Introduction

We recently demonstrated that switching from intravenous to subcutaneous infliximab is safe and well-accepted at short-term in IBD patients including those with intensified IV regimen. However, the long-term risk of relapse in these patients remains unknown.

Aims & Methods

We assessed the long-term effectiveness and acceptability of switching from intravenous to subcutaneous infliximab in patients with inflammatory bowel diseases (IBDs) treated with or without intensified intravenous regimen.
In this prospective multicenter observational study, IBD patients in clinical remission (partial Mayo score ≤ 2 or Harvey-Bradshaw index ≤ 4) were switched to a unique dose of subcutaneous infliximab (120 mg every other week). Pharmacological and biological data were collected at baseline, visit 1 (4–8 weeks post-switch), visit 2 (8–16 weeks post-switch), and visit 3 (16–24 weeks post-switch) and at last follow-up (median follow-up : 18 [15-20] months). Relapse was defined as clinical relapse or fecal calprotectin increase ≥ 150 mg/g compared with baseline.

Results

Among 184 eligible patients, 72.3% (n = 133/184) agreed to switch to subcutaneous infliximab. At visit 3, a relapse occurred in 10.2% (n = 6/59), 7.3% (n = 3/41), 16.7% (n=3/18), and 66.7% (n=10/15) (P < .001) of patients receiving 5 mg/kg every 8 weeks, 10 mg/kg every 8 weeks, 10 mg/kg every 6 weeks, and 10 mg/kg every 4 weeks, respectively. At 18 months, the rate of relapse was 13.6% (n=8/59), 17.7% (n=7/41), 33.3% (n=6/18), and 86.7% (n=13/15) (P < .001) of patients receiving 5 mg/kg every 8 weeks, 10 mg/kg every 8 weeks, 10 mg/kg every 6 weeks, and 10 mg/kg every 4 weeks, respectively. Dose escalation to 240 mg every other week or 120 mg every week led to recapture clinical remission in 82.1% (n 23/28). Infliximab serum levels increased after the switch (P < .0001) except for patients receiving 10 mg/kg every 4 weeks. In multivariable analysis, 10 mg/kg every 4 weeks regimen (OR= 61.0; [6.0-600.1], p <0.001) and 10 mg/kg every 6 weeks regimen (OR= 4.7; [1.1-20.2], p = 0.039) had a higher risk of relapse at 18 months as well as reduced (58.3%) or stable (52.6%) infliximab serum levels between baseline and visit 1 compared with increased serum levels (19.7%) (P = 0.006 and P = 0.008, respectively). Patients’ acceptability (10-point scale) was improved by the switch (6.9 ± 1.6 for IV vs 8.6 ± 1.4 at V1 after the switch; P < .0001) and did not decrease over time during SC maintenance regimen 8.8 ± 1.3 at V3 and 8.8 ± 1.3 at 18 months. No severe adverse event was reported.

Conclusion

Switching from intravenous to subcutaneous infliximab 120 mg every other week is safe and well accepted at long-term, leading to a low risk of relapse in IBD patients except for those receiving 10 mg/kg every 4 weeks requiring escalated SC dose.

Disclosure

These authors disclose the following: Anthony BUISSON 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. Maria Nachury 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. Mathurin Fumery 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. The remaining authors disclose no
conflicts.

Funding
The study was independent but received a grant from Celltrion Healthcare.

Introduction

Celiac disease (CeD) is triggered by gluten peptides that bind to HLA-DQ2 or -DQ8 in the small intestine leading to gluten specific Th1 T cell expansion and villous atrophy. The oral transglutaminase 2 inhibitor Zed1227 blocks the deamidation of gliadin peptides, a prerequisite for effective gliadin antigen presentation. The CEC-3 clinical trial demonstrated that Zed1227 effectively prevented mucosal damage in 160 CeD patients in remission challenged with 3 g gluten daily for 6 weeks (Schuppan D et al, NEJM 2021).

Aims & Methods

We analyzed regulatory T cell (Treg) gene expression pre and post gluten challenge in the 100 mg/d Zed1227 vs placebo treated patients using RNAseq from the patients’ small intestinal biopsies (Dotsenko V et al, Nat Immunol 2024). We focused on genes of Treg subtypes and related cells. Subanalysis was performed via different gene set enrichments for Treg subsets, regulatory pathways and cell types. Genes that were enhanced in favorable vs unfavorable villous height to crypt depth (V/C) ratio outcomes, also after placebo treatment, were analyzed. We further analyzed pre-disposing genes before challenge, favoring a beneficial or negative post challenge V/C outcome.

