Introduction

Symptomatic, endoscopic, and histological remission simultaneously, known as disease clearance (DC), has been proposed as an aspirational target in ulcerative colitis (UC). [1, 2] Mirikizumab (miri), an anti-IL-23p19 antibody, has demonstrated strong efficacy as shown by single and combined clinical endpoints in LUCENT Phase 3 trials. [3-5] This analysis evaluated the impact of miri on DC during LUCENT-1 (NCT03518086), LUCENT-2 (NCT03524092) and long-term LUCENT-3 (NCT03519945) trials and the association between DC and other clinical and patient-reported outcomes (PROs).

Aims & Methods

DC is defined as symptomatic remission [Mayo stool frequency (SF)=0, 1 with a ≥1 point decrease from baseline + rectal bleeding (RB)=0], and histologic-endoscopic mucosal remission [HEMR: Mayo endoscopic remission (ER: endoscopy subscore of 0 or 1, excluding friability) + Geboes score ≤2B.0]. PROs of interest included Fatigue NRS, IBDQ remission, SF-36, WPAI:UC, PGRS, and PGRC (see table footer). Clinical outcomes include clinical remission, corticosteroid-free remission, ER, HEMR, bowel urgency (BU) remission, SF remission, and RB remission. [2,5] The proportion of patients achieving DC was assessed at W12, W52, and W104. Treatment comparisons were made using a CMH test adjusting for randomization factors. Associations between the PROs and DC were evaluated at W12 and W52 in miri-treated patients. The associations between clinical outcomes and early achievement of DC in miri-treated patients at W12 and W52 were evaluated at W52 and W104, respectively. Non-responder imputation was used for all analyses.

Results

A significantly higher proportion of miri-treated patients achieved DC vs PBO at W12 [N=868 miri, 294 PBO] (DC: 16.0% vs 7.1%, p<0.0001) and W52 [N=365 miri, 179 PBO] (DC: 36.4% vs 19.6%, p=0.0002). Similar trends were seen for biologic failure subgroups at W12 (bio/JAKi-failed: [n=361 miri, 118 PBO; DC: 9.1% vs 5.9%]; bio&JAKi-naïve: [n=492 miri, 171 PBO; DC: 20.9% vs 7.6%]) and W52 (bio/JAKi-failed: [n=128 miri, 64 PBO; DC: 31.3% vs 12.5%]; bio&JAKi-naïve: [n=229 miri, 114 PBO; DC: 39.3% vs 23.7%]). At W104 (N=239 miri), 40.6% of patients achieved DC with 2-year treatment with miri. Specifically, 38.4% of bio/JAKi-failed (n=73) and 40.9% of bio&JAKi-naïve (n=159) patients achieved DC. Significantly greater improvement in all PROs was seen at W12 for patients who achieved DC vs those who did not at W12 in miri-treated patients. Similar associations were observed at W52, except in WPAI:UC overall work productivity (Table 1A). Patients achieving DC at W12 were more likely to achieve all clinical outcomes, except BU remission, at W52 versus those who did not achieve DC at W12. This trend was repeated in patients who achieved DC at W52 and continued to W104 (Table 1B).

Conclusion

Miri consistently demonstrated DC across induction, maintenance, and long-term studies. Over 36% of patients achieved DC after one year of miri treatment. The attainment of DC was associated with improvement in PROs in LUCENT-1 and -2. Early achievement of DC was associated with better long-term clinical outcomes.

