Introduction

Patient-derived organoids represent a valuable tool to unravel disease- and patient-specific mechanisms in inflammatory bowel diseases (IBD). We previously showed that organoids from patients with ulcerative colitis (UC) lose their acute inflammatory phenotype, and consequently established an inflammatory mix to re-induce inflammation in undifferentiated intestinal organoids¹. However, inducing solely inflammation might not be sufficient to study IBD-specific pathways as, for example, endoplasmic reticulum (ER) stress has been shown a role in the pathogenesis of IBD, and targeting the ER protein folding homeostasis of epithelial cells could be a new treatment target².

Aims & Methods

To effectively use organoids as a pre-clinical model for IBD, there is a critical need to 1) enable prolonged exposure to preclinical compounds, in an inflammatory setting, to decipher their mechanism of action and 2) establish different disease phenotypes to study disease mechanisms. To this aim, we optimized two mixes tailored to induce either an inflammatory (INF) or ER stress-driven inflammatory phenotype in differentiated intestinal organoids. Intestinal organoid cultures, isolated from endoscopy-derived non-inflamed colonic biopsies of nine patients with UC were expanded, mechanically dissociated, followed by culturing in an human expansion media¹ for two days. Next, the cultures were subjected to a differentiation media (human expansion media without the addition of WNT3a, nicotinamide and SB202190) for four consecutive days. On day six, organoids were exposed to either the differention media only, an INF mix (50 ng/ml TNF-α, 20 ng/ml IL-1β, 1 µg/ml Flagellin) or an ER stress mix (10 ng/ml TNFα, 20 ng/ml IL-1β, 1 µg/ml Flagellin, Tunicamycin 25ng/ml) for 48 hours in differentiation media. RNA was extracted and sequenced by Illumina Truseq mRNA (HiSeq4000). Differential gene expression and pathways were studied through DESeq2 and Ingenuity Pathway Analysis (|log2FC| >2, FDR <0.05).

Results

Transcriptomic analysis demonstrated a clear separation on principal component analysis of the untreated control and INF and ER mix exposure upon 48 hours of exposure. The INF mix exposure resulted in the upregulation of 324 and the downregulation of 148 genes compared to the untreated control, while the ER mix exposure resulted in 368 and 138 genes being up- and downregulated respectively compared to the untreated control. Inflammatory markers (CXCL1, CXCL2, CXCL11, IL1β, IL8) were significantly upregulated following exposure to both the INF mix and the ER stress mix. However, only organoids challenged with the ER stress mix showed a strong upregulation of ER stress markers (PDIA4 HSP90B1, HSPA5, DDIT3, all within |log2FC|>2). Ingenuity Pathways Analysis (IPA) of the contrast of the ER stress mix versus the INF mix highlighted the upregulation of ER stress-related pathways including ATF6 (ATF6-alpha) activates chaperone genes and ATF4 activates genes in response to endoplasmic reticulum stress.

Conclusion

Exposure of UC patient-derived differentiated colonic organoids for 48 hours to either the INF mix or ER stress mix significantly upregulated INF markers, while ER stress markers only resulted in being significantly upregulated after exposure to the ER stress mix. IPA confirmed that the dysregulated genes were part of ER stress-related pathways. These results will facilitate the use of organoids to mimic an INF or ER stress phenotype and will promote their use to study pre-clinical compounds for prolonged exposures (48 hours) in a disease-representative IBD model.

