Introduction

In the UNIFI study of ustekinumab (UST) for ulcerative colitis (UC), patients (pts) who achieved both histologic and endoscopic improvement of the mucosa (histo-endoscopic mucosal improvement [HEMI]) after induction with UST followed by maintenance had higher rates of clinical remission at 1 year and symptomatic remission at 3 years than those with histologic or endoscopic improvement alone.^1,2 Here we present long-term outcomes for pts who achieved symptomatic remission after induction with intravenous (IV) UST with or without HEMI.

Aims & Methods

In UNIFI, pts were randomised to IV UST (130 mg or ~6 mg/kg/body weight) or placebo (PBO). Patients who were in clinical response 8 weeks (w) following IV induction with UST were randomized to subcutaneous (SC) UST 90 mg q12w or q8w or SC PBO maintenance. At the discretion of the investigator, enrolment in this long-term extension study was optional for pts who completed 44w on maintenance. HEMI was defined as having both histologic improvement (<5% neutrophils in the epithelium, no crypt destruction, and no erosions, ulcerations, or granulations) and endoscopic improvement (Mayo endoscopic subscore of 0 or 1). Symptomatic remission was defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0. Efficacy 8w after IV induction was categorized as 1) disease clearance (achieving both HEMI and symptomatic remission), 2) symptomatic remission without HEMI, or 3) neither symptomatic remission nor HEMI. Time to treatment failure (UC-related surgery or hospitalization, adverse event of UC, or discontinuation of study agent due to an adverse event of worsening UC or lack of efficacy) was compared between cohorts by using a log-rank test.

Results

Eight weeks after IV induction, 79 pts achieved disease clearance, 142 pts achieved symptomatic remission but not HEMI, and 82 pts did not achieve symptomatic remission nor HEMI. Proportions of pts in symptomatic remission were highest for those who were in disease clearance after induction through 200 weeks (~4 years) of UST treatment (Table). The time to treatment failure was longer in pts with disease clearance than pts in symptomatic remission without HEMI (p=0.004), and in pts in symptomatic remission without HEMI than pts with neither symptomatic remission nor HEMI (p=0.043).

Table: Symptomatic remission through 4 years in pts receiving SC maintenance ustekinumab among those with disease clearance, symptomatic remission without HEMI, or neither symptomatic remission nor HEMI 8 weeks after IV ustekinumab induction
	Disease clearance	Symptomatic remission without HEMI	Neither symptomatic remission nor HEMI
Number of pts	79	142	82
Week 44 Symptomatic remission CS-free symptomatic remission	63 (79.7%) 60 (75.9%)	98 (69.0%) 97 (68.3%)	35 (42.7%) 34 (41.5%)
Week 92 Symptomatic remission CS-free Symptomatic remission	63 (79.7%) 60 (75.9%)	100 (70.4%) 98 (69.0%)	41 (50.0%) 39 (47.6%)
Week 152 Symptomatic remission CS-free Symptomatic remission	60 (75.9%) 57 (72.2%)	78 (54.9%) 76 (53.5%)	32 (39.0%) 31 (37.8%)
Week 200 Symptomatic remission CS-free Symptomatic remission	58 (73.4%) 56 (70.9%)	76 (53.5%) 74 (52.1%)	37 (45.1%) 35 (42.7%)
CS=corticosteroid; HEMI=histo-endoscopic mucosal improvement; IV=intravenous; SC=subcutaneous.

Conclusion

Patients with disease clearance 8w after IV induction had greater long-term symptomatic remission outcomes and longer time to treatment failure than those with symptomatic remission without HEMI or those with neither symptomatic remission nor HEMI after induction.

References

1. Li K, et al. Effects of ustekinumab maintenance therapy on endoscopic improvement and histologic improvement in the UNIFI Phase 3 study in ulcerative colitis (Poster 1008). Presented at UEGW 2019, October 22, 2019, Barcelona, Spain
2. Leong R, et al. Long-term outcomes after histologic-endoscopic mucosal healing: results from the UNIFI study in ulcerative colitis. Presented at ECCO/DDW 2022; February 16-19, 2022; Virtual.

