbVie, AstraZeneca, Alimentiv, BMS, Boehringer Ingelheim, Celltrion, Cosmo, Eli Lilly, Galapagos, GSK, J&J, Takeda, Pfizer, Polpharma, Prometheus, Tillotts, Ventyx; speaker: AbbVie, Boehringer Ingelheim, Celltrion, J&J, Takeda, Pfizer, Tillotts.
MG, KW, JCW, IM, AMcD, LB, CJR: Pfizer employees & shareholders.
SV: research: AbbVie, MSD, Pfizer, Galapagos, Takeda; consultancy: AbbVie, AbolerIS, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, J&J, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts, Zealand; speaker: AbbVie, Dr. Falk, Ferring, Hospira, MSD, Takeda, Tillotts.

Introduction

Consistent associations between higher remission rates and shorter disease duration have been reported for advanced therapies in Crohn’s disease (CD), but no direct comparisons between newer advanced treatments and efficacy with respect to CD duration have been examined. The efficacy of risankizumab (RZB), an interleukin (IL)23p19 inhibitor, and ustekinumab (UST), an IL12/23p40 inhibitor, in pts with CD have been reported.^1–3 Herein, using data from the phase 3 SEQUENCE study, the clinical and endoscopic efficacy of RZB vs UST, stratified by baseline (BL) CD duration, is reported.

Aims & Methods

The SEQUENCE open-label, multicenter, randomized, efficacy assessor-blinded study compared the efficacy and safety of RZB vs UST in pts with moderate to severe CD and prior anti-TNF failure (NCT04524611). Pts were randomized 1:1 to receive recommended induction and maintenance doses of RZB (N=255) or UST (N=265). A mandatory steroid taper began at week (W)2. Randomization was stratified by BL steroid use and number of failed anti-TNFs. This post hoc analysis evaluated CDAI clinical remission and endoscopic remission at W24 and W48, and endoscopic response, steroid-free CDAI clinical remission, and steroid-free endoscopic remission at W48, in pts stratified by disease duration (<2 years [Y], 2-5Y, 5-10Y, >10Y) (endpoints defined in Table footnote). Missing data due to COVID-19 and/or geopolitical conflict was handled using non-responder imputation while incorporating multiple imputation. P values are nominal.

Results

BL, baseline; CD, Crohn's disease; CDAI, CD activity index; CI, confidence interval; FCP, fecal calprotectin; hs-CRP, high-sensitivity C-reactive protein; SES-CD, simple endoscopic score for CD; TNF, tumor necrosis factor CDAI clinical remission - CDAI < 150; endoscopic remission - SES-CD ≤ 4 and ≥ 2 point reduction versus BL and no subscore > 1 in any individual variable, as scored by central reviewer; endoscopic response - decrease in SES-CD > 50% from BL (or for patients with isolated ileal disease and a BL SES-CD of 4, ≥ 2 point reduction from BL), as scored by central reviewer; Steroid-free CDAI clinical remission - CDAI clinical remission without receiving steroids; steroid-free endoscopic remission - endoscopic remission without receiving steroids Efficacy population includes all patients randomized to either ustekinumab (i.e., weight-based induction dose IV followed by maintenance dose 90-mg SC), or the selected dosing regimen for risankizumab (600 mg for induction, 360 mg for maintenance), and who received at least one dose of study drug. 5% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 and/or geopolitical conflict or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19 and/or geopolitical conflict. Response rate difference = (risankizumab - ustekinumab); 95% CI for difference is calculated based on normal approximation to the binomial distribution for the comparison of two treatment groups. P-value is based on Chi-square test. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 and/or geopolitical conflict. Pooled p-value from Chi-square is calculated following Li et al., Statistica Sinica. 1991; 1, 68-92. All P-values are nominal.

