Introduction

Filgotinib (FIL), a once-daily, oral, Janus kinase 1 preferential inhibitor, is approved for the treatment of ulcerative colitis (UC). FIL was effective in inducing and maintaining clinical remission and was well tolerated in the placebo-controlled phase 2b/3 SELECTION trial (NCT02914522).¹

Aims & Methods

The efficacy and safety of continued treatment with FIL 200 mg (FIL200) are being assessed in the long-term extension (LTE) study (SELECTIONLTE: NCT02914535). The study design of SELECTION has been published previously.¹ We now report the efficacy and safety of open-label FIL200 through up to 5 years of treatment: LTE week 192 in completers and LTE week 240 in induction non-responders. Completers were defined as patients who completed the SELECTION induction and maintenance studies, and non-responders were those without response at SELECTION week 10; all of whom entered the LTE study. A data cut-off of 23 March 2023 was used for this interim analysis. Proportions of patients who were in partial Mayo Clinic Score (pMCS) remission (pMCS ≤1) and Inflammatory Bowel Disease Questionnaire (IBDQ) remission (score ≥170) were reported both as observed cases and using non-responder imputation (NRI). Adverse events (AEs) and AEs of special interest (AESIs) were evaluated using exposure-adjusted incidence rates per 100 patient-years of exposure (PYE).

Results

This interim analysis included 148 completers and 372 non-responders. AEs and AESIs in patients treated with open-label FIL200 (2464.7 PYE) showed no new safety signals, and safety events were comparable to those seen in previous analyses. The proportions of patients who were in pMCS and IBDQ remission are shown in the Table. The proportions of patients who were in pMCS remission increased during SELECTION to reach 72.4% (FIL200, as observed) at week 58/LTE baseline and increased further during SELECTIONLTE (85.0% at LTE week 192) in completers. Proportions in pMCS remission increased more gradually over SELECTIONLTE, reaching 66.7% (FIL200–FIL200, as observed) at LTE week 240 in non-responders. Similar patterns were seen for IBDQ remission; 78.5% (FIL200, as observed) of completers were in IBDQ remission at week 58/LTE baseline, increasing to 84.8% by LTE week 192. In non-responders, increases in the proportions of patients who were in IBDQ remission were gradual, reaching 77.8% (FIL200–FIL200, as observed) at LTE week 240. NRI analyses showed similar but much more conservative results than the as observed analyses for both groups for both endpoints.

Conclusion

Filgotinib 200 mg was effective in maintaining symptomatic remission and health-related quality of life for up to 5 years. No new safety signals were identified, and rates of AEs under long-term exposure were comparable to those previously reported.^1–4 Prolonged treatment with filgotinib is efficacious for the long-term management of UC, and together with its proven safety profile, results in an acceptable benefit–risk profile.

Table. Proportions of patients in pMCS or IBDQ remission in SELECTION and SELECTIONLTE (observed case and NRI).

References

1. Feagan BG et al. Lancet 2021;397:2372–84.
2. Feagan BG et al. J Crohns Colitis 2022;16(Suppl1):i456–7.
3. Feagan BG et al. J Crohns Colitis 2023;17(Suppl1):i47–50.
4. Feagan BG et al. UEG Journal 2023;11(Suppl 8).

Disclosure

The SELECTION trial was sponsored by Gilead Sciences, Inc. (Foster City, CA, USA), for which Galapagos NV (Mechelen, Belgium) was a collaborator. The SELECTIONLTE trial was sponsored by Galapagos NV (Mechelen, Belgium), who funded these analyses.

