Introduction

The efficacy and safety of upadacitinib (UPA), an oral, reversible Janus kinase (JAK) inhibitor approved for the treatment of moderately to severely active Crohn’s disease (CD),^1.2 has been demonstrated in two phase 3 induction studies (U-EXCEL, NCT03345849³; U-EXCEED, NCT03345836⁴) and a phase 3 maintenance study (U-ENDURE, NCT03345823⁵). An association between shorter disease duration and improved outcomes has been shown in post hoc analyses of clinical trial data with other advanced CD therapies.^6,7 We therefore conducted a post hoc analysis of data from these phase 3 UPA studies to assess the potential impact of CD duration on UPA efficacy.

Aims & Methods

Patients in the induction studies were randomized 2:1 to receive UPA 45 mg (UPA45) or placebo (PBO) once daily for 12 weeks.^2,3 Patients achieving clinical response per stool frequency and/or abdominal pain score (SF/APS) criteria were re-randomized 1:1:1 in the maintenance study to UPA 30 mg (UPA30), UPA 15 mg (UPA15), or PBO once-daily for 52 weeks.⁴ Efficacy was evaluated in patient subgroups stratified by CD duration at baseline (< 2 years, 2–5 years, >5–10 years, and >10 years). Endpoints evaluated at week 12 (induction) and week 52 (maintenance) included achievement of clinical remission (per average daily very soft/liquid SF/APS and per Crohn’s Disease Activity Index [CDAI]), normalization of fecal calprotectin and high-sensitivity C-reactive protein levels for patients with elevated baseline levels, endoscopic response, endoscopic remission, and mucosal healing.

Results

Baseline patient and disease characteristics were generally similar across CD duration subgroups during induction (N = 1021). UPA45 demonstrated nominally greater improvement vs PBO in efficacy endpoints across most CD duration subgroups at week 12 (Table). UPA45-treated patients with a shorter disease duration had numerically greater endoscopic improvement vs patients with longer disease duration, and nominally greater endoscopic improvement vs patients receiving PBO at week 12 (Table). Further, the clinical remission rate per CDAI at week 12 was numerically higher with UPA45 vs PBO in patients with CD duration < 2 years, and was nominally higher vs PBO in other CD duration subgroups (Table). Consistent with induction outcomes, UPA30 and UPA15 demonstrated nominally or numerically greater improvement in efficacy endpoints vs PBO regardless of disease duration at week 52 (Table); there was also a general trend towards greater improvements in efficacy outcomes in patients with a shorter disease duration.
​Table. Efficacy Outcomes by Baseline CD Duration During Induction and Maintenance Studies

Conclusion

Regardless of disease duration, UPA demonstrated positive clinical and endoscopic outcomes in patients with moderately to severely active CD. Achievement of endoscopic endpoints was numerically higher in patients with shorter vs longer duration of CD, suggesting initiation of UPA earlier in the disease course may lead to better outcomes for patients.

References

1. RINVOQ. Summary of Product Characteristics. AbbVie Deutschland GmbH & Co. KG; 2023. Accessed 24 April 2023. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf
2. RINVOQ. Summary of Product Characteristics. AbbVie Inc.; 2023. Accessed 27 March 2023. https://www.medicines.org.uk/emc/product/12830/smpc.
3. Loftus E, et al. United European Gastroenterol J. 2022;10(S8):103.
4. Colombel J-F, et al. Gastroenterology. 2022;162(7):S-1394.
5. Panés J, et al. Am J Gastroenterol. 2022;117:S10.
6. Faleck DM, et al. Clin Gastroenterol Hepatol. 2019;17(12):2497–2505.
7. Peyrin-Biroulet L, et al. J Crohn's Colitis. 2022;16(Suppl 1):i045–i048.