Table 1. A. Association Between Disease Clearance Achievement and Improvement in Patient-Reported Outcomes in Miri-treated Patients					Table 1. B. Association of Early Disease Clearance and Subsequent Achievement of Long-term Positive Clinical Outcomes in Miri-treated Patients
W12	W12 DC: (Y/N) [N=139 vs 729]	W52	W52 DC: (Y/N) [N=133 vs 232]		W52	W12 DC: (Y/N) [N=93 vs 272]	W104	W52 DC: (Y/N) [N=111 vs 128]
Fatigue NRS change from baseline, LSM (std)	-2.5 (0.2) vs. -1.8 (0.1)***	Fatigue NRS change from baseline, LSM (std)	-3.2 (0.2) vs. -2.3 (0.2)**		Clinical Remission, n (%)	59 (63.4) vs. 123 (45.2)**	Clinical Remission, n (%)	73 (65.8) vs. 56 (43.8)***
IBDQ remission, n (%)	114 (82.0) vs. 385 (52.8)***	IBDQ remission, n (%)	116 (87.2) vs. 148 (63.8)***		CS-free Remission, n (%)	55 (59.1) vs. 109 (40.1)**	CS-free Remission, n (%)	71 (64.0) vs. 55 (43.0)**
SF-36 PCS change from baseline, LSM (std)	8.8 (0.6) vs. 5.4 (0.3)***	SF-36 PCS change from baseline, LSM (std)	10.7 (0.6) vs. 8.0 (0. 5)***		Endoscopic Remission, n (%)	64 (68.8) vs. 150 (55.1)*	Endoscopic Remission, n (%)	87 (78.4) vs. 69 (53.9)***
SF-36 MCS change from baseline, LSM (std)	6.9 (0.7) vs. 4.7 (0.3)**	SF-36 MCS change from baseline, LSM (std)	8.0 (0.7) vs. 6.3 (0.6)*		HEMR, n (%)	55 (59.1) vs. 103 (37.9)**	HEMR, n (%)	68 (61.3) vs. 46 (35.9)***
WPAI:UC Overall Work Productivity change from baseline, LSM (std)	-29.0 (2.5) vs. -18.0 (1.3)***	WPAI Overall Work Productivity change from baseline, LSM (std)	-34.9 (2.4) vs. -29.0 (2.1)		BU Remission, n (%)	44 (47.3) vs. 114 (41.9)	BU Remission, n (%)	58 (52.3) vs. 62 (48.4)
PGRS change from baseline, LSM (std)	-1.9 (0.1) vs. -1.0 (0.04)***	PGRS change from baseline, LSM (std)	-2.3 (0.1) vs. -1.7 (0.1)***		SF Remission, n (%)	83 (89.2) vs. 203 (74.6)**	SF Remission, n (%)	103 (92.8) vs. 106 (82.8)*
PGRC, LSM (std)	1.7 (0.1) vs. 2.4 (0.05)***	PGRC, LSM (std)	1.5 (0.1) vs. 1.8 (0.1)**		RB Remission, n (%)	87 (93.5) vs. 224 (82.4)*	RB Remission, n (%)	106 (95.5) vs. 109 (85.2)**
Note: * p<0.05; ** p<0.01; ***p<0.001. DC = Symptomatic Remission & HEMR. Fatigue Numeric Rating Scale (NRS) = a single item patient-reported outcome measure that assesses fatigue on an 11-point NRS scale ranging from 0 (no fatigue) to 10 (fatigue as bad as you can imagine). Inflammatory Bowel Disease Questionnaire (IBDQ) = A 32-item patient-completed questionnaire that assesses four domains of IBD-related quality of life: "Bowel Symptoms", "Systemic Symptoms", "Emotional Function", and "Social Function". A higher total score of all 32-items combined indicates better IBD-related quality of life. An IBDQ score equal or greater than 170 points has been suggested for disease remission. Medical Outcomes Study 36-Item Short Form Health Survey Version 2 Standard (SF-36) = a 36-item patient-reported outcome measure designed to assess health-related quality of life in eight domains: physical functioning, role-physical, role-emotional, bodily pain, vitality, social functioning, mental health, and general health. The mental and physical well-being domains ladder to the Mental Component Summary (MCS) score and the Physical Component Summary (PCS) score. The MCS and PCS summary scores range from 0 to 100, where higher scores indicate better levels of function and/or better health. WPAI:UC = Work