Medical writing support for the development of this abstract was provided by Katie Pillidge, PhD, of PharmaGenesis London, London, UK, and was funded by Alfasigma S.p.A.
The authors thank Alessandra Oortwijn for her contributions to this study.
AM and CR are employees of Alfasigma S.p.A at the time of abstract submission.
BGF reports grants and personal fees from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Janssen Biotech/Centocor, Johnson & Johnson/Janssen, Pfizer, Receptos and Takeda; and personal fees from Ablynx, ActoGeniX, AdMIRx, Akebia Therapeutics, Allergan, Atlantic Pharmaceuticals, Avaxia Biologics, Avir Pharma… Disclosures truncated – see poster for full details.
KM reports personal fees from AbbVie, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly, Gilead Sciences, Janssen Pharmaceuticals, JIMRO, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, Takeda… Disclosures truncated – see poster for full details.
GR reports personal fees and/or speaker fees from AbbVie, AstraZeneca, Augurix Diagnostics, Boehringer Ingelheim, Bristol Myers Squibb, Calypso Biotech, Celgene, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Fisher, Genentech, Gilead Sciences, Janssen Pharmaceuticals, MSD, Novartis, Pfizer, Phadia, Pierre Fabre, Roche, Takeda, Tillotts Pharma, UCB, Vifor Pharma… Disclosures truncated – see poster for full details.
DL reports consulting, advisory board and transport fees from AbbVie, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Janssen Pharmaceuticals, MSD, Novartis, Pfizer, Prometheus, Roche and Takeda.
SV reports financial support for research from AbbVie, Galapagos, Johnson & Johnson, Pfizer and Takeda; speaker and/or consultancy fees from AbbVie, Abivax, AbolerIS Pharma, AgomAb Therapeutics, Alimentiv, Arena Pharmaceuticals… Disclosures truncated – see poster for full details.
SD reports personal fees from AbbVie, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring Pharmaceuticals, Gilead Sciences, Hospira, Inotrem, Janssen Pharmaceuticals, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB and Vifor Pharma.
EVL has consulted for AbbVie, Alvotech, Amgen, Arena Pharmaceuticals, Astellas, Avalo Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly, Fresenius Kabi, Genentech, Gilead Sciences, Gossamer Bio, GSK, Iterative Health, Iota Biosciences, Janssen Pharmaceuticals, KSL Diagnostics… Disclosures truncated – see poster for full details.
IB reports personal fees from Galapagos, Gilead Sciences, Janssen Pharmaceuticals, Pfizer, Pharmacosmos, Takeda and Vifor Pharma.
SS reports personal fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos/Gilead Sciences, Hikma Pharmaceuticals, I-Mab, Janssen Pharmaceuticals, Morphic Therapeutic, MSD, Mylan, Pfizer, Protagonist Therapeutics, Provention Bio, Sandoz/Hexal, Takeda, Theravance Biopharma and Ventyx Biosciences
HJK has received consultancy fees from AbbVie, Johnson & Johnson, Celltrion and Takeda.
MF is an employee and shareholder of Galapagos NV.
AM is a former employee and shareholder of Galapagos NV, and an employee of Alfasigma S.p.A.
CR is a former employee and shareholder of Galapagos NV, and an employee of Alfasigma S.p.A.
LPB has received consulting fees from Abivax, AbbVie, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celltrion, CONNECT Biopharma, Cytoki Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, Gossamer Bio, GSK, HAC Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen Pharmaceuticals, Medac, Mopac, Morphic, MSD, Norgine… Disclosures truncated – see poster for full details.

Introduction

Response to hepatitis B vaccine (HBV) is variable in inflammatory bowel disease (IBD) patients with seroconversion rates of 34-89%. Strategies suggested to improve the seroconversion rates are double dose, accelerated schedule, or addition of booster dose with variable results. This study compared the standard (20 µg) dose and double (40 µg) dose of HBV vaccination in IBD patients.

Aims & Methods

Patients of IBD were randomized to 1:1 to receive standard or double dose of HBV at 0, 1 and 6 months. Anti-HBs titers were assessed at 1 month after the third dose. Response was defined as an adequate immune response (AIR, anti-HBs titer >10 mIU/mL) and effective immune response (EIR, anti-HBs titer >100 mIU/mL). Total mayo score and Crohn’s disease activity index (CDAI) was used to identify the active disease. IBD medications with immunosuppressive effects were categorized as immunomodulators, corticosteroids, tofacitinib and biologic group. Multivariable logistic regression analysis was done to identify the predictors of AIR and EIR.