BL Demographic and Disease Characteristics

Disease Duration at Baseline (BL)

<2 years

2-5 years

>5-10 years

>10 years

RZB N=36

UST N=43

RZB N=59

UST N=62

RZB N=67

UST N=71

RZB N=93

UST N=89

Age (years), mean (SD) Sex (male), n (%) Body mass index (kg/m2), mean (SD) Average daily stool frequency, mean (SD) Average daily abdominal pain, mean (SD) CDAI, mean (SD) SES-CD, n; mean (SD) Fecal calprotectin (mg/kg), median (IQR) hs-CRP (mg/L), n; median (IQR) Anti-TNF failure history (> 1), n (%) Corticosteroid use (yes) - n %) Crohn's disease location per SES-CD, n (%) Ileal only Colonic only Ileal-colonic

36.7 (13.9) 18 (50) 21.6 (4.2) 5.1 (2.5) 1.9 (0.5) 312.5 (58.3) n = 36 14.4 (8.2) n = 33 1429 (2877) n = 35 5 (30) 2 (6) 11 (31) 6 (17) 20 (56) 10 (28)

34.2 (13.2) 18 (42) 22.9 (5.4) 5.0 (2.6) 2.0 (0.6) 314.8 (55.3) n = 43 15.5 (7.7) n = 41 2116 (2811) n = 40 19 (45) 5 (12) 14 (33) 9 (21) 16 (37) 18 (42)

33.1 (12.6) 35 (59) 23.1 (5.9) 5.3 (2.4) 2.0 (0.5) 318.6 (56.1) n = 59 12.9 (6.7) n = 47 1453 (2552) n = 58 10 (22) 11 (19) 11 (19) 9 (15) 23 (39) 27 (46)

36.0 (13.7) 35 (56) 25.4 (6.6) 5.6 (2.8) 2.0 (0.5) 314.6 (63.3) n = 62 15.2 (8.3) n = 49 1535 (2079) n = 60 10 (25) 11 (18) 16 (26) 12 (19) 20 (32) 30 (48)

36.3 (13.5) 42 (63) 24.1 (4.8) 6.0 (3.2) 2.0 (0.5) 317.4 (65.1) n = 67 14.0 (7.4) n = 53 1016 (2217) n = 63 9 (31) 19 (28) 16 (24) 9 (13) 25 (37) 33 (49)

35.1 (13.8) 35 (49) 23.3 (5.8) 5.2 (2.4) 1.9 (0.6) 304.0 (68.3) n = 71 13.7 (7.4) n = 57 1515 (2070) n = 71 8 (15) 14 (20) 15 (21) 10 (14) 28 (39) 33 (46)

43.0 (11.3) 41 (44) 24.9 (5.9) 5.5 (2.6) 1.9 (0.5) 296.8 (62.7) n = 93 13.2 (6.6) n = 74 593 (1472) n = 90 7 (13) 27 (29) 20 (21) 18 (19) 34 (37) 41 (44)

44.3 (12.2) 43 (48) 26.6 (5.6) 6.3 (2.3) 1.8 (0.6) 309.7 (61.3) n = 89 13.1 (6.4) n = 68 1115 (2306) n = 86 8 (20) 31 (35) 26 (29) 14 (16) 42 (47) 33 (37)

RZB N=36

UST N=43

Response Rate Difference % (95% CI) P-value

RZB N=59

UST N=62

Response Rate Difference % (95% CI) P-value

RZB N=67

UST N=71

Response Rate Difference % (95% CI) P-value

RZB N=93

UST N=89

Response Rate Difference % (95% CI) P-value

CDAI clinical remission at week 24, n/N; % (95% CI) CDAI clinical remission at week 48, n/N; % (95% CI) Endoscopic response at week 24, n/N; % (95% CI) Endoscopic response at week 48, n/N; % (95% CI) Endoscopic remission at week 48, n/N; % (95% CI) Steroid-free CDAI clinical remission at week 48, n/N; % (95% CI) Steroid-free endoscopic remission at week 48, n/N; % (95% CI)

23/36 63.9% (48.2, 79.6) 23/36 63.9% (48.2, 79.6) 19/36 52.8% (36.5, 69.1) 19/36 52.8% (36.5, 69.1) 11/36 30.6% (15.5, 45.6) 23/36 63.9% (48.2, 79.6) 11/36 30.6% (15.5, 45.6)

22/43 51.2% (36.2, 66.1) 19/43 44.2% (29.3, 59.0) 14/43 32.6% (18.6, 46.6) 11/43 25.6% (12.5, 38.6) 8/43 18.6% (7.0, 30.2) 19/43 44.2% (29.3, 59.0) 8/43 18.6% (7.0, 30.2)

