Introduction

The only established treatment for celiac disease is a strict gluten-free diet. This treatment has commonly good results, but it requires huge effort from the patients to avoid gluten exposure. Recently we showed that gluten-specific T-cell clones persist for many decades in treated celiacs and the same clones are reactivated after gluten challenge [1]. These disease-driving T cells are thus an attractive target for non-dietary therapy [2]. New mechanistic findings from treatment of multiple sclerosis with the drug teriflunomide suggest that teriflunomide induces selective apoptosis of activated high-affinity T cells [3]. We tested this hypothesis for celiac disease and report here from a phase 2a pilot study (ID EudraCT No.: 2020-002307-18).

Aims & Methods

Fifteen treated patients with biopsy-verified celiac disease were included in the study. They were block-randomized 2:1 to either active substance or placebo capsules. All participants took 7 capsules once daily for a week as a loading dose [4]. On day 7, they started taking one capsule daily for a week while also receiving a gluten challenge (8g of gluten/day) daily for three days. On day 14, they provided a blood sample for analysis of the study's primary endpoint; induction of the activation marker CD38 on HLA-DQ2.5:gluten tetramer+ T cells [5]. All patients who received the active substance underwent an accelerated elimination phase using cholestyramine and they were followed up with two visits after treatment completion. Plasma concentrations of teriflunomide were determined during and after the end of treatment.

Results

All patients completed the study according to the protocol with no reports of serious adverse events or symptoms. The mean plasma concentration of high-dose teriflunomide during induction treatment ranged from 79.3 to 19.0 mg/L. Analysis of the primary endpoint of the study showed no effect on CD38 on HLA-DQ2.5:gluten tetramer+ T cells. Moreover, secondary endpoints such as frequency of HLA-DQ2.5:gluten tetramer+ CD4+ T cells, gut-homing CD103+ CD8+ T cells and γδ T cells in blood samples taken on day 14, as well as cytokine release of IL-2 in serum four hours after the first gluten intake, showed no difference between the teriflunomide group and the placebo group. Tetramer analysis during follow-up visits at 6 and 22 weeks also showed no difference between the groups.

Conclusion

This study marks the first investigation of medication for celiac disease with direct phenotypic analysis of HLA-DQ2.5:gluten tetramer+ T cells, along with other sensitive biomarkers that gauge activity of disease-relevant T cells in blood. The planned immunotherapy using teriflunomide showed no signs of safety issues or adverse effects. However, the study did not achieve its primary endpoint. Our findings refute the proposed hypothesis that teriflunomide induces apoptosis by activating disease-specific T cells.

References

1. Risnes, L.F., et al., Disease-driving CD4+ T cell clonotypes persist for decades in celiac disease. J Clin Invest, 2018. 128(6): p. 2642-2650.
2. Christophersen, A., et al., Therapeutic and Diagnostic Implications of T Cell Scarring in Celiac Disease and Beyond. Trends Mol Med, 2019. 25(10): p. 836-852.
3. Klotz, L., et al., Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects. Sci Transl Med, 2019. 11(490).
4. Yao, X., et al., A population pharmacokinetic study to accelerate early phase clinical development for a novel drug, teriflunomide sodium, to treat systemic lupus erythematosus. Eur J Pharm Sci, 2019. 136: p. 104942.
5. Zuhlke, S., et al., CD38 expression on gluten-specific T cells is a robust marker of gluten re-exposure in coeliac disease. United European Gastroenterol J, 2019. 7(10): p. 1337-1344.

Introduction

Eosinophilic Esophagitis (EoE) is a chronic, inflammatory, immune-mediated disease, characterised by eosinophilic infiltration. EoE requires a lifelong pharmacological treatment, aimed at achieving clinical (ie. symptoms of esophageal dysfunction), endoscopic and histological remission, and slowing down the possible process of esophageal fibrosis. Recently, a novel formulation of budesonide orodispersible tablet (BOT) has become available, showing a high efficacy in randomised placebo-controlled trials. Nowadays, only few real-life data are available in literature.

Aims & Methods

This is a multicentre, prospective, observational study, aimed to evaluate in real-life setting the long-term safety profile and the clinical, endoscopic and histological effectiveness of BOT in EoE patients. Patients diagnosed with EoE, aged ≥ 18 years, treated with BOT 1 mg bid, as induction treatment for 12 weeks (T1), and with 1 mg qd as maintenance for 52 weeks (T2), were enrolled. Clinical, demographic and medication data were collected at baseline. BOT treatment outcomes were evaluated after T1 and after T2, considering EoE Endoscopic Reference Score (EREFS) for endoscopic appearance, and 3-segments eosinophilic peak infiltration for histological assessment. Moreover, the Dysphagia Symptom Questionnaire (DSQ) and Health-Related Quality of Life (HRQoL) were also collected in order to evaluate clinical response.