Disclosure

RCU has served as an advisory board member or consultant for AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, and Takeda; received research support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, and Pfizer; and is funded by a National Institutes of Health (NIH) K23 Career Development Award K23KD111995-01A1.
LP-B has received personal fees from AbbVie, Allergan, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Enterome, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Hikma, InDex Pharmaceuticals, Inotrem, Janssen, Lilly, MSD, Mylan, Nestle, Norgine, Oppilan Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer, Pharmacosmos, Roche, Samsung Bioepis, Sandoz, Sterna, Sublimity Therapeutics, Takeda, Theravance, Tillots, and Vifor; research grants from AbbVie, Fresenius Kabi, MSD, and Takeda; and stock options from CTMA.
JFC has received research grants from AbbVie, Janssen, and Takeda; payment for lectures from AbbVie, Amgen, Ferring, Shire, and Takeda; consulting fees from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enterome, Ferring, Genentech, Janssen, Medimmune, Merck, Novartis, Pfizer, Protagonist Therapeutics, Sandoz, Second Genome, Seres Therapeutics, Shire, Takeda, Theradiag, and Theravance; and holds stock options in Genfit and Intestinal Biotech Development.
EJL has received research grants from Janssen, Pfizer, and Takeda; educational grants from AbbVie, Janssen, MSD, and Takeda; speaker fees from AbbVie, Falk, Ferring, Hospira, Janssen, MSD, Pfizer, and Takeda; served on advisory boards for AbbVie, Arena, Celgene, Ferring, Galapagos, Gilead, Hospira, Janssen, MSD, Pfizer, and Takeda; and served as a consultant for AbbVie.
MF has received financial support for research from AbbVie, Amgen, Biogen, EG, Janssen, Pfizer, Takeda and Viatris; consultancy fees from AbbVie, Agomab Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, Medtronic, MSD, Pfizer, Regeneron, Samsung Bioepis, Sandoz, Takeda, and Thermo Fisher Scientific; and speaker fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Falk, Ferring, Janssen-Cilag, Lamepro, MSD, Pfizer, Sandoz, Takeda, Truvion Healthcare and Viatris.
TM has received grants and honoraria from EA Pharma, AbbVie, Pfizer, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Nippon Kayaku Co., and Zeria Pharmaceutical Co; honoraria from Kyorin Pharmaceutical Co., JIMRO Co., Nichi-lko Pharmaceutical Co., and Takeda; and grants from Daiichi-Sankyo.
CD, APL, VPR, ED, SIA, and AG are employees or contractors of AbbVie, and may own AbbVie stock and/or stock options.
RP has received consultancy and/or speaking honoraria from Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB.
Funding
AbbVie Inc. 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 Tracy Wetter, PhD, and Akua Adu-Boahene, MD, MPH, of JB Ashtin, and funded by AbbVie.

Introduction

Recently, artificial intelligence-based computer-aided detection (CADe) for colonoscopy is garnering significant attention due to its effectiveness in increasing adenoma detection rate (ADR). However, theoretically, CADe system cannot decrease exposure error which polyps obscured by an object. In this regard, computer-aided quality improvement (CAQ) which expects to induce the meticulous mucosal inspection and leading to a reduction of blind spot area. In this study, we developed and evaluated CAQ for colonoscopy.

Aims & Methods

This was a single center, retrospective study from period April 1, 2022 to February 25, 2023. We randomly extracted colonoscopy videos and created 18,922 training images. Quadrant images were made from one image and three endoscopists annotated the following scores; i) appropriateness for mucosal inspection, ii) appropriate distance, and iii) presence of blind area in the field of view (e.g., fold or flexure). We conducted supervised machine learning using annotated images. The CAQ deployed multi-head deep convolutional neural network model which can output multiclass prediction from one image. Consequently, the CAQ system outputs aforementioned score from whole colonoscopy video. To validate its performance, we retrospectively analyzed colonoscopy procedures performed by seven endoscopists using the CAQ. We compared calculated CAQ model scores and expertise of endoscopists.

Results

29 videos were included as validation samples (8 videos were performed by non-expert endoscopists) As a result, there was a significant difference in the proportion of appropriate images during the examination between experts and non-experts (median 56% vs. 49%, p=0.005, Mann–Whitney U test) and there was also a significant difference in the evaluation score of the distance between the colon mucosa and the endoscope (median 4.2 vs. 3.2, p=0.0004, Mann–Whitney U test). In addition, there was a significant difference in the scores evaluating the presence of blind areas in the field of view (median 1.6 vs. 1.2, p=0.0007, Mann-Whitney U test).