12.7 (-8.9, 34.4) P =.3 19.7 (-1.9, 41.3) P =.1 20.2 (-1.3, 41.7) P =.1 27.2 (6.3, 48.1) P <.05 12.0 (-7.1, 31.0) P =.2 19.7 (-1.9, 41.3) P =.1 12.0 (-7.1, 31.0) P =.2

30/59 50.8% (38.0, 63.6) 33/59 55.9% (43.3, 68.6) 26/59 44.5% (31.7, 57.2) 24/59 40.7% (28.1, 53.2) 20/59 33.9% (21.8, 46.0) 33/59 55.9% (43.3, 68.6) 19/59 32.2% (20.3, 44.1)

26/62 41.9% (29.7, 54.2) 27/62 43.5% (31.2, 55.9) 12/62 19.4% (9.5, 29.2) 8/62 12.9% (4.6, 21.2) 6/62 9.7% (2.3, 17.0) 26/62 41.9% (29.7, 54.2) 4/62 6.5% (0.3, 12.6)

8.9 (-8.9, 26.6) P =.3 12.4 (-5.3, 30.1) P =.2 25.1 (9.0, 41.2) P <.01 27.8 (12.7, 42.8) P <.001 24.2 (10.1, 38.4) P <.01 14.0 (-3.6, 31.6) P =.1 25.8 (12.4, 39.2) P <.001

40/67 59.7% (48.0, 71.4) 39/67 58.2% (46.4, 70.0) 33/67 49.3% (37.3, 61.2) 31/67 46.3% (34.3, 58.2) 19/67 28.4% (17.6, 39.2) 39/67 58.2% (46.4, 70.0) 19/67 28.4% (17.6, 39.2)

39/71 54.9% (43.4, 66.5) 31/71 43.7% (32.1, 55.2) 23/71 32.4% (21.5, 43.3) 18/71 25.4% (15.2, 35.5) 16/71 22.5% (12.8, 32.3) 31/71 43.7% (32.1, 55.2) 16/71 22.5% (12.8, 32.3)

4.8 (-11.7, 21.3) P =.6 14.5 (-2.0, 31.1) P =.1 16.9 (0.7, 33.0) P <.05 20.9 (5.3, 36.6) P <.05 5.8 (-8.7, 20.3) P =.4 14.5 (-2.0, 31.1) P =.1 5.8 (-8.7, 20.3) P =.4

59/93 63.4% (53.7, 73.2) 60/93 64.5% (54.8, 74.2) 37/93 39.8% (29.8, 49.7) 41/93 44.1% (34.0, 54.2) 31/93 33.3% (23.8, 42.9) 60/93 64.5% (54.8, 74.2) 31/93 33.3% (23.8, 42.9)

26/89 29.2% (19.8, 38.7) 31/89 34.8% (24.9, 44.7) 21/89 23.6% (14.8, 32.4) 21/89 23.6% (14.8, 32.4) 13/89 14.6% (7.3, 21.9) 31/89 34.8% (24.9, 44.7) 13/89 14.6% (7.3, 21.9)

34.2 (20.6, 47.8) P <.0001 29.7 (15.8, 43.6) P <.0001 16.2 (2.9, 29.5) P <.05 20.5 (7.1, 33.9) P <.01 18.7 (6.7, 30.8) P <.01 29.7 (15.8, 43.6) P <.0001 18.7 (6.7, 30.8) P <.01

Baseline characteristics were mostly similar across treatments and disease duration subgroups, except total number of pts and proportion of pts failing >1 anti-TNFs (both lower in the <2Y subgroup), and fecal calprotectin (lower with increasing CD duration) (Table). With RZB vs UST, a numerically greater proportion of pts achieved all endpoints, irrespective of disease duration (Table). A greater proportion of pts in all subgroups achieved endoscopic response with RZB vs UST at W48 (<2Y: P<05; 2-5Y, P<001; 5-10Y, P<.05, > 10Y, P<.01), with a similar trend for RZB vs UST observed for most, but not all, disease duration subgroups for W24 endoscopic response and W48 endoscopic remission (Table). The numerically highest rates of endoscopic response were observed with RZB in pts with a disease duration ≤2Y, andwhile the numerically greatest treatment differences with RZB vs UST were observed in pts with a disease duration of ≤5Y (Table). The safety profiles of RZB and UST in CD were previously reported.^1–3

Conclusion

At W24 and W48, numerically higher rates of efficacy were observed with RZB vs UST treatment for all endpoints across disease duration subgroups, with notable consistent differences observed for endoscopic response. Endoscopic response rates with RZB were numerically highest in pts with a disease duration of ≤2Y, supporting early intervention for patients with CD.⁴

References

1 D’Haens, G. et al. The Lancet. 2022; 399, 2015–2030.
2 Ferrante, M. et al. The Lancet. 2022; 399, 2031–2046.
3 Feagan, B. G. et al. N Engl J Med. 2016; 375, 1946–1960.
4 Colombel, J.-F. et al. Gastroenterology. 2017; 152, 351-361.e5.