References

1. Arnauts et al., Gastroenterology, 2020
2. Cao et al., Inflammatory Bowel Diseases, 2016

Disclosure

LG and KA report no conflict of interest.
JS reports financial support for research from Galapagos and Viatris; receives speakers’ fees from Abbvie, Falk, Takeda, Pfizer, Galapagos, Ferring, Janssen, and Fresenius; and does consultancy for Janssen, Ferring, Fresenius, Abbvie, Galapagos, Celltrion, Pharmacosmos, and Pharmanovia.
MF reports financial support for research from AbbVie, Amgen, Biogen, EG, Janssen, Pfizer, Takeda, and Viatris; receive speakers’ fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Falk, Ferring, Janssen-Cilag, Lamepro, MSD, Mylan, Pfizer, Samsung Bioepis, Sandoz, Takeda, and Truvion Healthcare; and does consultancy for AbbVie, Agomab Therapeutics, Boehringer Ingelheim, Celltrion, Eli Lilly, Janssen-Cilag, Medtronic, MRM Health, MSD, Pfizer, Regeneron, Samsung Bioepis, Sandoz, Takeda, and Thermo Fisher
SV reports speaker and/or consultancy fees from AbbVie, Abivax, AbolerIS Pharma, AgomAb Therapeutics, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Biora Therapeutics (formerly Progenity), Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, Gilead Sciences, GSK, Hospira, IMIDomics, Janssen Pharmaceuticals, Johnson & Johnson, Lilly, Materia Prima, Mestag Therapeutics, MiroBio, Morphic Therapeutic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Prometheus Biosciences, Robarts Clinical Trials, Surrozen, Takeda, Theravance Biopharma, Tillotts Pharma, VectivBio, Ventyx Biosciences and Zealand Pharma; grants from AbbVie, Galapagos, Johnson & Johnson, Pfizer and Takeda; and participation on a data safety monitoring board for Sanofi.
BV reports research support from AbbVie, Biora Therapeutics (formerly Progenity), Landos Biopharma, Pfizer, Sosei Heptares and Takeda; speaker fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring Pharmaceuticals, Galapagos, Janssen Pharmaceuticals, Lily, MSD, Pfizer, R-Biopharm, Sandoz, Takeda, Tillots Pharma, Truvion Healthcare and Viatris; consultancy fees from Abbvie, Alfasigma, Alimentiv, Applied Strategic, AstraZeneca, Atheneum, BenevolentAI, Biora Therapeutics (formerly Progenity), Boxer Capital, Bristol Myers Squibb, Galapagos, Guidepont, Landos, Lily, Mylan, Inotrem, Ipsos, Janssen Pharmaceuticals, Pfizer, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris; and stock options from Vagustim.
This study was funded by Landos Biopharma

Introduction

The recently developed Ulcerative Colitis Severity Index (UCSI) has been previously reported to be more accurate than the Mayo Clinic score to predict 1‑year endoscopic improvement (EI) at baseline (defined as a Mayo endoscopic score ≤1) for patients with moderate-to-severe ulcerative colitis (UC), using data from the UNIFI ustekinumab phase 3 clinical trial.¹ Validation of the UCSI with additional therapies is needed to elucidate the potential of the UCSI to improve UC treatment by predicting long-term outcomes.

Aims & Methods

To further evaluate the utility of the UCSI as a predictive tool to determine EI, this study reports the predictive value of the UCSI using upadacitinib (UPA) phase 3 trial data in patients with moderate-to-severe UC (ClinicalTrials.gov identifier: NCT02819635).² This post-hoc analysis assessed the intention-to-treat population receiving UPA 45 mg once daily 8‑week induction treatment and randomized to UPA 30 mg or UPA 15 mg in maintenance (n=444). Baseline UCSI scores for 409 participants (35 were missing data) were calculated as the sum of 6 subscores derived from prior biologic failure, albumin <40 g/L, C-reactive protein >5 mg/L, endoscopic erosions/ulcerations, histology structural/architectural changes, and Mayo stool frequency scores. Receiver Operating Characteristic (ROC) analysis was conducted for all specified efficacy endpoints. Area under the curve (AUC) and 95% confidence interval were calculated for 7 endpoints, including 1-year EI predicted by baseline UCSI and Mayo Clinic score. A nonparametric approach was used to compare AUC between UCSI and Mayo Clinic score, and to calculate p-values. The UCSI cut-off to predict 1-year EI was determined using the Youden index (defined as Youden = Sensitivity + Specificity – 1), which is the maximum potential effectiveness of a diagnostic or predictive test that maximizes the distance between the chance diagonal line and the point (x,y) on the ROC curve, a point farthest from random.