Disclosure

Laurent Peyrin-Biroulet has received consulting fees from AbbVie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharma, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech/Roche, Gilead, Gossamer Bio, GlaxoSmithKline, HAC-Pharma, IAG Image Analysis, InDex Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic Therapeutic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus Biosciences, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, and Ysopia; has received grants from Celltrion, Fresenius Kabi, and Takeda; has received an honoraria for lectures from AbbVie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech/Roche, Gilead, Janssen, Lilly, Medac, MSD, Pfizer, Sandoz, Takeda, Tillots, Viatris, and Vifor; and has received support travel fees from AbbVie, Amgen, Celltrion, Connect Biopharma, Ferring, Galapagos, Genentech/Roche, Gilead, Gossamer Bio, Janssen, Lilly, Medac, MSD, Pfizer, Sandoz, Takeda, Thermo Fisher, and Tillots.
Rupert Leong has received grant support from Endochoice, Ferring, GESA, Janssen, NHMRC, and Shire and consulting fees from AbbVie, Aspen, Celgene, Dr Falk Pharma, Ferring, Hospira, Janssen Research & Development, LLC, MSD, Novartis, Pfizer, and Takeda.
Bruce E. Sands has received consultant or speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, Alimentiv, Amgen, Arena, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora (Progenity), Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Connect Biopharma, Cytoki Pharma, Lilly, Entera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead, Genentech/Roche, GlaxoSmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kalyope, 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 Operating Company, Takeda, Target RWE, Theravance, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, and Viela Bio and owns stock options in Ventyx Biosciences
Ye Miao, Colleen Marano are employees of Janssen Research & Development, LLC, a wholly owned subsidiary of Johnson & Johnson, and may own stock in Johnson & Johnson.
Silvio Danese has received consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Lilly, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB Inc., and Vifor and lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda.

Introduction

Risankizumab (RZB) is an interleukin [IL]-23 p19 inhibitor approved for the treatment of Crohn’s disease (CD). In the SEQUENCE head-to-head trial in patients with moderately to severely active CD, RZB was more effective in achieving endoscopic outcomes over ustekinumab (UST; IL-12/IL-23 p40 inhibitor),¹ with higher rates of endoscopic remission, regardless of CD location, observed in post hoc analyses.^2-3 Here, we evaluate the changes from baseline in Simple Endoscopic Score for Crohn’s Disease (SES-CD) total score and SES‑CD components at weeks 24 and 48.

Aims & Methods

SEQUENCE was an open-label, multicenter, randomized, efficacy assessment–blinded study in adults with moderately to severely active CD who had experienced inadequate response to ≥ 1 anti-tumor necrosis factor (TNF) therapy. Patients in the primary efficacy analysis set were randomized 1:1 to receive RZB (intravenous [IV] 600 mg induction dose at weeks 0, 4, and 8, followed by a subcutaneous [SC] 360 mg maintenance dose every 8 weeks starting at week 12) or UST (single weight-based IV induction dose, followed by a SC 90 mg maintenance dose every 8 weeks starting at week 8) up to week 48. A mandatory corticosteroid taper started at week 2. In this post hoc analysis, the mean changes from baseline in total SES-CD score and individual SES-CD components (affected surface, ulcerated surface, size of ulcers, and presence of narrowing) at weeks 24 and 48 were evaluated. Data include patients with nonmissing values at both baseline and the corresponding visit; all P values are nominal.

Results

Of 520 enrolled patients (RZB, 255; UST, 265), evaluable endoscopy data were available at week 24 for 461 patients (RZB, 238; UST, 223) and at week 48 for 379 patients (RZB, 210; UST, 169). Baseline SES-CD scores were generally similar between treatment groups (Table). At week 24, treatment with RZB resulted in greater improvement in total SES‑CD from baseline compared with UST (−6.6 vs −3.9; nominal P < .0001), and similarly, improvements at week 48 were greater with RZB vs UST (−7.3 vs −4.8; nominal P = .0006). Further, numerically greater improvements were observed with RZB vs UST across all individual SES-CD components at weeks 24 and 48, with notable differences between RZB and UST seen in the individual SES-CD components of affected surface, ulcerated surface, and size of ulcers (nominal P < .01).