Productivity and Activity Impairment Questionnaire-Ulcerative Colitis (WPAI-UC) is a 6-item patient-reported outcome measure that assesses UC-related impairment of daily activity and work productivity over the past 7 days. Scores are represented as impairment percentages, with higher numbers indicating greater impairment and less productivity. (change from baseline) PGRS = A 1-item patient-rated questionnaire designed to assess the patients’ rating of their disease symptom severity over the past 24 hours. Responses are graded on a 6-point scale in which a score of 1 indicates the patient has no symptoms (that is, “none”) and a score of 6 indicates that the patient’s symptom(s) are “very severe.” PGRC = A patient-rated instrument designed to assess the patients’ rating of change in their symptom(s). Responses are graded on a 7-point Likert scale in which a score of 1 indicates that the subject’s symptom(s) is “very much better,” a score of 4 indicates that the subject’s symptom has experienced “no change,” and a score of 7 indicates that the subject’s symptom(s) is “very much worse.” Symptomatic remission = MMS SF=0 or SF = 1 with a ≥ 1 point decrease from baseline and RB = 0. HEMR =endoscopic remission (MMS ES = 0 or 1 (excluding friability)) and a Geboes subscore of 0 for grades 2b (lamina propria neutrophils), 3 (neutrophils in epithelium), 4 (crypt destruction), and 5 (erosion or ulceration). Clinical remission = MMS SF = 0 or 1 with a ≥ 1 point decrease from baseline, RB = 0, and ES = 0 or 1 (excluding friability). CS-free remission = At LUCENT-2 W40 (W52 of continuous treatment), clinical remission at W40, symptomatic remission at W28, and no CS use for ≥12 weeks prior to W40. At LUCENT-3 W52 (W104 of continuous treatment), corticosteroid-free remission is defined as clinical remission at W52 and no corticosteroid use for at least 12 weeks prior to W52. Endoscopic remission = MMS ES = 0 or 1 (excluding friability). BU remission = Urgency NRS Score = 0 or 1. SF remission = MMS SF=0, or SF=1 with a >= 1-point decrease from induction baseline. RB remission = MMS RB=0. Associations between DC and categorical outcomes were analyzed using a CMH test adjusted for randomization factors, and corresponding odds ratios were determined. Non-responder imputation was used to impute missing values. For continuous outcomes, associations were analyzed using analysis of covariance with mBOCF using a model that included baseline outcome value and randomization factors. Relative effect sizes were determined. Abbreviations: BU = Bowel Urgency; CS = corticosteroid; CMH = Cochran-Mantel-Haenszel; HEMR = histologic-endoscopic mucosal remission; IBDQ = inflammatory bowel disease questionnaire; LSM = least squares mean; MCS = mental component score; MMS = modified Mayo score; N = number of patients in the analysis population; n = number of patients in the specified category; NRS = numeric rating scale; PCS = physical component score; PGRC = patient global rating of change; PGRS = patient global rating of severity; RB = Rectal Bleeding; SF = Stool Frequency; SF-36 = 36-item short-form health survey; std = standard error; UNRS = Urgency Numeric Rating Scale; W = week; mBOCF = modified baseline observation carried forward; WPAI = work productivity activity impairment questionnaire.