Results

In AUC‑ROC analyses of the UCSI and Mayo Clinic score to predict 1-year efficacy outcomes, the UCSI and Mayo Clinic score were similar (p-values ranging from 0.36 to 0.84). Both were considered poor with AUC‑ROC ranging from 0.51 to 0.57. A cut-off point of 13 for UCSI based on the Youden index yielded low prediction capabilities. A cut-off of 10 was found in the initial derivation paper to dichotomize the likelihood of EI (‘Low’ as UCSI score ≥10, ‘High’ as UCSI <10).¹ Using this cutpoint, there was again no difference in rates of EI (56.4% vs 50.2%, respectively) (Table).

Table. Accuracy of the UCSI for Prediction of 1-year Endoscopic Improvement (MES ≤1) in the ITT* Population, Based on a Threshold Score of 10
CI, confidence interval; EI, endoscopic improvement; ITT, intention-to-treat; MES, Mayo Endoscopic Score; OD, once daily; UCSI, Ulcerative Colitis Severity Index; UPA, upadacitinib. *The ITT population (UPA 45 mg OD group) comprises participants who received UPA 45 mg OD 8-week induction treatment and who were enrolled under the protocol for the 52-week maintenance treatment period in Cohort 1 and randomized to UPA 30 mg or 15 mg OD.
Likelihood of endoscopic improvement	Number of participants achieving EI out of total (%)	Sensitivity (95% CI)	Specificity (95% CI)	Positive predictive value (95% CI)	Negative predictive value (95% CI)	Positive likelihood ratio (95% CI)	Negative likelihood ratio (95% CI)​
Low (UCSI score ≥10)	120/239 (50.2)	44 (37.8-51.1)	62 (54.8-68.5)	56.5 (49.0-63.9)	49.8 (43.5-56.1)	1.16 (0.9-1.5)	0.90 (0.8-1.1)
High (UCSI score <10)	96/170 (56.4)

Conclusion

The UCSI did not predict endoscopic outcomes when tested with this phase 3 dataset for UPA in UC, with UPA achieving EI regardless of the likelihood of achieving this outcome at 1 year, based on the UCSI threshold of 10. Further analysis with other datasets is needed to explore the predictive value of the UCSI for other therapies. The re-randomization study design might have affected the predictive value of the UCSI, and further analyses on treat-through studies are needed.

References

¹Wong CL, Dulai PS, Marshall JK, et al. Predicting endoscopic improvement in ulcerative colitis using the Ulcerative Colitis Severity Index. Inflamm Bowel Dis. 2024;30:370-381. Doi:10.1093/ibd/izad074; ²Vermeire S, Danese S, Zhou W, et al. Efficacy and safety of upadacitinib maintenance therapy for moderately to severely active ulcerative colitis in patients responding to 8 week induction therapy (U-ACHIEVE Maintenance): overall results from the randomised, placebo-controlled, double-blind, phase 3 maintenance study. Lancet Gastroenterol Hepatol. 2023;8:976-989. Doi: 10.1016/S2468-1253(23)00208-X

Disclosure

NN has received honoraria from Janssen, AbbVie, Takeda, Pfizer, Merck, Sandoz, Novartis, and Ferring. ECLW reports no conflicts of interest. PSD has received consulting and/or research support from Takeda, Pfizer, Janssen, BMS, Gilead, Novartis, and Lily; owns stock options in DigbiHealth; and has received royalties from PreciDiag. JKM has received honoraria from Janssen, AbbVie, Allergan, Bristol Myers Squibb, Ferring, Janssen, Lilly, Lupin, Merck, Pfizer, Pharmascience, Roche, Shire, Takeda, and Teva. VJ has received consulting/advisory board fees from AbbVie, Alimentiv Inc, 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, SCOPE, Second Genome, Sorriso, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion; and has received speaker’s fees from AbbVie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, and Fresenius Kabi. WR has served as a speaker for Abbott Laboratories, AbbVie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, and Yakult; served as a consultant for Abbott Laboratories, AbbVie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, AstraZeneca, Avaxia, Roland Berger GmBH, Bioclinica, Biogen IDEC, Boehringer Ingelheim, Bristol Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernst & Young, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millennium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, SetPoint Medical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, Tigenix, UCB, Vifor, Zealand, Zyngenia, and 4SC; and served as on the advisory board for Abbott Laboratories, AbbVie, Aesca, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Biogen IDEC, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestlé, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, SetPoint Medical, Takeda, Therakos, Tigenix, UCB, Zealand, Zyngenia, and 4SC. EC, CHC, and XP are employees of AbbVie Corporation.