Conclusion

In this study, developed CAQ system could quantify the skill of the endoscopists. Such CAQ would be expected to standardize the observation technique of colonoscopy.

Introduction

Upadacitinib (UPA) is an oral Janus kinase inhibitor approved for treating moderately to severely active Crohn’s disease (CD).^1-3 Sustained efficacy and safety were reported after 2 years (yrs) of UPA therapy in the U-ENDURE maintenance and long-term extension (LTE) studies.⁴ Here, we evaluated the long-term efficacy and safety of up to 3 yrs of total UPA maintenance therapy in patients with moderately to severely active CD in the ongoing U-ENDURE LTE study.

Aims & Methods

Patients who completed the U-ENDURE 52-week (wk) maintenance study were eligible for the subsequent LTE study and continued their previously assigned treatment (UPA 15 mg [UPA15] once-daily [QD] or UPA 30 mg [UPA30] QD). This analysis included all patients who completed 52 wks of maintenance treatment followed by an additional 96 wks in the LTE study (total of 3 yrs of maintenance therapy), with efficacy assessed from LTE wk 0 to wk 96. Inadequate responders were eligible to receive rescue therapy (open-label UPA30 or protocol-approved CD-related medications); patients who received rescue therapy were analysed separately. Clinical and endoscopic endpoints were evaluated using both as-observed (AO) (in text and Table) and nonresponder imputation (NRI) methods (Table); mean change from baseline of induction in high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP) were evaluated using AO analysis (in text). Safety was assessed from maintenance wk 0, with up to 292 wks of cumulative maintenance and LTE treatment exposure (cut-off date: 19 Nov 2024).

Results

Baseline (wk 0 of induction) demographics and clinical characteristics were generally well-balanced among UPA15- or UPA30-treated patients enrolled in the LTE. From LTE wk 0 to wk 96, AO efficacy rates remained stable in each treatment group for clinical remission per stool frequency (SF)/abdominal pain score (APS) (UPA15: 78.3% to 83.1%; UPA30: 84.7% to 84.3%; Table) or Crohn’s Disease Activity Index (CDAI) (UPA15: 81.3% to 83.1%; UPA30: 86.1% to 88.6%; Table); similar results were observed in corticosteroid-free clinical remission. From LTE wk 0 to wk 96, efficacy rates remained stable for endoscopic response (UPA15: 59.6% to 70.8%; UPA30: 71.2% to 70.1%; Table), and endoscopic remission (UPA15: 42.4% to 50.8%; UPA30: 53.0% to 56.7%; Table). Clinical or endoscopic remission was sustained through LTE wk 96. Mean change from induction baseline was stable from LTE wk 0 through wk 96 for inflammatory markers, hs-CRP (UPA15: -12.4, -12.0; UPA30: -12.7, -10.1) and FCP (UPA15: -2752, -3263; UPA30: -1850, -2055) (AO). Across efficacy endpoints, similar results were found per NRI. No new safety signals were identified in this safety analysis among UPA15- or UPA30-treated patients.⁴ The safety profile was consistent with the known safety profile of UPA in CD.^1
​

Conclusion

Sustained efficacy for clinical, endoscopic, and inflammatory markers was observed in patients who completed up to 3 yrs of UPA maintenance therapy, with no new safety signals identified.¹

References

1. Loftus EV, Jr. and Panés J et al. N Engl J Med. 2023;88:1966-80.
2. AbbVie Inc. RINVOQ (Upadacitinib) [package insert] U.S. Food and Drug Administration website. https://www.rxabbvie.com/pdf/rinvoq_pi.pdf. Revised May 2023.
3. AbbVie DG& CoK. RINVOQ. (Upadacitinib) [package insert] Summary of Product Characteristics. European Medicine Agency website. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf. Revised Feb 2025.
4. G D'Haens, et al. J Crohn's Colitis. (Abstract). 2024;18:i17–i18.