Table. Total SES-CD and Individual SES-CD Components Over Time
Parameter, mean (SD)	Baselinea		Change From Baseline at Week 24a		Change From Baseline at Week 48b
	RZB (n = 238)	UST (n = 223)	RZB (n = 238)	UST (n = 223)	RZB (n = 210)	UST (n = 169)
Total SES-CD	13.4 (7.1)	13.8 (7.2)	−6.6 (7.4)***	−3.9 (6.4)	−7.3 (7.4)***	−4.8 (6.8)
SES-CD components
Affected surface	4.7 (2.9)	5.0 (3.3)	−2.5 (2.9)***	−1.5 (3.0)	−2.6 (3.0)**	−1.8 (3.1)
Ulcerated surface	3.6 (2.4)	3.7 (2.3)	−1.9 (2.4)***	−1.2 (2.0)	−2.1 (2.4)**	−1.4 (2.2)
Size of ulcers	4.3 (2.5)	4.4 (2.5)	−2.2 (2.7)***	−1.4 (2.2)	−2.5 (2.7)***	−1.7 (2.1)
Presence of narrowing	0.8 (1.3)	0.7 (1.2)	−0.1 (1.3)	0.1 (1.1)	−0.1 (1.2)	0.1 (1.1)
RZB, risankizumab; SES-CD, Simple Endoscopic Score for Crohn’s Disease; UST, ustekinumab. **Nominal P < .01; ***nominal P < .001 vs UST based on Student’s t test. aValues only include patients with nonmissing values at both baseline and week 24. bValues only include patients with nonmissing values at both baseline and week 48. Patients discontinuing the study before week 24 or 48 were not included in the analysis for that respective timepoint.

Conclusion

In this head-to-head study, RZB was more effective than UST in improving endoscopic disease activity per SES-CD scores in patients with CD who had experienced inadequate response to anti-TNF therapy. Differences were observed both at weeks 24 and 48 and were driven by SES-CD components of the size of ulcers, ulcerated surface, and affected surface.

References

1. Peyrin-Biroulet L, et al. United European Gastroenterol J. 2023;11:919−922. Abstract LB01.
2. Peyrin-Biroulet L, et al. J Crohns Colitis. 2024;18:i90−i91. Abstract DOP10.
3. Peyrin-Biroulet L, et al. J Crohns Colitis. 2024;18:i104−i105. Abstract DOP18.

Disclosure

PMI has received speaking fees, research grants, and/or advisory fees from AbbVie, Arena, Boehringer Ingelheim, BMS, Celgene, Celltrion, Dr Falk, Ferring, Galapagos, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Samsung Bioepis, Sandoz, Sapphire, Shire, Takeda, Tillotts, Topivert, VH2, Vifor, and Warner Chilcott.
J-FC has been a consultant or advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Arena, Celgene, Celltrion, Enterome, Ferring, Genentech, Gilead, J&J, Lilly, Medimmune, Merck, Nextbiotix, Novartis, Otsuka, Pfizer, Protagonist, Second Genome, Seres, Shire, Takeda, and Theradiag. He is a speaker for AbbVie, Celgene, Ferring, and Takeda; holds stock options for Intestinal Biotech Development, and GENFIT; and has received research grants from AbbVie, J&J, and Takeda.
GD’H has been an advisor for AbbVie, Ablynx, Active Biotech AB, Agomab, Alimentiv, Allergan, Alphabiomics, Amakem, Amgen, AM, Applied Molecular Therapeutics, Arena, AstraZeneca, Biogen, BMS, Boehringer Ingelheim, Celltrion, DSM, Echo, Engene, Exeliom, Dr Falk, Ferring, Galapagos, Genentech/Roche, Gilead, GSK, Gossamerbio, Immunic, J&J, Kintai, Lilly, Lument, Lycera, Medtronic, MSD, Mitsubishi Tanabe, Novo Nordisk, Otsuka, Pfizer, Photopill, ProciseDx, Prodigest, Progenity, Prometheus laboratories/Nestlé, Protagonist, RedHill, Samsung Bioepis, Sandoz, Seres, Setpoint, Shire, Takeda, Teva, Tillotts, Topivert, Versant, and Vifor.
MF has received research grants from AbbVie, Biogen, EG, Janssen, Pfizer, Takeda, and Viatris; consultancy fees from AbbVie, AgomAb, Boehringer Ingelheim, Celgene, Celltrion, Janssen-Cilag, Lilly, MRM Health, MSD, Pfizer, Takeda, and ThermoFisher; and speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk, Ferring, Janssen-Cilag, MSD, Pfizer, Takeda, Truvion, and Viatris.
FC has received consulting fees from AbbVie, Biogen, BMS, Celgene, Ferring, Galapagos, Gilead, Janssen, Lilly, Lionhealth, MSD, Mundipharma, Pfizer, Roche, and Takeda; lecture fees from AbbVie, Allergy Therapeutics, Biogen, Ferring, Janssen, Pfizer, and Takeda; and unrestricted research grants from AbbVie, Giuliani, MSD, Sofar, and Takeda.
BS has received consulting fees from AbbVie, Abivax, Arena, Boehringer Ingelheim, BMS, Celgene, Dr Falk, Endpoint Health, Galapagos, Gilead, Janssen, Lilly, Pfizer, Prometheus, and Takeda, and speaker’s fees from AbbVie, BMS, CED Service, Dr Falk, Ferring, Galapagos, Janssen, Lilly, Novartis, Pfizer, and Takeda.
SvH, BK, TA, and AG are full-time employees of AbbVie and may own AbbVie stock or stock options.
LP-B has received personal fees from AbbVie, Abivax, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic, Novartis, OM, ONO, OSE Immunotherapeutics, Pandion, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, VectivBio, Ventyx, Viatris, Vifor, and Ysopia.