Introduction

Ozanimod, an oral sphingosine 1-phosphate 1 and 5 receptor modulator, was efficacious and well tolerated for up to 52 weeks in adults with moderately to severely active ulcerative colitis (UC) in the phase 3 True North study (NCT02435992).Alterations in the degradation and formation of type III collagens, a major component of the extracellular matrix of the intestinal wall, may play a role in the pathogenesis of UC.

Aims & Methods

The objective of this analysis was to assess the effect of ozanimod on type III collagen levels and turnover and the association of type III collagen levels and turnover with ozanimod efficacy in the True North study. In a 10-week induction period, patients in Cohort 1 were randomized to receive oral ozanimod 0.92 mg (n=429) or placebo once daily (n=216) in a double-blind manner and patients in Cohort 2 received open-label ozanimod at the same daily dose (n=367). At Week 10, patients with a clinical response to ozanimod in either cohort underwent rerandomization to receive double-blind ozanimod (n=230) or placebo (n=227) for 52 weeks (maintenance period). Type III collagen biomarker plasma levels were assessed at baseline, Week 10, and Week 52. Associations between type III collagen biomarker levels and disease activity or efficacy outcomes were assessed using Spearman’s rho correlation and logistic regression, respectively.

Results

At Week 10, treatment with ozanimod resulted in significantly decreased type III collagen degradation (C3M), increased type III collagen formation (PRO-C3), and decreased type III collagen turnover (C3M/PRO-C3) vs placebo (Table). Significant reductions in C3M and C3M/PRO-C3 were observed in patients with vs without a clinical response in all treatment groups (P<0.001), while significant increases in PRO-C3 were observed in responders vs nonresponders (P<0.001; Cohort 1 only). The significantly greater reductions in C3M/PRO-C3 were observed with ozanimod vs placebo regardless of prior exposure to biologics or tumor necrosis factor inhibitors. Changes in C3M, PRO-C3, and C3M/PRO-C3 levels from baseline to Week 10 were significantly correlated with improvements in all disease activity scores from baseline to Week 10 with ozanimod and placebo. These changes in C3M, PRO-C3, and C3M/PRO-C3 continued through Week 52 (Table) in patients who continued ozanimod. At Week 52, significantly greater reductions in C3M/PRO-C3 ratios were observed in responders vs nonresponders in patients who continued ozanimod.

Table. Adjusted mean percent change from baseline in type III collagen biomarker levels (95% CI)
	Induction (Week 10)			Maintenance (Week 52)
	Placebo: Cohort 1	Ozanimod: Cohort 1	Ozanimod: Cohort 2	Ozanimod/ placebo	Ozanimod/ ozanimod
C3M	−0.3 (−4.2, 3.8) n=165	−10.6*** (−13.1, −8.0) n=346	−11.5*** (−14.1, −8.9) n=298	−16.4 (−20.1, −12.5) n=112	−20.8 (−23.8, −17.6) n=157
PRO-C3	−2.1 (−5.9, 1.8) n=164	5.0** (2.1, 7.9) n=343	8.4*** (5.3, 11.6) n=293	−1.1 (−6.1, 4.1) n=108	8.9** (4.2, 13.8) n=155
C3M/PRO-C3	1.5 (−4.1, 7.5) n=163	−14.6*** (−18.0, −11.1) n=343	−17.7*** (−21.1, −14.1) n=292	−14.8 (−20.3, −8.9) n=108	−27.3*** (−31.4, −23.1) n=155
**P<0.01, ***P<0.001 vs placebo: Cohort 1 for induction or ozanimod/placebo for maintenance.

Conclusion

These data show that patients with UC who were treated with ozanimod had decreased plasma type III collagen degradation and turnover, with greater reductions in ozanimod responders than nonresponders. This further supports the evaluation of type III collagen fragments as potential markers of treatment response in patients with UC.