References

1. D’Amico, F., et al., Disease Clearance as a New Outcome in Ulcerative Colitis: a Systematic Review and Expert Consensus. Inflammatory Bowel Diseases, 2023.
2. Ramos, L., J. Teo-Loy, and M. Barreiro-de Acosta, Disease clearance in ulcerative colitis: Setting the therapeutic goals for future in the treatment of ulcerative colitis. Front Med (Lausanne), 2022. 9: p. 1102420.
3. D'Haens, G., et al., Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med, 2023. 388(26): p. 2444-2455.
4. Sands, B.E., et al., Two-Year Efficacy and Safety of Mirikizumab Following 104 Weeks of Continuous Treatment for Ulcerative Colitis: Results From the LUCENT-3 Open-Label Extension Study. Inflamm Bowel Dis, 2024.
5. Magro, F., et al., Resolving Histological Inflammation in Ulcerative Colitis With Mirikizumab in the LUCENT Induction and Maintenance Trial Programmes. Journal of Crohn's and Colitis, 2023. 17(9): p. 1457-1470.

Disclosure

J-F. Colombel reports research grants from AbbVie, Janssen, and Takeda; payment for lectures from AbbVie, Allergan, Amgen, Ferring, Shire, and Takeda; consulting fees from AbbVie, Amgen, Anaptys Bio, Arena, BMS, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galmed, Genentech, GlaxoSmithKline, Janssen, Kaleido, Imedex, Immunic, Iterative Scopes, Landos, Merck, Microba, Novartis, Otsuka Pharmaceutical, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, and Vifor; and holds stock options in Intestinal Biotech Development.
T. Kobayashi served as an advisory board member, consultant, or speaker for AbbVie, Activaid, Alfresa Pharma, Alimentiv, Bristol Myers Squibb, Celltrion, Covidien, EA Pharma, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Janssen Pharmaceuticals, JIMRO, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda and Zeria Pharmaceutical and has received research funding from AbbVie, Alfresa Pharma, EA Pharma, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Pfizer, Sekisui Medical, Takeda and Zeria Pharmaceutical. research grants from Abbvie GK, Activaid, Alfresa Pharma Corporation, Bristol-Myers Squibb Eli Lilly Ferring Pharmaceuticals Japan K.K., Gilead Sciences, Inc., JMDC Inc., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., received scholarship contributions from Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd Zeria Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., and belonged to study group sponsorship by Alfresa Pharma Corporation, JIMRO Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd. ZeriaPharmaceutical Co., Ltd. And received advisory/consultancy fees from Abbie GK, Activaid, Celltrion Healthcare, EA Pharma Co., Ltd., Eli Lilly, Ferring Pharmaceuticals Japan K.K., Gilead Sciences, Janssen Pharmaceutical K.K., KISSEI Pharmaceutical Co., Ltd, itsubishi Tanabe Pharma Corporation, Pfizer Japan Inc, Takeda Pharmaceutical Co., Ltd.
J. Wu, B. Zhu, I. Redondo, and R. Moses are employees of Eli Lilly.
V. Jairath reports consulting / advisory board for AbbVie, Alimentiv, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli 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, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion; speaker for AbbVie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, Fresenius Kabi.
C. Siegel reports consulting for AbbVie Inc, Bristol Myers Squibb, Fresnius Kabi, Eli Lilly and Company, Janssen Pharmaceuticals, Napo Pharmaceuticals Inc, Pfizer Inc, ProciseDx, Prometheus, Takeda Pharmaceutical Company, and Trellus Health Inc; being a speaker for continuing medical education activities for AbbVie Inc, Janssen Pharmaceuticals, Pfizer Inc, and Takeda Pharmaceutical Company; and receiving grant support from AbbVie Inc, Janssen Pharmaceuticals, Pfizer Inc, and Takeda Pharmaceutical Company.
B. Siegmund received research grants from Pfizer and Arena; consulting fees from AbbVie, Abivax, Arena, Bristol Myers Squibb, Boehringer, CED Service, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, and PsiCro; speaker honoraria from AbbVie, Bristol Myers Squibb, CED Service, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, and Pfizer; and is President of the European Crohn's and Colitis Organisation.
F. Magro has served as a speaker and received honoraria from: AbbVie, Biogen, Falk, Ferring, Hospira, Laboratórios Vitória, Merck Sharp & Dohme, and Vifor.

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

Eosinophilic esophagitis (EoE) is a chronic type 2 inflammatory disease with increasing incidence and prevalence. Patients with EoE usually present with symptoms of dysphagia that impact their quality of life. In the 3-part, Phase 3 LIBERTY EoE TREET study (NCT03633617), dupilumab improved histologic, symptomatic, and endoscopic aspects of EoE up to 52 weeks.

Aims & Methods

The aim of this analysis was to assess the effect of dupilumab on symptoms of dysphagia in the 28-week extended treatment period of LIBERTY EoE TREET in patients who switched from placebo to dupilumab at 24 weeks. In Parts A and B, patients received dupilumab 300 mg or placebo weekly (qw) for 24 weeks. Patients who completed Parts A and B entered Part C - a 28-week extended treatment period in which all patients received dupilumab 300 mg qw; patients entering Part C remained blinded to their treatment in Parts A and B. Dysphagia Symptom Questionnaire (DSQ) score and number of days with dysphagia (assessed using the DSQ) were calculated over a 14-day period. Percent change in DSQ score and in number of days with dysphagia from Week 24 through Week 52 vs the Week 24 baseline were assessed for patients who switched from placebo to dupilumab 300 mg qw at Week 24 and or continued on dupilumab 300 mg.

Results

Mean (SD) DSQ score after 24 weeks of placebo was 24.7 (19.6) and 21.5 (18.4) in Parts A (n=37) and B (n=37), respectively. Significant improvements in DSQ score were observed within 4 weeks of the switch to dupilumab 300 mg qw (mean percent reduction: 31.5% and 29.9%). After 28 weeks (at Week 52), mean percent reduction in DSQ score was 63.6% and 59.7%. After 24 weeks of placebo, mean (SD) days with dysphagia was 6.6 (4.7) and 6.0 (4.7) in Parts A and B, respectively. At Week 52, there was a 63.2% and 46.8% mean reduction in the number of days with dysphagia.

Conclusion

In patients who initially received 24 weeks of placebo, weekly treatment with dupilumab 300 mg resulted in rapid (within 4 weeks) and sustained (up to 28 weeks) improvement in symptoms of dysphagia as assessed by the DSQ score. The magnitude of the improvement in dysphagia observed after switching from placebo to dupilumab was similar to that seen at 4 weeks in patients who originally initiated dupilumab in Parts A and B of the study.