Disclosure

Edward V. Loftus Jr. has served as a consultant for AbbVie, Abivax Astellas, Avalo, Biocon, Bristol Myers Squibb, Celltrion, Eli Lilly, Fresenius Kabi, Genentech, Gilead, Iota Biosciences, Iterative Health, Janssen, Merck, Morphic Therapeutics, Ono Pharma, Takeda, and TR1X Bio; has received research grants from AbbVie, Genentech, Gilead, Janssen, Merck, and Takeda; and is a shareowner of Exact Sciences and Moderna.
Geert D’Haens has served as advisor and/or speaker for AbbVie, Abivax, Agomab, Akros, Alimentiv, Anaptys Bio, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Galapagos, Glaxo Smith Kline, Index Pharmaceuticals, Johnson and Johnson, Merck, Polpharm, Prometheus Biosciences, Sanofi, Spyre, Takeda, and Tillotts.
Edouard Louis has received research grants from Janssen, Pfizer, and Takeda; received educational grants from AbbVie, Janssen, MSD, and Takeda; received speaker fees from AbbVie, Falk, Ferring, Hospira, Janssen, MSD, Pfizer, and Takeda; served on advisory boards for AbbVie, Arena, Celgene, Ferring, Galapagos, Gilead, Hospira, Janssen, MSD, Pfizer, and Takeda; and served as a consultant for AbbVie.
Miguel Regueiro has served as a consultant, speaker, and is an advisory board member for AbbVie.
Vipul Jairath has received consulting/advisory board fees from AbbVie, Alimentiv, Arena, 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, Scope Eyecare, Second Genome, Sorriso, Takeda, TD Securities, Teva, TopiVert, Ventyx, Vividion; received speaker’s fees from AbbVie, Ferring, Bristol Myers Squibb, Galapagos, Janssen, Pfizer, Takeda, and Fresenius Kabi.
Fernando Magro has been a speaker and has received honoraria for services from AbbVie, Biogen, Falk, Ferring, Hospira, Laboratorios Vitoria, Merck, and Vifor.
Hiroshi Nakase reports receiving personal fees from AbbVie, Kissei Pharmaceutical, KYORIN Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Janssen Pharmaceutical K.K., Takeda, Pfizer Japan, EA Pharma, Zeria Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Daiichi Sankyo, Gilead, Viatris, JIMRO, and grants for commissioned/joint research from Hoya Group Pentax Medical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, AbbVie.
Elena Dubcenco, Irina Fish, Kimmie Kim,Yibo Wang,Samuel I. Anyanwu, Fernando Aponte, and Sina Ogholikhan are employees of AbbVie and may own stock options.
Irina Blumenstein has received consultant honoraria from AbbVie Deutschland, Amgen GmbH, Bristol Myers Squibb, Janssen-Cilag GmbH, Fresenius Kabi Deutschland, Pharmacosmos GmbH, Pfizer GmbH, Shire Deutschland GmbH, Takeda Pharma GmbH; honoraria from AbbVie Deutschland, Biogen GmbH, DGVS, Dr. Falk Pharma GmbH, EndoAkademie, Ferring Arzneimittel, Fraunhofer, Fresenius Kabi Deutschland, Kompetenznetz Darmerkrankungen, MSD Sharp Dohme, Mylan GmbH, Pfizer GmbH, Janssen-Cilag GmbH, Shire Deutschland GmbH, Takeda Pharma GmbH.
Funding: AbbVie funded this study (U-ENDURE; NCT03345823) and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.
Acknowledgements: AbbVie and the authors thank the participants, study sites, and investigators who participated in this clinical trial. Paulette A. Krishack, PhD, of AbbVie, provided medical writing support, and S. Michael Austin, of AbbVie, provided editorial support.