Disclosure

Jean-Frederic Colombel received research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; payment for lectures from AbbVie, Allergan, Amgen, Ferring Pharmaceuticals, Shire, and Takeda; consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Ferring Pharmaceuticals, Galmed Research, Genentech, GlaxoSmithKline, Imedex, Immunic, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Lilly, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, and Vifor; and holds stock options in Intestinal Biotech Development.
Laurent Peyrin-Biroulet received personal fees from AbbVie, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic Pharma, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax, Samsung, Ventyx, Roivant, and Vectivbio
Shomron Ben-Horin has received Advisory Board fees and/or Consulting fees from Janssen, AbbVie, CellTrion, Takeda, Schering Plough, Pfizer, Ferring, Falk Pharma, GSK, BMS, Novartis, Roche, Galmed, Evinature, PredictaMed and Eli Lilli, holds Stocks/options in Galmed, Evinature, PredictaMed and Alma Therapeutics and received research grant support from Janssen, AbbVie, CellTrion, Takeda, Pfizer and Galmed.
Christina Ha has received financial support from advisory board fees from AbbVie, Bristol Myers Squibb, Bausch Health, Roivant, Janssen, Pfizer, and Takeda; consultant fees from AbbVie; educational grant funding from Bristol Myers Squibb, Pfizer, Janssen, AbbVie and the Helmsley Charitable trust
Britta Siegmund has served as consultant for AbbVie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro; Speaker fees: AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (served as representative of the Charité).
Fernando Aponte, Kristina Kligys, Javier Zambrano, Toni Anschutz, and Andrew Garrisonare full-time employees of AbbVie and may own AbbVie stock or options.
Funding and Acknowledgments: AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and authors thank all the trial investigators and the patients who participated in this clinical trial.
Medical writing support was provided by Stephanie Parsons, PhD, and copy editing support was provided by Angela T. Hadsell, BS, both employees of AbbVie.

Introduction

Mirikizumab (miri), a p19-directed IL-23 antibody, has been shown to be effective in patients with moderately-to-severely active ulcerative colitis (UC) in Phase 3 trials (LUCENT-1 NCT03518086; LUCENT-2 NCT03524092).¹ The relationship between symptomatic, endoscopic, and clinical remission and levels of the inflammatory biomarker faecal calprotectin (fCAL) was studied for miri-treated patients enrolled in the trials.

Aims & Methods

This post hoc analysis evaluated patients treated with intravenous (IV) miri 300mg every 4 weeks (Q4W) until week (W)12 in induction (n=868) followed by subcutaneous miri (n=365) Q4W up to W52 (miri induction responders at W12 who were rerandomized for the maintenance period) or placebo. The improvement in fCAL at W12 and W52 between miri and placebo were compared using Cochran Mantel Haenszel, adjusting for randomization stratification factors. Missing data were imputed as nonresponse. The relationship between achieving symptomatic, endoscopic, or clinical remission (defined in Table) and fCAL levels at W4, W12 and W52 was assessed using receiver operating characteristic (ROC) approaches. Predictability was measured by area under the ROC curve (AUC), and AUC≤0.5 indicates no predictability. Optimal fCAL threshold was obtained based on Youden Index.