Disclosure

Dellon ES. Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Dr. Falk Pharma, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio – consultant. Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Shire/Takeda – research funding. Allakos, Aqilion, Holoclara, Invea – educational grants.
Chehade M. Adare Pharma Solutions/Ellodi, Allakos, AstraZeneca, BMS, Nexstone Immunology, Phathom, Recludix Pharma, Regeneron Pharmaceuticals Inc., Sanofi, and Shire/Takeda ‒ consultant. Adare Pharma Solutions/Ellodi, Allakos, AstraZeneca, Celgene/BMS, Danone, Regeneron Pharmaceuticals Inc., and Shire/Takeda ‒ research funding.
Bredenoord AJ. Alimentiv, Aqilion, AstraZeneca, Dr. Falk Pharma, Eupraxia, Laborie, Medtronic, Reckitt, Regeneron Pharmaceuticals Inc., and Sanofi ‒ consultant. Dr Falk Pharma, Norgine, Nutricia, Sanofi, SST, Regeneron Pharmaceuticals Inc., and Thelial ‒ research funding. Alimentiv, Aqilion, AstraZeneca, Dr Falk Pharma, Eupraxia, Laborie, Medtronic, Reckitt, Regeneron Pharmaceuticals Inc., and Sanofi ‒ speaker fees.
Spergel JM. Allakos, DBV Technologies, Novartis, Regeneron Pharmaceuticals Inc., and Shire/Takeda – consultant. DBV Technologies and Regeneron Pharmaceuticals Inc. ‒ research grant support.
Xia C, McCann E, Khodzhayev A, Radwan A. Regeneron Pharmaceuticals Inc. – employees and shareholders.
Tilton ST, Pela T, Jacob-Nara JA. Sanofi – employee, may hold stock and/or stock options in the 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

The Epi-IBD cohort is a prospective European population-based cohort of 1,390 patients diagnosed with inflammatory bowel disease (IBD) in 2010 and 2011 according to Copenhagen criteria. Of these, 482 were diagnosed with Crohn’s Disease (CD), 817 with ulcerative colitis (UC) and 91 with IBD unclassified (IBDU). The Epi-IBD cohort was established to examine differences in incidence, treatment strategies, disease course and prognosis among IBD patients in Eastern and Western Europe.

Aims & Methods

This study aims to describe the use of biological therapy as well as the treatment prior to biological therapy. IBD patients were followed prospectively from the time of diagnosis until the 31^st December 2020, death, emigration or loss of follow-up. Clinical data on surgery, hospitalizations, and medical treatment, were captured throughout the follow-up period and entered into a validated web-database, www.epi-ibd.org.

Results

During a median follow-up period of 10.7 (interquartile range (IQR), 10.0-11.4) years, 34% (N=165/482) of CD and 15% (N=122/817) of UC patients were started on biological therapy. Biological therapy was initiated within the first year after diagnosis in 16.8% (N=81/482) of all CD and 3.8% (N=31/817) of all UC patients. In median biological therapy was started at 1.0 year (IQR, 0.3-3.1) and 2.7 years (IQR, 1.6-4.0) after CD and UC diagnosis, respectively. First-line biological therapy was infliximab in 74% (N=213/287) and adalimumab in 22% (N=64/287) of the patients. The remaing (N=10/287) received either Golimumab, Vedolizumab, Ustekinumab or were part of a trial/unknown. The sequences of biological therapies are displayed in Sankey diagrams, Figures 1 and 2. Herein illustrated is that 34% (N=56/165) CD and 34% (N=41/122) UC received at least two different biological drugs. Immunomodulators were initiated simultaneously to the first biological therapy in 19% (N=31/165) of CD patients and in 9% (N=11/122) of UC patients. Overall 63% (N=104/165) CD and 51% (N=62/122) UC patients were receiving concomittant immunomodulators with the first biological therapy.
The sequences of therapy leading up to biological therapy are displayed in Sankey diagrams, Figures 3 and 4. Herein illustrated is that the most common sequence of treatment before the first biological therapy for CD was 1) Steroids, 2) Immunomodulators (21%, N=34/165), and for UC was 1) 5-aminosalicylic-acid (5ASA), 2) Steroids, 3) Immunomodulators (39%, N=48/122). Prior to the first biological therapy one, two and three or more courses of systemic steroid were used in 41%, 28% and 17% (N=67, 47 and 28) of CD patients and 43%, 24% and 26% (N=52, 29 and 32) of UC patients. In 14% (N=23/165) and 7% (N=9/122) of CD and UC patients, systemic steroids were not used prior to first biological therapy. In patients having immunomodulators prior to biological therapy, these were administered for a median of 0.5 (IQR, 0.1-1.9) years and 1.1 (IQR, 0.2-3,2) years in CD and UC, respectively. For 5ASA this was 0.8 (IQR, 0.2-1.5) years for CD and 2.2 (IQR, 0.8-4.3) years for UC.