Results

Eighty-eight patients of IBD were randomized to receive standard (45, 51.1%) or double (43, 48.9%) dose of HBV. 79 of 88 patients had ulcerative colitis (UC) and 9 had Crohn’s disease (CD). 49 (55.7%) patients had active disease while 39 (44.3%) were in remission. At the end of the study, total 63 (71.61%) patients achieved AIR and 51 (60%) achieved EIR. AIR (88.4 % vs. 55.6 %, p 0.001) and EIR (69.8% vs. 46.7%, p = 0.028) rates were significantly higher with double dose compared to standard dose of HBV. Patients with active IBD had higher AIR (87.5% vs. 44%, p = 0.001) and EIR (70.8% vs. 32%, p = 0.007) rates with double dose of HBV. Patients with IBD in remission also had higher AIR (89.5% vs. 70%) and EIR (78.4% vs. 65%) rates with double dose of HBV, though statistically non-significant.
Multivariable analysis identified the use of double dose of HBV {odds ratio (OR) 10.865, 95% confidence interval (CI): 2.418-48.817} and biologic (OR 0.022, 95% CI: 0.001-0.421) as predictors to achieve AIR. Similarly, double dose of HBV (OR 3.0, 95% CI: 1.087-8.280) and use of biologic (OR 0.074, 95% CI: 0.006-0.931) also predicted the EIR.

Conclusion

Double dose of HBV vaccine demonstrated a superiority over standard dose of vaccine for achieving both AIR and EIR. Use of biologic impaired the response. Double dose of HBV should be used in IBD patients to improve the seroconversion rates.

Disclosure

No conflict of Interest

Introduction

Ulcerative colitis (UC) and Crohn’s disease (CD), collectively inflammatory bowel disease (IBD), are characterized by chronic gastrointestinal tract inflammation. Recently, there has been interest in the use of selective oral tyrosine kinase 2 (TYK2) inhibitors for IBD treatment, which inhibit signalling downstream of multiple pro-inflammatory cytokines and may have an improved safety profile relative to non-specific Janus kinase (JAK) inhibition. Here, we use a transcriptomic approach to assess the involvement of TYK2-dependent signalling pathways in IBD, and how these are impacted by currently available treatments.

Aims & Methods

TYK2-dependent gene signatures were characterized using cytokine stimulation studies and co-expression analysis. Involvement of signature modules in IBD was assessed using disease model data generated from Takeda curated public datasets from 4059 biopsy samples from 2993 unique patients in 15 UC and 38 CD clinical studies, including assessments of golimumab, infliximab, ustekinumab, and vedolizumab. Pathway differential expression analysis was performed using Gene Set Enrichment Analysis (GSEA) and single-sample GSEA methods.^1,2

Results

Seven TYK2-dependent gene signature modules were defined, including two for type I interferon (IFN), three for IL-23, and two for IL-12. Type I IFN signatures were strongly enriched in both UC and CD, while enrichment of IL-23 was stronger in UC than CD, and enrichment of IL-12 was stronger in CD than UC. In each case, gene signature module enrichment was associated with greater disease severity. Pathway enrichment analysis of data from individual clinical studies demonstrated that specific type I IFN and IL-12 modules were significantly reduced, but not completely ameliorated, following treatment with golimumab, infliximab, ustekinumab, or vedolizumab. Further assessment of response to therapy in these studies showed that enrichment of type I IFN, IL-23, and IL-12 signature modules was associated with non-response to golimumab, infliximab, and vedolizumab.

Conclusion

Enrichment of TYK2-dependent gene signatures, including type I IFN, IL-23, and IL-12, is associated with both UC and CD. These TYK2-dependent enrichments are not fully mitigated through currently available treatments, and may be associated with non-response to treatment. It is important that all three signalling pathways are considered in the development of future treatment options.

References

1. Barbie DA, et al. Nature 2009;462:108–12.
2. Subramanian A, et al. Proc Natl Acad Sci U S A 2005;102:15545–50.

Disclosure

IP, NS, JT, PP, HW, PT, and VA are employees and shareholders of Takeda; AND was an employee and shareholder of Takeda at the time of the analysis. SSS-O is a consultant for and shareholder of CytoReason and AS-M, RS, ND, IW, and YC are employees and shareholders of CytoReason, which has received research funding from Takeda.