Disclosure

Acknowledgment: This study was sponsored by Bristol Myers Squibb. Writing and editorial assistance was provided by Traci Stuve, MA, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb.
GD: served as an advisor for AbbVie, Agomab Therapeutics, Alimentiv, Applied Molecular Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Cytoki, Eli Lilly, Exeliom Biosciences, Ferring, Galapagos, GlaxoSmithKline, Gossamer Bio, Immunic, Johnson & Johnson, Pfizer, Polpharma, ProciseDx, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Seres, Takeda, Tillotts, and Versant; received speaker fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Johnson & Johnson, Pfizer, Takeda, and Tillotts.
RM, CW, YH, JZ, AP, and SH: employees and/or shareholders of Bristol Myers Squibb.
BES: received speaker fees from and consulted for Abivax, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, and Takeda; received consulting fees from AbbVie, Adiso Therapeutics, Alimentiv, Amgen, Arena, Artizan Biosciences, Artugen, AstraZeneca, Bacainn Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celltrion, ClostraBio, Cytoki Pharma, Connect Biopharma, Entera, Evommune, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Therapeutics, Inotrem, Ironwood Pharmaceuticals, Kaleido Biosciences, Kallyope, MiroBio, Morphic Therapeutics, MRM Health, OSE Immunotherapeutics, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma, Surrozen, Synlogic, Target RWE, Teva, Theravance, TLL Pharmaceutical, USWM Enterprises, Viela Bio, and VTA Labs; received personal fees and stock options for consulting from Thelium Therapeutics and Ventyx.
JHM: employed at Nordic Bioscience A/S, a company involved in the discovery and development of biochemical biomarkers.

Introduction

In patients with colorectal cancer (CRC), intestinal dysbiosis has been observed, with abnormal colonization of the colonic mucosa by pathogenic Escherichia coli strains producing a cyclomodulin named cytotoxic necrotizing factor (CNF). Cyclomodulins are bacterial toxins capable of altering the cell cycle of the infected cell. One of the mechanisms involved in host defence against pathogens and in carcinogenesis is autophagy. However, the role of autophagy in the host response to the infection by CNF-producing E. coli, designated as CyPEC, has not yet been described.

Aims & Methods

Thus, the aim of this study was to investigate the role of autophagy in colorectal carcinogenesis in the context of CyPEC infection.
Mice predisposed to CRC development with autophagy deficiency specifically intestinal epithelial cells (Apc^Min/+/Atg16l1^ΔIEC mice) and their control littermates with functional autophagy (Apc^Min/+ mice) were infected with the clinical CyPEC strain 21F8. Tumor size and number were determined using a dissecting microscope. The mouse colons were collected and used for histological score assessment, and to analyse the levels of markers of autophagy, cell proliferation, apoptosis and inflammation by immunoblot, immunohistochemical staining and ELISA.

Results

We showed that in Apc^Min/+/Atg16l1^ΔIEC mice, infection with the CyPEC 21F8 strain led to increases in the number and the size of colonic tumours, compared with the uninfected condition. However, this was not observed in Apc^Min/+ mice. The increase in tumorigenesis in Apc^Min/+/Atg16l1^ΔIEC mice upon 21F8 infection versus uninfected condition was associated with increased pro-inflammatory cytokine production, enhanced cellular proliferation and decreased apoptosis in colonic epithelial cells.

Conclusion

Our results suggest that autophagy is necessary to limit the pro-carcinogenesis effects of the CyPEC 21F8 strain, thereby decreasing colorectal tumorigenesis. In another word, autophagy deficiency could be a susceptibility factor for the development of CRC in a host with colonization by CyPEC strains.

Introduction

Therapeutic sequencing is a burning question in patients with ulcerative colitis (UC) requiring an advanced therapy. Whether starting with a less effective but safer and more convenient drug is a loss of chance for UC patients or can be rescued by later treatments is key point.