Results

93% of the top 100 most significant regulatory genes were upregulated in Zed1227-treated patients compared to those treated with a placebo. These regulatory genes included TGF-beta signaling genes such as Smad7 and MERTK, cholesterol- and fatty acid related genes, such as ACAT1 and NPC1L1, specific autophagy/apoptosis related genes such as VPS35, SQSTM1, BMF, and inhibitory genes like SOCS2. Zed1227 treated patient samples with a maintained post challenge V/C ratio showed evidence for upregulated iTreg genes. Interestingly, Treg genes from placebo-treated subjects were upregulated in correlation with better inflammatory control under gluten challenge compared to worse control.
Moreover, in pre-challenge duodenal samples we identified protective genes that help maintain tolerance during gluten challenge, as reflected by a better post challenge V/C ratio. Examples are ubiquitin ligase RNF167, BAD, FOXN3, BAG1 and CLAUDIN15, whereas other genes like IRF9, CD96 and HLA-/TAP1 were predictive of a more pronounced V/C ratio decline after gluten exposure.

Conclusion

Our data derived from superbly analyzed pre- and post challenge duodenal biopsies demonstrate an active anti-inflammatory immune modulation, largely Treg cell mediated, in CeD in patients prior to and during gluten challenge. Zed1227 treatment potently activates this regulatory response. The balance of several beneficial vs detrimental predisposing Treg-related genes may play a causative role in the variable sensitivity of CeD patients to gluten exposure. Our data support future Treg based therapies to attenuate inflammation in CeD and other (intestinal) autoimmune diseases.

References

Schuppan, D., Mäki, M., Lundin, K. E. A., Isola, J., Friesing-Sosnik, T., Taavela, J., Popp, A., Koskenpato, J., Langhorst, J., Hovde, Ø., Lähdeaho, M. L., Fusco, S., Schumann, M., Török, H. P., Kupcinskas, J., Zopf, Y., Lohse, A. W., Scheinin, M., Kull, K., Biedermann, L., … CEC-3 Trial Group (2021). A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease. The New England journal of medicine, 385(1), 35–45. https://doi.org/10.1056/NEJMoa2032441
Dotsenko, V., Tewes, B., Hils, M., Pasternack, R., Isola, J., Taavela, J., Popp, A., Sarin, J., Huhtala, H., Hiltunen, P., Zimmermann, T., Mohrbacher, R., Greinwald, R., Lundin, K. E. A., Schuppan, D., Mäki, M., Viiri, K., & CEC-3 Investigators (2024). Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease. Nature immunology, 25(7), 1218–1230. https://doi.org/10.1038/s41590-024-01867-0

Disclosure

V.D. and K.V. received funding from Dr. Falk Pharma to Tampere University to conduct the study. B.T., T.Z., R.M. and R.G. are employees of Dr. Falk Pharma. The data presented here are the subject of patent applications EP24173619.8 and EP24173615.6 filed by Dr. Falk Pharma, and B.T., T.Z., R.M., R.G., V.D. and K.V. are inventors on these applications. M.H. and R.P. are employees of Zedira. J.T. is a consultant for Jilab Oy and Dr. Falk Pharma. K.E.A.L. is a consultant for Amyra, Bioniz Pharmaceuticals, Chugai Pharmaceutical, Dr. Falk Pharma, Itrexon Actobios, TOPAS Therapeutics and Takeda California. D.S. is the data and safety monitor for Boehringer Ingelheim (Phil.) and is a consultant for the Dr. Falk Pharma, Takeda, Immunic, Sanofi and TOPAS Therapeutics. J.I. is the owner of Jilab Oy. M.M. is the founder, owner and Chair of the Board of Maki HealthTech (MHT). MHT receives Management/Advisory Affiliation fees from Dr. Falk Pharma and other funding not related to the research from Topas Therapeutics, Calypso Biotech, Vaccitech, ImmunogenX, Equillium and Immunic. MHT holds patents (patent number 7361480 (United States) and European Patent Office Number 1390753) licensed to Labsystems Diagnostics from where MHT receives royalties via Tampere University Hospital. All other authors declare no competing interests.

Introduction

In patients admitted for an acute severe ulcerative colitis (ASUC) episode responding to intravenous (IV) steroids, the most effective treatment regimen is unknown. The benefit of early infliximab (IFX) therapy remains to be established in this indication.