Introduction

Both vedolizumab and ustekinumab can be considered for the treatment of ulcerative colitis (UC) but head-to-head trials are lacking. We aimed to compare the effectiveness of vedolizumab and ustekinumab after anti-TNF failure in UC patients.

Aims & Methods

All consecutive patients with UC treated with ustekinumab or vedolizumab after being exposed to at least one anti-TNF in 10 French centers between January 2019 and August 2022 were included retrospectively. The primary endpoint was clinical remission (Mayo score partial ≤ 2) without corticosteroid (SFCR) at week 16 (W16). Secondary endpoints were endoscopic remission (SFCR and endoscopic Mayo score ≤ 1 or fecal calprotectin < 150 µg/g), and histological healing (endoscopic remission and histological (Nancy index ≤ 1)). All the comparisons were performed using propensity score analyses (inverse probability of treatment weighting) adjusted for age, gender, smoking status, disease duration and extension, number of prior biologics or prior primary failure to biologics, the co-prescription of 5-ASA, corticosteroids or immunosuppressants, and disease severity.

Results

Among a total of 316 patients included, 165 and 151 received ustekinumab and vedolizumab, respectively. Baseline characteristics (gender, age, disease location, co-prescription of 5-ASA or corticosteroids) were similar between the two groups except for disease duration (ustekinumab, 9.3 vs vedolizumab 7.2 year; p=0.003), co-immunosuppressants (5.4% vs 20.5%, <0.001), and prior exposition to > 2 biologics (46.6% vs 5.9%, p<0.001). At W16, SFCR was respectively 40.3% and by 37.9% in the ustekinumab and vedolizumab groups (aOR = 1.10 [0.39-3.12], p=0.085). SFCR rates were 62.2% vs 53.2% (p=0.52) after one failure, 33.7% vs 44.3% (p=0.52) after two biologics and 19.1% vs 2.6% (p=0.03) after 3 biologics failure, in the ustekinumab and vedolizumab groups, respectively.
Endoscopic remission and histologic healing rates at week 16 were respectively of 17.5% vs 5.3% (aOR = 3.77 [1.25-11.36], p=0.018) and 11.1% vs 2.1% (aOR = 5.85 [1.47-23.30], p=0.012) in the groups ustekinumab and vedolizumab.

Conclusion

While no difference in terms of clinical remission was observed, ustekinumab appears to be more effective than vedolizumab to induce endoscopic and histological remission after failure of anti-TNFs in UC.

Disclosure

AbbVie, Ferring, Janssen, MSD, Takeda, Pfizer, Celgene, Biogen, Amgen, Boehringer Ingelheim, Hospira et Celltrion

Introduction

Pancreatic adenocarcinoma (PDAC) usually presents aspecific symptoms leading to a long diagnostic delay (DD). Furthermore time-to-treatment (TTT) depends on several factors including time for examinations, histological confirmation and/or oncological evaluation.

Aims & Methods

Our aim was to investigate: a)the association between presenting complaints or risk factors and DD; b)correlation between DD and disease stage; c) whether DD and TTT or DD+TTT(overall delay:OD) impact on overall survival (OS); d) whether TTT or OS differs in patients followed at a third-level referral center (3LRC) vs community hospitals (CH).
Single-center prospective cohort of consecutive PDAC patients, recording demographics, presenting complaints, stage, imaging, endoscopic-ultrasound(EUS), cytological diagnosis, first treatment (chemotherapy/surgery), survival. DD was considered time between first symptom onset and first imaging detecting PDAC; TTT from first imaging to first treatment, overall delay (OD) as DD+TTT. Mann-Whitney test was used to compare continuous variables, Kendall tau for correlation analysis, ROC curves for defining cut-offs; survival analysis with Kaplan–Meier method, and results compared by log-rank test. Overall survival(OS) was defined as the time between diagnosis and death.