Results

Two-hundreds ninety-two patients (232 males, 79%; mean age 37±14) treated with BOT were enrolled, in 8 Italian Centres and 1 Israelian Centre. The most frequent symptoms at diagnosis were dysphagia (82%) and food bolus impaction (68%). At least 1 allergic comorbidity was present in 67% of patients. 259 patients were evaluated at T1: endoscopic remission was achieved in 53% of patients, with a reduction of the mean EREFS score from 3±2 to 2±1 (p<0.0001). Histological remission was obtained in 93% of patients, with 19/259 treatment non-responders. The DSQ showed a significant reduction from 30±23 vs 6±12 (p<0.001). HRQoL questionnaire score passed from 112±37 to 153±30 (p<0.0001). 136 patients completed 1 year of treatment, and 76% of them resulted in endoscopic remission. In particular, the presence of stenosis passed from 31/292 at baseline (T0) to 1/136 at T2 (p<0.0001). Histological remission was maintained in 92%, while 11/136 lost histological response after BOT tapering. As well as for T1, both DSQ (4±10) and HRQoL score (153±28) resulted improved (p<0.0001). Side effects occurred in 36 out of 292 patients (12%), and the main one was candidiasis (25/36, 70%). Only 15 of patients needed to stop the treatment. All data are resumed in Table 1.

Conclusion

This study confirms the effectiveness of the treatment with BOT in both inducting and maintaining remission of EoE in a real-life setting, either considering clinical, endoscopic and histologic outcomes. Our data also showed a good safety profile, with a few patients requiring drug interruption.

References

Geow R, Arena G, Siah C, Picardo S. A retrospective real-world study on the safety and efficacy of budesonide orodispersible tablets for the induction therapy of eosinophilic oesophagitis. Therap Adv Gastroenterol. 2024 Oct 16;17:17562848241290346. doi: 10.1177/17562848241290346. PMID: 39421000; PMCID: PMC11483688.
Lucendo AJ, Miehlke S, Schlag C, Vieth M, von Arnim U, Molina-Infante J, Hartmann D, Bredenoord AJ, Ciriza de Los Rios C, Schubert S, Brückner S, Madisch A, Hayat J, Tack J, Attwood S, Mueller R, Greinwald R, Schoepfer A, Straumann A; International EOS-1 Study Group. Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial. Gastroenterology. 2019 Jul;157(1):74-86.e15. doi: 10.1053/j.gastro.2019.03.025. Epub 2019 Mar 26. PMID: 30922997.
Straumann A, Lucendo AJ, Miehlke S, Vieth M, Schlag C, Biedermann L, Vaquero CS, Ciriza de Los Rios C, Schmoecker C, Madisch A, Hruz P, Hayat J, von Arnim U, Bredenoord AJ, Schubert S, Mueller R, Greinwald R, Schoepfer A, Attwood S; International EOS-2 Study Group. Budesonide Orodispersible Tablets Maintain Remission in a Randomized, Placebo-Controlled Trial of Patients With Eosinophilic Esophagitis. Gastroenterology. 2020 Nov;159(5):1672-1685.e5. doi: 10.1053/j.gastro.2020.07.039. Epub 2020 Jul 25. PMID: 32721437.

Introduction

The efficacy of IL-23 blockade has implicated IL-23 in the pathogenesis of inflammatory bowel disease (IBD) and myeloid cells that express FcγRI (CD64) have been identified as the primary cellular source of IL-23 in inflamed IBD gut tissue [1, 2]. Guselkumab (GUS), risankizumab (RZB), and mirikizumab (MIRI) are monoclonal antibodies (mAbs) specifically directed against the IL-23p19 subunit. GUS is a fully human IgG1 mAb, RZB is a humanized IgG1 mAb, and MIRI is a humanized IgG4 mAb. Guselkumab has a native Fc domain while RZB and MIRI contain mutations in the Fc domain that diminish binding to FcγRs.

Aims & Methods

Here, we evaluated CD64 and IL-23 transcript expression in IBD patient gut biopsies, binding of GUS, RZB, and MIRI to IL-23 and CD64, and their potency for neutralization of recombinant or endogenous, locally produced, IL-23 in in vitro assays. IL23A, IL12B, and FCGR1A (CD64) expression was analyzed from bulk and single-cell RNA sequencing datasets. IL-23 binding affinity was evaluated using a kinetic exclusion assay. Binding of GUS, RZB, and MIRI to CD64 was assessed in cells with recombinant expression of CD64. Potency for inhibition of recombinant IL-23 was evaluated by impact on IL-23-induced phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) in human peripheral blood mononuclear cells. Potency for inhibition of endogenous, locally produced IL-23 was determined in a co-culture of THP-1 (a CD64⁺ monocyte cell line activated to produce IL-23) and an IL-23 reporter cell line (measuring biologically active IL-23).