Results

Greater proportions of miri-treated patients compared to placebo achieved fCAL≤250 ug/g at W4, W12, and W52. A total of 19.0% vs. 12.5%, 34.3% vs. 20.1%, 50.7% vs 19.3% patients achieved fCAL≤250 ug/g at W4, W12, and W52 miri vs. placebo, respectively. Greater proportions of patients achieving symptomatic, endoscopic, and clinical remission reached the predefined threshold of fCAL≤250 ug/g or the optimum fCAL threshold obtained from the ROC (see Table footnote) in this study compared with those not achieving the endpoints (Table). W4 fCAL levels had 70.5% predictability for W12 endoscopic remission and 64.9% for clinical remission, but lower predictability for symptomatic remission (59.1%). W12 fCAL levels had 83.0% predictability for W12 endoscopic remission, 78.5% for clinical remission, and 67.4% for symptomatic remission. W52 fCAL levels had higher predictability for W52 endoscopic (76.6%) and clinical remission (72.7%) than for symptomatic remission (62.3%).

Table. Faecal Calprotectin Normalization at Week 12 in LUCENT-1 and Week 52 in LUCENT-2 per achievement of efficacy outcomes

		Symptomatic Remission		Endoscopic Remission		Clinical Remission
Week 4		Achieving (N=360)	Not Achieving (N=406)	Achieving (N=290)	Not Achieving (N=478)	Achieving (N=193)	Not Achieving (N=571)
	fCAL ≤ 250 ug/g	109 (30.3)	79 (19.5)╪	122 (42.1)	65 (13.6) ╪	77 (39.9)	110 (19.3)╪
	Optimum fCAL threshold	193 (53.6)	159 (39.2)╪	158 (54.5)	106 (22.2)╪	103 (53.4)	168 (29.4)╪
Week 12		Achieving (N=364)	Not Achieving (N=398)	Achieving (N=293)	Not Achieving (N=472)	Achieving (N=199)	Not Achieving (N=562)
	fCAL ≤ 250 ug/g	200 (55.0)	116 (29.2)╪	216 (73.7)	100 (21.2)╪	151 (75.9)	164 (29.2)╪
	Optimum fCAL threshold	237 (65.1)	149 (37.4)╪	216 (73.7)	93 (19.7)╪	151 (75.9)	157 (27.9)╪
Week 52		Achieving (N=230)	Not Achieving (N=44)	Achieving (N=188)	Not Achieving (N=93)	Achieving (N=166)	Not Achieving (N=107)
	fCAL ≤250 ug/g	161 (70.0)	22 (50.0)*	151 (80.3)	38 (40.9)╪	133 (80.1)	49 (45.8)╪
	Optimum fCAL threshold	161 (70.0)	21 (47.7)*	134 (71.3)	24 (25.8)╪	129 (77.7)	42 (39.3)╪

ES=Endoscopic Subscore; fCAL=Faecal Calprotectin; RB = Rectal Bleeding; SF=Stool Frequency.
Data shown as n(%). *p<0.05 and ^╪p<0.001 from Fisher's exact test. Symptomatic remission: SF=0 or 1 with a ≥1-point decrease from baseline, RB=0. Endoscopic remission: ES=0 or 1 (excluding friability). Clinical remission: SF=0 or 1 with a ≥1-point decrease from baseline, RB=0, and ES=0 or 1 (excluding friability). Optimal fCAL for symptomatic/endoscopic/clinical remission: ≤585/≤390/≤415 ug/g at Week 4; ≤365/≤230/≤230 ug/g at Week 12; ≤230/≤150/≤205 ug/g at Week 52.

Conclusion

These results support the use of fCAL as an early predictor of clinical outcomes and as a non-invasive biomarker for predicting clinical outcomes.