Results

Two hundred eighty three patients were included, mean age 66, 40 with incidental diagnosis. Patients with jaundice had a significantly shorter median DD (18 days;p=0.003), while pain (69 days; p<0.001), pancreatitis (146 days; p=0,014), new onset diabetes (66 days; p=0,015) had longer median DD. Ever smokers had borderline significantly longer DD (52 days non-smokers; p=0.07). DD correlated with disease stage (Kendall’s tau=-0.167;p<0.0001). OD>92days (HR 1.73;p=0.02), DD>51days (HR 1.73;p=0.007) and TTT>49 days (HR 1.56;p=0.03) were significantly associated with shorter OS at cox regression adjusted for stage and age. Patients entirely cared in 3LRC presented a significantly shorter median TTT (49 vs 56days;p=0.048) compared to CH.

Conclusion

Presenting symptoms influence DD in PDAC patients, which in turn, when >51 days impairs survival. A TTT>49 days and an OD of >3 months also significantly impairs survival. While DD might be reduced with higher awareness for specific warning symptoms (especially in idiopathic pancreatitis), TTT might be reduced optimizing waiting time to EUS and/or first oncological evaluation through dedicated pathways for PDAC patients.

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

Thiopurines (TP) (azathioprine AZA, and 6 mercaptopurine 6MP) are immunosuppressive drugs (IS) used in the treatment of chronic inflammatory bowel diseases (IBD), particularly Crohn's disease (CD). The aim of our work is to see if they still have an indication in monotherapy, in the era of biotherapies and small molecules.

Aims & Methods

This is a retrospective analytical study conducted at the Hepato-Gastroenterology and Proctology Department "Medicine B" from January 2012 to July 2022. 740 patients were followed for CD during this period. 407 patients were put on TP. Age, sex, different characteristics of CD, indication for and type of TP treatment, and course of treatment were collected from all patients. SPSS 20.0 software was used for statistical analysis. The khi-2 test was used to compare categorical variables. The binary logistic regression model was used for multivariate analysis.

Results

There were 375 patients followed up for CD on TP monotherapy (92.13%) and 32 on combination therapy (7.86%). The sex ratio was F/H=1.5. The average age was 39.8 years (15-72). The location was ileal in 69 patients (16.95%), colonic in 78 patients (19.16%), ileocolic in 257 patients (63.14%), 6 patients (1.47%) had upper gastrointestinal tract involvement of CD and 3 patients (0.73%) had anal CD. 99 patients (24.32%) had ano-perineal lesions (APL). The phenotype was stenosing in 47 cases (11.54%), fistulizing in 159 cases (39%), stenosing and fistulizing in 60 cases (14.74%) and inflammatory in 141 cases (34.64%). The type of TP used was AZA in 299 patients (73.46%) and 6MP in 108 patients (26.53%). TP was indicated as maintenance treatment in 270 cases (66.33%), as monotherapy in the absence of biotherapy (which was not available before 2016) in fistulizing forms in 105 cases (25.8%), and in case of cortico-dependency in 32 cases (7.86%).
Clinical remission was obtained with monotherapy in 326 cases (86.93%) and with combotherapy in 24 cases (75%), this difference is statistically non-significant p=0.08. Mucosal healing was noted with monotherapy in 124 cases (33%) in patients who performed a control endoscopy, and with combotherapy in 15 cases (46.87%), this difference is statistically not significant p=0.07.
CRP was negatived in monotherapy in 149 patients (39.73%) and in combination therapy in 27 patients (84.37%), this difference is statistically significant p<0.001. Fecal calprotectin was not always available. Among the patients who had it performed (65: 15.97%), it was negative in 18 cases (41.86%) in monotherapy and 3 cases (13.63%) in combination therapy. This difference is statistically significant p=0.015. Metabolite dosing was also rarely available. In cases where this was done (43 cases: 10.56%), 6-TGN was in the therapeutic range only in 14 cases (32.55%) and in 36 cases (83.72%) for 6-MMP, requiring therapeutic adjustment.
In multivariate analysis and adjusting for the different confounding parameters, it was found that only the combination therapy was a predictive factor for mucosal healing [OR=1.8; [0.8 - 3.9]; p=0.01].

Conclusion

The results of this study show that TPs still have a place in the therapeutic arsenal of CD, but that their combination with biotherapy allows more clinical and biological remission and especially mucosal healing.