Aims & Methods

In the APPETISER study, we compared the effectiveness of two strategies based on the choice of the first biologic owing to either the drug efficacy in network meta-analyses and randomized controlled trials (vedolizumab or infliximab) or better acceptability (full subcutaneous therapy: adalimumab and golimumab) to induce and maintain steroid-free clinical remission during the first 24 months.
We collected real-world data from an IBD referral center including all consecutive UC patients ≥ 18 years-old who started a first line of biologic for active UC with follow-up > 6 months. Prior colectomy or severe acute colitis were excluded. Patients were included in either effectiveness-based sequencing (EBS) if they started with infliximab or vedolizumab, or in acceptability-based sequencing (ABS) if they received adalimumab or golimumab as first-line biologic.
The primary endpoint was remission defined according to PRO2 (PRO2-remission) as the absence of bleeding, normalization of transit (Mayo stool frequency subscore = 0) and no steroid. PRO2-remission was defined as a binary criterion each month (the statistical unit being the month and not the patient).
The secondary endpoints concerned the analysis by patient and were CFREM (partial Mayo score ≤ 2 without steroid) at week 12 and 52, endoscopic remission (CFREM + score Endoscopic Mayo ≤ 1) at week 12, time to drug discontinuation and time to colectomy.
All comparisons were adjusted using propensity scores on potential confounders. Analysis by month was performed using mixed models to account for repeated data.

Results

Overall, 130 patients were included including 60 patients in the EBS group (IFX= 50 and VDZ= 10) and 70 in the ABS group (ADA= 48 and GLM= 22).
The populations had similar characteristics at baseline apart from concomitant immunosuppressant more frequent in EBS group (55.9% vs 21.7%). 2^nd line treatment was started in 26.7% of patients in EBS group (ADA in 48.8%, VDZ 25.5% and ustekinumab 18.8%) and 87.1% of patients in ABS group (IFX in 54.1%, VDZ 31.1%).
After adjustment, the rate of CFREM was significantly higher in EBS arm than in ABS arm at week 12 (70.8% vs 33.0%, p < 0.001) and week 52 (72.8% vs 42.1%, p = 0.017). The rate of endoscopic remission at W12 was 22.1% and 10.0% in EBS and ABS arms, respectively (p =0.086).
For the primary endpoint, 3350 months were analyzed (1180 in EBS arm and 1175 in ABS arm). The percentage of months spent in PRO2-CFREM in the first 24 months (primary endpoint) was greater in EBS arm than in ABS arm (74.2% vs 46.6%; p<0.001). The percentage of months spent in CFREM was higher in the IV arm in the first 6 months (60.4% vs 18.9%), and was not rescued later: between M7 and M12 (73.1% vs 38.6%), M13 and M18 (79.9% vs 57.0%) or M19 and M24 (83.3% vs 64.6%) (p < 0.001 for all comparisons).
Regarding long-term data, EBS group had a lower risk to first-line biologic discontinuation (aHR=6.5 [2.8-15.3], p <0.001) and a clear trend for lower risk of colectomy (aHR=4.5 [0.9-22.3], p =0.068).

Conclusion

Our data highlight that the choice of first-line biological therapies is highly impacting the evolution of ulcerative colitis and cannot be rescued by later treatments. Thus, the results of the APPETISER study advocate for the use of the most effective therapeutic option as first line of biologic.

Disclosure

Anthony BUISSON: Consulting fees for Abbvie, Amgen, Arena, Biogen, Celltrion Healthcare, CTMA, Galapagos/Alfa Sigma, GutyCare/Resilience, Janssen, MSD, Nexbiome, Pfizer, Roche, Sandoz, Takeda, Tillotts. And Viatris. Lecture fees for Abbvie, Amgen, Biogen, Celltrion Healthcare, Galapagos/Alfa Sigma, Janssen, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma. Research grants from: Abbvie, Celltrion Healthcare, Galapagos/Alfa Sigma, Janssen, Lessaffre, Lilly, Pfizer, Takeda.

Introduction

Therapeutic drug monitoring (TDM) of intravenous (IV) infliximab is increasingly practiced to improve therapeutic outcomes of patients with inflammatory bowel diseases (IBD). Recently, a subcutaneous (SC) formulation of infliximab was approved for maintenance treatment of IBD [1].
In the present work, we introduce a software tool to guide infliximab dosing by predicting infliximab concentrations after switching to the SC formulation.

Aims & Methods

The infliximab population pharmacokinetics (popPK) model was previously developed using data from pivotal trials [2]. The popPK model code was reconstructed using R (v4.3.0). A software tool was developed using the Shiny package (v1.7.4). Bayesian forecasting was implemented using mapbayr (v0.10.0), which was used to estimate individual PK parameters through maximum a posteriori estimation.