Aims & Methods

In this French multicentre, parallel group, open-label randomised controlled trial, thiopurine and biologics-naïve adults admitted for ASUC defined by a Lichtiger score >10 were included between December 2016 and June 2021 if they responded to IV steroids. Response to IV steroids was defined according to the absence of Oxford criteria. They were randomly assigned to receive an early combination therapy with IFX (5 mg/kg IV at week 0, 2 and 6 and then every 8 weeks) and azathioprine (AZA) (2 and 2.5 mg/kg/day) with a quick steroid discontinuation of AZA (2 and 2.5 mg/kg/day) and standardized steroid tapering regimen (AZA arm). Steroids use was prohibited after day 7 in the IFX+AZA arm and after week 14 in the AZA arm.
The primary endpoint was treatment failure at week 52 (w52), defined as absence of steroid-free clinical remission according to total Mayo Clinic score (≤2 with no individual subscore >1) at w52, absence of endoscopic response (Mayo endoscopic subscore of 0 or 1 according to local reading) at w52, or use of a prohibited treatment for relapse (partial Mayo score >5), severe adverse event leading to interruption of any of the allocated treatment, colectomy or death during the study period.
A sample size of 73 patients per group was calculated to detect 24%-difference between both group with a 1:1 randomization ratio, a 80% power and a 5% two-sided alpha risk. Due to challenges in recruiting patient, the steering committee decided to prematurely terminate the study in September 2019 blindly of any study results, after including 64 patients.

Results

64 were randomised (32 males, median age of 34.5 [IQR 26.3-50.3] years, 38% with pancolitis, Lichtiger score of 13.0 [95%CI 12-14], CRP of 29.0 [12.8-96.8] mg/L and serum albumin of 31.2 [27.7-35.6] g/L at baseline): 32 were assigned to IFX+AZA arm and 32 to AZA arm. Components of the composite primary endpoint are given in table 1.

	IFX + AZA arm (n=32)	AZA arm (n=32)
Death	0	0
Colectomy	0	0
use of a prohibited treatment for relapse	6 (18.8%)	10 (31.2%)
severe adverse event leading to interruption of any of the allocated treatment	5 (15.6%)	3 (9.4%)
Retracted consent	1 (3.1%)	0
Absence of steroid-free clinical remission at w52	5 (15.6%)	8 (25.0%)
Mayo endoscopic subscore ≥2	6 (18.8%)	8 (25.0%)

In the ITT population, treatment failure at w52 was observed in 81.5% in the AZA arm versus 53.3% in the IFX+AZA arm (OR 3.85, 95%CI [1.15-12.88], p=0.03). In the PP population, treatment failure at week 52 was observed in 81.5% (22/27) in the AZA arm versus 50.0% (13/26) in the IFX + AZA arm (OR 4.40, 95%CI [1.28-15.18], p=0.02). In total 121 treatment emergent adverse events (AE) were reported in 40 patients including 23 serious AE in 18 patients (11 in the IFX + AZA arm vs 7 in the AZA arm, p=0.24). Serious AE included infectious AE in 6 cases (1 vs 5, p=0.20) and UC relapse in 9 (4 vs 5, p=0.60). No deaths were reported.

Conclusion

At w52, combination therapy with IFX + AZA and quick steroids discontinuation was more effective than AZA with standard steroids tapering regimen to prevent treatment failure in patients with ASUC responding to IV steroids. In routine practice, pre-emptive use of early combination therapy with IFX + AZA should be encouraged in ASUC patients responding to IV steroids (EudraCT 2014-005212-42).

Disclosure

this study was funded by Pfizer

Introduction

Vedolizumab (VDZ) is a gut-selective humanised monoclonal anti-α₄β₇ integrin antibody for treatment of ulcerative colitis (UC) and Crohn’s disease (CD). The GEMINI Long-Term Safety (LTS) study demonstrated the durable efficacy and safety of vedolizumab for inflammatory bowel disease (IBD) treatment. Patients experiencing clinical benefit from vedolizumab in GEMINI LTS (NCT00790933) or VERSIFY (NCT02425111) studies could continue treatment in the vedolizumab extended access programme (XAP).

Aims & Methods

​​​​​​The XAP study was a phase 3b/4, prospective, open-label, multinational, interventional study (NCT02743806)^1,2 conducted from Aug 2016 to Jan 2023 to investigate long-term treatment persistence and safety of vedolizumab 300mg IV every 4 weeks (Q4W) or every 8 weeks (Q8W) in adults with UC or CD.