References

1. D’Haens G, et al. NEJM 2023;388(26):2444-2455. DOI: 10.1056/NEJMoa2207940

Disclosure

SV has received research support from AbbVie, Johnson & Johnson, Pfizer, Galapagos, and Takeda; lecture fees from AbbVie, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Ferring, Galapagos, Genentech-Roche, Gilead, Janssen, Johnson & Johnson, Lilly, Materia Prima, Merck Sharp & Dohme, Pfizer, Takeda, Tillotts Pharma, and Zealand Pharma; and consulting fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma Merck, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma, and Zealand Pharma.
ML has served as a Consultant for AbbVie, Pfizer, Takeda, Lilly, Bristol-Meyers Squibb, Target RWE, and Prometheus and has received research support from Pfizer, Takeda, and Janssen.
PD has consulted for Abbvie, Abivax, Adiso, Bristol Myers Squibb, GSK, Janssen, Lilly, Pfizer, and Takeda; grant support from Bristol-Myers Squibb, Janssen, Pfizer, and Takeda; Licensing royalties from PreciDiag.
CM has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma; royalties from Springer Publishing; research support from AbbVie, Ferring, Pfizer.
F C-D, RM, and BZ are employees and minor shareholders of Eli Lilly and Company.
JP is an employee of Syneos Health.
ST has served as a paid consultant to AbbVie, Allergan, Amgen, Asahi, Bioclinica, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, ChemoCentryx, Cosmo, Enterome, Equillium, Ferring, GSK, Genentech, Genzyme, Giuliani SpA, Immunocore, Immunometabolism, Janssen, Lilly, MSD, Merck, Mestag, Neovacs, Novo Nordisk, NPS Pharmaceuticals, Pfizer, Proximagen, Receptos, Roche, Satisfai Health, Sensyne Health, Shire, Sigmoid Pharma, Sorriso, Takeda, Topivert, UCB, VHsquared, Vifor, and Zeria; he has received grants and/or has grants pending from AbbVie, ECCO, Helmsley Trust, IOIBD, Janssen, Lilly, Norman Collisson Foundation, Pfizer, UCB, UKIERI, and Vifor; he has received honoraria from AbbVie, Amgen, Biogen, Ferring, Lilly, Pfizer, and Takeda; and he has had travel/accommodation expenses covered or reimbursed by AbbVie, Amgen, Biogen, Ferring, Lilly, Johnson & Johnson, Pfizer, and Takeda.
RP reports personal fees from Abbott, AbbVie, Alimentiv [formerly Robarts], Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Lilly, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, HC3 Communications, Janssen, Meducom, Merck, Mylan, Oppilan, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Receptos, Roche, Sandoz, Satisfai Health, Schering-Plough, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus Health, and UCB.

Introduction

PRA023 is a humanized monoclonal antibody against tumor necrosis factor–like cytokine 1A (TL1A), a key pro-inflammatory cytokine and pro-fibrosis regulator, in development for inflammatory bowel diseases. In a phase 2 double-blind, placebo-controlled study (ARTEMIS-UC) assessing the efficacy and safety of PRA023 induction treatment in adults with moderately to severely active ulcerative colitis (UC), a significantly greater proportion of patients who received PRA023 achieved the primary endpoint of clinical remission after 12 weeks. This post hoc analysis assessed the impact of PRA023 on health-related quality of life using the Inflammatory Bowel Disease Questionnaire (IBDQ-32).

Aims & Methods

Adults with a modified Mayo score of 4 to 9, centrally read endoscopy subscore of ≥2, rectal bleeding subscore of ≥1, and history of insufficient response, loss of response, and/or intolerance to conventional and/or advanced therapies (≤4 advanced agents from ≤3 classes allowed) were stratified by prior biologic exposure and genetic-based diagnostic status and randomized 1:1 to placebo or intravenous PRA023 (1000 mg on day 1, and 500 mg at weeks 2, 6, and 10). IBDQ outcomes measures include: IBDQ response (score of ≥16-point from baseline), IBDQ remission (total score ≥170), and mean change from baseline in total and domain scores after 12 weeks of induction therapy. Score changes from baseline were compared among treatment groups, and the impact of prior advanced therapy exposure on IBDQ remission was assessed. Higher scores represent better quality of life.

Results

Of the 135 patients in the study, 60/67 (89.6%) in the placebo arm and 68/68 (100%) in the PRA023 arm completed the 12-week induction period. Baseline characteristics were similar between the treatment groups. Significantly greater proportions of patients in the PRA023 group achieved IBDQ response (82.4% PRA023 vs 49.3% placebo, ∆33.1%, p<0.0001) and IBDQ remission (51.5% PRA023 vs 19.4% placebo, ∆32.1%, p=0.0001) at week 12. Prior advanced therapy use did not affect the placebo-adjusted proportion of patients experiencing IBDQ remission in those who received PRA023 (Δ34.4% vs Δ30.0%, respectively, for prior and no prior advanced therapy). The total IBDQ score and all IBDQ domain subscores (bowel symptoms, systemic symptoms, emotional function, and social function) were significantly improved after 12 weeks of PRA023 induction treatment compared to placebo (Table 1).