External validation data were obtained from the prospective, multicenter REMSWITCH trial [3]. For each patient, a pre-switch infliximab trough concentration (TC) was used to predict a post-switch TC. Predicted and observed post-switch TCs were compared, and absolute and relative prediction errors (PE) were calculated. Prediction errors were compared between patients with and without relapse. Relapse was defined as an increase in fecal calprotectin ≥150 mg/g from baseline.

A simulation study was performed to demonstrate how the software tool can guide the IV-to-SC switch. Simulation conditions were:
- Dosing: 10 mg/kg IV every four weeks (q4w) to 240 mg SC every two weeks (q2w)
- Patient: 70 kg, no antibodies towards infliximab (ATI), no co-administration of methotrexate
- Pre-switch TC: 17.6 mg/L

Results

A total of 77 patients contributed one pre/post-switch TC pair each. Three patients had detectable ATI in the pre-switch sample. Three other patients were cotreated with methotrexate.
Predicted infliximab TCs were unbiased in the absence of relapse (Table 1). However, the model tended to overpredict infliximab TC in patients who experienced a relapse.

_{Table 1. Predictive performance of the model.}

	No relapse (N=60)		Relapse (N=17)
	Median	[IQR]	Median	[IQR]
aPE (mg/L)	-0.06	[-2.4–3.3]	+3.8	[-1.0–5.7]
rPE (%)	-0.6	[-20.1–30.2]	+34.3	[-10.0–67.1]

^{Abbreviations: aPE, absolute prediction error (calculated as; predicted - observed); IQR, interquartile range; N, number of patients; rPE, relative prediction error (calculated as; [predicted - observed] / observed * 100%).}

In the IV-to-SC simulation case, individual PK parameters (clearance 0.44 L/day, central volume of distribution 2.9 L, peripheral volume of distribution 27.0 L, and intercompartmental clearance 13.0 L/day) resulted in a post-switch TC of 18.6 mg/L right before the third SC injection. The simulation thus predicted no drop in TC after switching, thus presenting a likely safe switch strategy (considering the general belief that TCs drive efficacy).

Conclusion

The clinically validated, in-house developed software tool (https://lpmx.shinyapps.io/infliximab/) allows interactive simulations and personalized predictions to guide infliximab dosing while switching formulations. Predictions for patients without relapse were unbiased yet precision is likely compromised by variable SC bioavailability or possibly by time-varying PK. Overprediction of TC is likely driven by increased disease activity, characterized by an increased infliximab clearance and thus lower-than-expected infliximab observations, serving as a clinical alarm signal and warranting closer monitoring [4,5].

References

[1] S. Schreiber et al., “Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease,” Gastroenterology, vol. 160, no. 7, pp. 2340–2353, Jun. 2021, doi: 10.1053/j.gastro.2021.02.068.
[2] “Remsima European Public Assessment Report.pdf.”
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Disclosure

YH and ZW are supported by a research grant by Research Foundation Flanders–FWO (1SHAA24N, 1SF2922N). MF has received consulting/lecture fees from AbbVie, Amgen, Arena, Biogen, Celltrion Healthcare, CTMA, Galapagos, Janssen, MSD, Pfizer, Takeda, Tillotts. MSD, Gilead, Celgene, Sandoz, and Ferring. MN has received board membership, consultancy, or lecture fees from AbbVie, Adacyte, Amgen, Arena, Biogen, CTMA, Celltrion Healthcare, Ferring, Fresenius-Kabi, Janssen, Mayoli-Spindler, MSD, Pfizer, and Takeda. AB has received consulting fees from AbbVie, Amgen, Arena, Biogen, Celltrion Healthcare, CTMA, Galapagos, Janssen, MSD, Nexbiome, Pfizer, Roche, Takeda, and Tillotts; and lecture fees from AbbVie, Amgen, Biogen, Galapagos, Janssen, Mayoli-Spindler, MSD, Norgine, Pfizer, Roche, Takeda, Tillotts, and Vifor Pharma. ED has received consultancy fees from Alimentiv and argenx, lecture fees from Galapagos and Celltrion, and financial support from Janssen, Prometheus, and Sandoz. The remaining authors disclose no conflicts.