Conclusion

In this multicenter European population-based cohort, different prescribing patterns for biologics emerge: 34% of CD and 15% of UC patients received biologics within 10 years after diagnosis. Infliximab was the most common first-line biological therapy. Only about half of the patients received concomitant immunomodulators. Prior to the first biological therapy, most patients were exposed to systemic steroids and many to repeated courses.

Introduction

Janus Kinase (JAK) inhibitors are licensed for the treatment of ulcerative colitis with the benefits of a fast onset of action and a short half-life.[i] This makes them a potential treatment option for patients hospitalised with UC, including those previously treated with, or unsuitable for, infliximab or cyclosporine. There is currently limited published evidence in this setting, drawn from small case series.

Aims & Methods

We performed a retrospective analysis of data collected at 14 sites in the United Kingdom, including both tertiary IBD centres (n=10) and general hospitals (n=4) between January 2019 to January 2024. We included patients who were hospitalised due to active UC and commenced a JAK inhibitor for that indication during the same admission. Baseline data included disease duration and extent, prior exposure to advanced therapies, clinical and endoscopic assessments of disease activity and laboratory parameters. We reviewed treatments administered during the same admission, including corticosteroids and advanced therapies.
Coprimary endpoints were colectomy rate at 30 days and 12 months. 12 week, 6 month and 12month persistence data was collected. Adverse outcomes and treatment persistence at the same time points were also recorded.

Results

80 patients (filgotinib (n=15), tofacitinib (n=25) and Upadacitinib (n=40) were included, with a minimum of 12 weeks follow-up. 43/80 (54%) were male, mean age was 37±14, mean admission albumin 35 and CRP 52. Extent of disease was E1 1/80 (1%), E2 31/80 (39%) and E3 48/80 (60%).
63/80 (79%) of patients had prior anti-TNF exposure (infliximab 47/80 (59%), including 13/80 (16%) of whom had received it as a previous rescue therapy). 31/80 (39%) were on prednisolone at admission.
50/80 (63%) had a baseline endoscopic assessment within 72 hours of admission, of which 34/50 (68%) had severe (Mayo 3) endoscopic activity.
During admission, prior to JAK inhibitor administration, treatments given included IV hydrocortisone (93%), methylprednisolone (5%), infliximab (4%) and cyclosporine (1%).
Colectomy rates were 8% and 14% at day 30 and week 12 respectively. In patients for whom 12-month follow-up data were available, 5/34 (15%) had undergone a colectomy at that timepoint.
There was one recorded herpes zoster infection and no recorded thromboses or major adverse cardiovascular events.

Table 1. JAK Inhibitor & Treatment Persistence

JAK Inhibitor	Started during admission (%)	12 week persistence (%)	6 month persistence (%)	12 month persistence (%)
Filgotinib	15/80 (19)	13/15 (87)	9/14 (64)	7/10 (70)
Tofacitinib	25/80 (31)	18/25 (72)	9/25 (36)	8/23 (35)
Upadacitinib	40/80 (50)	32/40 (80)	14/21 (66)	0/1 (0)

Conclusion

JAK inhibitors appear to offer a valuable treatment option for patients hospitalised with active UC. This appears to be the case even in patients with prior anti-TNF exposure. 86% of patients avoided colectomy at 12 weeks, with a similar proportion colectomy-free at 12-months. The risk of adverse events was small. Our study is, to our knowledge, the largest dataset examining the initiation of JAK inhibitors for those hospitalised with UC.

References

[i] Agrawal M, Kim ES, Colombel J-F. JAK inhibitors safety in ulcerative colitis: practical implications. Journal of Crohn's and Colitis. 2020;14(Supplement_2):S755-S60.