Table 1. Inflammatory Bowel Disease Questionnaire (IBDQ) Outcomes with PRA023 Induction Therapy

IBDQ outcomes	Placebo	PRA023	% Difference vs placebo (95% CI)	P value
IBDQ response (%, n/N)†‡	49.3 (33/67)	82.4 (56/68)	33.1 (17.2–46.8)	<0.0001
IBDQ remission (%, n/N)‡	19.4 (13/67)	51.5 (35/68)	32.1 (16.0–45.9)	0.0001
-Prior advanced therapy	18.8 (6/32)	53.1 (17/32)	34.4 (10.9–53.1)	-
-No prior advanced therapy	20.0 (7/35)	50.0 (18/36)	30.0 (7.8–48.4)	-
Change in IBDQ scores from BL, mean±SD -Total score	20.8±37.59	48.6±34.85	26.8 (14.6–38.9)	<0.0001
-Bowel symptoms subscore	7.1±12.27	17.2±11.79	9.4 (5.3–13.4)	<0.0001
-Systemic symptoms subscore	3.0±5.97	7.0±6.56	4.0 (2.0–6.0)	0.0002
-Emotional function subscore	6.6±14.59	16.1±13.25	8.9 (4.3–13.5)	0.0002
-Social function subscore	4.1±7.74	8.2±7.38	4.4 (2.0–6.8)	0.0004

^†Prespecified secondary endpoint.
^‡Nonresponder imputation was applied to response and remission endpoints.
Abbreviations: BL, baseline; IBDQ, Inflammatory Bowel Disease Questionnaire.
P values are nominal except IBDQ response.

Conclusion

PRA023 significantly improved quality-of-life measures in patients with moderately to severely active UC, regardless of prior advanced therapy use. The greatest benefits were reported in the bowel symptoms and emotional function domains.

Disclosure

LPB has served as a consultant for or has received fees from AbbVie, Allergan, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Eli Lilly and Company, Enterome, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, Hikma, Index Pharmaceuticals, Inotrem, Janssen, MSD, Mylan, Oppilan Pharma, OSE Immunotherapeutics, Nestlé, Norgine, Roche, Pandion Therapeutics, Pfizer, Pharmacosmos, Samsung Bioepis, Sandoz, sterna biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tillotts Pharma, and Vifor; has received grants from AbbVie, Fresenius Kabi, MSD, and Takeda; and has stock options from CTMA.
BES has served as a consultant for 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 Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion Healthcare, ClostraBio, Connect Biopharma, Cytoki Pharma, Eli Lilly and Company, Entera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead, Genentech, GSK, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kallyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, and Viela Bio and has received stock options from Ventyx Biosciences.
SD has received consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Eli Lilly and Company, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, and Vifor and lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda.
DTR has served as a consultant for AbbVie, AltruBio, Aslan Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Chronicles, Corp/Syneos, ClostraBio, Connect Biopharma, Eco R1, Eli Lilly and Company, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen Pharmaceuticals, Kaleido, Pfizer, Prometheus Biosciences, Reistone Biopharma, Seres Therapeutics, Takeda, Target RWE, and Trellus Health and has received grant support from Takeda, Helmsley Charitable Trust, and the Gastro-Intestinal Research Foundation.
DDN, QD, AM, and BD are employees and shareholders of Prometheus Biosciences.
CM has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma, BIOJAMP, Bristol Myers Squibb, Celltrion Healthcare, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Takeda, Pendopharm, Pfizer, Prometheus Biosciences, Roche, and Sanofi; speaker's fees from AbbVie, Amgen, AVIR Pharma, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Takeda, Pendopharm, and Pfizer; royalties from Springer Publishing; and research support from Ferring and Pfizer.
TER has been a speaker for Takeda Pharmaceuticals, Janssen, Pfizer, Bristol Myers Squibb, and Abbvie; has served on advisory boards for AbbVie, Ardelyx, Arena, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Eli Lilly and Company, Ferring, Genentech/Roche, Gilead, Intercept, Iterative Scopes, Janssen, Pfizer, Prometheus Biosciences, Sanofi, and Takeda; and has been a shareholder for Iterative Scopes.
RP has been a consultant for Abbott, AbbVie, Abivax, Alimentiv (formerly Robarts), Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly and Company, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, GSK, BIOJAMP, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB; has received speakers fees from AbbVie, Amgen, Arena, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda; and has served on advisory boards for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, GSK, BIOJAMP, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda, and Ventyx.