Results

The study enrolled 331 patients (UC=142; CD=189) including 20 rolling over from VERSIFY and 311 patients from GEMINI LTS. Patients treated with vedolizumab in the XAP study had either dose frequency reduction Q4W to Q8W or were maintained on their current Q8W or Q4W dosing; 297 patients started the XAP study on Q8W dosing, of which 295 received at least one dose of vedolizumab in XAP. At XAP study baseline, mean (SD) disease duration was 13.9 (6.8) and 13.2 (6.8) yrs for patients with UC and CD, respectively; most patients were in clinical remission (Table 1). In total, 283/295 patients (95.9%) were persistent on Q8W dosing for ≥6 months without relapse (UC: 129/132 [97.7%] and CD: 154/163 [94.5%]). Median (range) duration of vedolizumab treatment in the XAP study was UC: 3.8 (0–6) and CD: 4.2 (0–6) yrs. Only 27 patients (9.2%) were re-escalated from Q8W to Q4W dosing during the study (UC: 11/132 [8.3%] and CD: 16/163 [9.8%]); median (range) duration from last dose in the qualifying study to dose escalation in XAP was 1.5 (0.6–3.0) and 1.2 (0.2–5.2) yrs for UC and CD groups, respectively; the corresponding duration from last dose in the qualifying study to relapse was 1.4 (0.4–4.0) and 1.2 (0.06–5.4) yrs. Adverse events (AEs) after enrolment into XAP occurred in 61.3% of patients with UC and 62.4% with CD (treatment-related in 2.1% UC and 4.2% CD) but only 4.2% UC and 1.6% CD had AEs leading to study discontinuation (treatment-related: 0.7% UC, 0.5% CD); 13.4% UC and 16.4% CD had serious AEs (treatment-related: 0.7% UC, 0.5% CD). Severe infections occurred in 2 patients with UC (1.4% including 1 patient with COVID-19) and in 1 patient with CD (0.6%), none were considered treatment-related. There was 1 death from COPD reported during the study.

Table 1. Baseline Patient Characteristics
Parameter	UC Vedolizumab N=142 from GEMINI LTS				CD Vedolizumab N=169 from GEMINI LTS, N=20 from VERSIFY
	Dose frequency reduction to Q8W (N=121)	Dose frequency escalation to Q4W (N=10)	Q4W Maintenance (N=8)	Total (N=142)a	Dose frequency reduction to Q8W (N=128)	Dose frequency escalation to Q4W (N=14)	Q4W Maintenance (N=26)	VERSIFY Q8W Maintenance (N=20)	Total (N=189)b
Age, mean (SD), years	47.0 (11.6)	46.2 (10.7)	55.1 (13.6)	47.7 (11.8)	42.6 (11.8)	37.7 (5.7)	44.6 (13.8)	38.4 (14.6)	42.1 (12.1)
Clinical remission, n (%)	118 (97.5)	8 (80.0)	5 (62.5)	133 (93.7)	118 (92.2)	13 (92.9)	19 (73.1)	15 (75.0)	166 (87.8)
Partial Mayo score, mean (SD)	0.4 (0.9)	0.9 (1.3)	1.3 (1.8)	0.5 (1.0)	NA	NA	NA	NA	NA
Harvey Bradshaw Index score, mean (SD)	NA	NA	NA	NA	1.3 (2.1)	1.8 (1.6)	3.3 (2.8)	-	1.7 (2.3)
Prior anti-TNFα therapy, n (%)	22 (18.2)	4 (40.0)	2 (25.0)	28 (19.7)	41 (32.0)	8 (57.1)	13 (50.0)	11 (55.0)	73 (38.6)
Concomitant medications, n (%) CS CS + IMM IMM	5 (4.1) 2 (1.7) 24 (19.8)	1 (10.0) 0 1 (10.0)	0 0 3 (37.5)	6 (4.2) 2 (1.4) 29 (20.4)	6 (4.7) 2 (1.6) 28 (21.9)	1 (7.1) 0 5 (35.7)	1 (3.8) 0 4 (15.4)	4 (20.0) 0 8 (40.0)	12 (6.3) 2 (1.1) 45 (23.8)
aIncludes 3 patients who had multiple dose changes; bIncludes 1 patient from GEMINI LTS who had multiple dose changes.

Conclusion

This long-term, prospective study reported high patient persistence on vedolizumab Q8W after the reduction of dosing frequency, together with low rates of dose frequency escalation to Q4W and relapse. Safety results were consistent with the known safety profile of vedolizumab; no new safety signal was identified.

References

1. Vermeire S, et al. J Crohns Colitis 2020;14(8):1066-73.
2. Danese S, et al. Aliment Pharmacol Ther 2021;53(2):265-72.

Disclosure

Silvio Danese: Lecture fees: AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim; Consultancy: AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim. Grazyna Rydzewska: Lecture fees: AbbVie, Ferring, Johnson & Johnson, Takeda, Pfizer Inc, Celltrion, Sandoz, Boehringer Ingelheim; Alfa Sigma, ProMed, Biocodex, Sanprobi; Consultancy: AbbVie, Ferring, Johnson & Johnson, Takeda, Pfizer Inc, Celltrion, Sandoz, Sobi, ProMed. Stephen Jones: consultant to Takeda. Shashi Adsul and Dirk Lindner: employees of Takeda and hold Takeda stock/stock options; medical writing support was provided by Excel Medical Affairs and funded by Takeda. Séverine Vermeire: Grants: AbbVie, Galapagos, Johnson & Johnson, Pfizer, Takeda; consulting/and or speaker fees: AbbVie, AbolerIS, AgomAb, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Cytoki, Dr Falk, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots, Zealand.