Introduction

Ulcerative colitis (UC) is an inflammatory disorder of the colon of unknown aetiology characterised by intestinal barrier dysfunction associated with colonic epithelial goblet cell depletion and a shift in intestinal stem cell retention and function^1,2. Pancreastatin (PST), an intestinal epithelial cells-derived peptide highly expressed in colonic tissues of patients with active UC, positively correlates with UC early onset, disease severity, and inflammatory markers³. However, the effect of PST inhibition on colonic epithelial barrier function remains undetermined.

Aims & Methods

This study aimed to investigate the impact of pancreastatin inhibitor 8 (PSTI8) on colonic epithelial barrier function in a preclinical mouse model of UC. Male and female C57BL/6 mice were treated intrarectally with PSTi8 (2.5mg/mL/kg) or PBS for six days and received 5% dextran sulfate sodium (DSS) to induce colitis or water (control) for five days. The disease activity index (DAI) was assessed daily. ELISA quantified inflammatory cytokines, interleukin (IL)-6, IL-18 and IL-22. Markers to characterise differentiated goblet cells (Mucin, MUC2), transcription factors for goblets’ lineage commitment (growth factor independent, GFI1 and Kruppel-like factor, KLF1), and colonic stem cells plasticity (fast-cycling Lgr5, fetal-like Ly6a, and reserve Hopx cells) were quantified via RT-PCR and immunofluorescence.

Results

PSTi8 treatment increased stool consistency (p<0.01) and delayed the onset of bleeding in colitic male mice compared to PBS-treated mice (2-4 days). Conversely, no differences in the DAI were noted between colitic PSTi8 and PBS-treated female mice. In non-colitic conditions, PSTi8 treatment increased (p<0.03) IL-22 in males and decreased (p<0.01) its level in female mice with no effect of IL-6. In colitic conditions, although IL-22 levels were decreased (p<0.01) in female mice and IL-6 levels were increased (p<0.001) in male mice, PSTi8 treatment did not show any effect. Conversely, in colitic females, IL-18 was significantly increased (p<0.02), and PSTi8 abolished that increase. The mRNA expression level of MUC2 remains unaltered in male and female non-colitic and colitic mice treated or not with PSTi8. Yet, immunofluorescence staining in non-colitic and colitic conditions demonstrated a decrease of MUC2 in PSTi8-treated female mice. In concordance, transcription factors KLF1 and GFI1 were significantly increased (p<0.001 and p<0.02, respectively) in colitic female mice, and PSTi8 treatment abolished that increase. No differences were seen in male mice except for a significant increase of KLF1 in PSTi8-treated colitic mice. In colitic conditions, fast-cycling cells marker Lgr5 expression in both sexes was significantly decreased (p<0.0001), and treatment with PSTi8 did not show any effect. However, in colitic male mice, fetal-like stem cells makers Ly6a expression was significantly increased (p<0.007), and PSTi8 treatment significantly decreased (p<0.02) that expression. Although a significant decrease (p<0.0001) of reserve cells marker Hopx was only seen in colitic female mice, PSTi8 treatment did not regulate that marker in male and female mice.

Conclusion

PST inhibition protects male mice from DSS-mediated colitis while exacerbating susceptibility to colitis in female mice. PST inhibition regulates the expansion of goblet and intestinal stem cells in a sex-dependent manner. Further investigation is needed to delineate the signalling pathways involved in PST action on the mucosa in both sexes. Targeting PST may lead to novel therapeutic strategies in UC.

References

1. Singh V, Johnson K, Yin J, et al. Chronic Inflammation in Ulcerative Colitis Causes Long-Term Changes in Goblet Cell Function. Cmgh. 2022;13(1):219-232.
2. Yui S, Azzolin L, Maimets M, et al. YAP/TAZ-dependent reprogramming of colonic epithelium links ECM remodeling to tissue regeneration. Cell Stem Cell. 2018;22(1):35-49.e7.
3. Eissa N, Elgazzar O, Hussein H, Hendy GN, Bernstein CN, Ghia JE. Pancreastatin reduces alternatively activated macrophages, disrupts the epithelial homeostasis and aggravates colonic inflammation. A descriptive analysis. Biomedicines. 2021;9(2):1-18.