Results

Analysis of bulk and single cell RNA sequencing datasets showed that FCGR1A, IL23A, and IL12B were significantly increased in inflamed versus non-inflamed IBD gut biopsies, and that IL23A was predominantly expressed by FCGR1A-expressing myeloid cells. GUS, RZB, and MIRI displayed single-digit picomolar binding affinity for IL-23. GUS demonstrated binding to CD64, while no binding was observed for RZB or MIRI. GUS, RZB, and MIRI demonstrated comparable potency for inhibition of signaling by recombinant IL-23 in human PBMCs. However, in a co-culture of IL-23–producing CD64⁺ THP-1 cells with an IL-23–responsive reporter cell line, GUS demonstrated enhanced potency compared to RZB and MIRI for inhibition of IL-23 signaling.

Conclusion

Our transcriptomic analysis supported previous observations of CD64⁺ myeloid cells as a key source of IL-23 production in inflamed IBD gut tissue. GUS binding to CD64 on IL-23–producing cells likely contributed to the enhanced functional potency of GUS compared to RZB and MIRI for inhibition of IL-23 signaling in the co-culture assay. These in vitro data support a hypothesis for optimal localization of GUS in inflamed tissues where CD64⁺ IL-23–producing myeloid cells are increased and in proximity to IL-23–responsive lymphoid cells, enabling GUS to more potently neutralize IL-23 at its source of production.

References

1. Chapuy, L., et al., IL-12 and Mucosal CD14+ Monocyte-Like Cells Induce IL-8 in Colonic Memory CD4+ T Cells of Patients With Ulcerative Colitis but not Crohn's Disease. J Crohns Colitis, 2020. 14(1): p. 79-95.
2. Chapuy, L., et al., Two distinct colonic CD14(+) subsets characterized by single-cell RNA profiling in Crohn's disease. Mucosal Immunol, 2019. 12(3): p. 703-719.

Disclosure

RA served as a paid or unpaid consultant for or received honoraria from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Ferring, Fresenius Kabi, Galapagos, Gilead, GSK, InDex Pharmaceuticals, Janssen, Kiniksa Pharmaceuticals, Merk Sharp & Dohme, Novartis, Pfizer, Roche, Samsung Bioepis, Stelic, sterna biologicals, Takeda, and Tillotts.
JRA served as a consultant for Abbvie, Ferring, Finch, Iterative Scopes, Janssen, Merck, Pfizer, Roivant, Seres Therapeutics, and Roivant Adiso; served as a speaker for Abbvie, Bristol Myer Squibb, and Janssen; and received research support from Janssen, Merck, and Pfizer.
MTA is a consultant or served on advisory boards for AbbVie, Arena Pharmaceuticals Inc. (now Pfizer), Bristol Myers Squibb, Celsius Therapeutics, Lilly, Gilead, Janssen Pharmaceuticals, Janssen Global Services, Pfizer, Prometheus Biosciences, and UCB; and received fees for lecturing from Alimentiv, Janssen Pharmaceuticals, Prime, and WebMD Global LLC.
AH, HI, TF, EL, MD, PB, TS, JW, IS, KK, AF and KS are employees of Janssen Research & Development, LLC and may hold stock in Johnson & Johnson.

Introduction

Immune checkpoint inhibitors (ICIs), a new class of immunotherapeutic agents, are the first-line treatment for many advanced epithelial cancers. Gastrointestinal irAEs, particularly diarrhea and colitis, affect approximately 40% of ICI-treated patients and often lead to therapy discontinuation.¹ High-dose corticosteroids represent the first-line treatment, but about one-third of patients show inadequate response and require second-line immunosuppressants such as Infliximab or Vedolizumab.² As the body of evidence about the role of gut microbiota in the pathogenesis of GI irAE grows, fecal microbiota transplantation (FMT) is emerging as a potential treatment for steroid- and biologic-refractory ICI-induced colitis.³ Although data are still preliminary, FMT represents a promising therapeutic strategy in this setting.

Aims & Methods

The aim of this study is to evaluate the safety and efficacy of FMT in patients referred to our Microbiome clinic for steroid- and biologic-refractory ICI-induced colitis. After clinical evaluation, patients were treated with FMT via colonoscopy from healthy donors. FMT was performed as already described, following international clinical guidelines.^4,5 Following the endoscopic procedure, patients were evaluated at 1, 4, 8, and 12 weeks. We collected data on: patient characteristics, cancer type, cancer treatment and its suspension, severity of diarrhea before FMT (graded via CTCAE)⁶, time in weeks from initiation of cancer therapy to onset of diarrhea, grade of diarrhea following treatment and resumption of ICI.

Results

Our cohort included 7 patients with steroid- and biologic-refractory ICI-induced colitis (grade 1: n=0 ; grade 2: n=1 ; grade 3: 5=x; grade 4: n=1). Four patients were affected by renal cell carcinoma, 2 by melanoma, 1 by pulmonary cancer. All patients were treated with PD-1/PDL-1 inhibitors or CTLA-4 ( Nivolumab: n= 3; Nivolumab and Ipilimumab: n=2; Durvalumab: n= 1; Pembrolizumab: n= 1) and 6 patients interrupted ICI due to gastrointestinal irAEs. All patients received single FMT from healthy donors via colonoscopy. Following FMT, diarrhea improved to grade ≤ 1 in 6 patients (85%) at week 1, 4, 8, and 12 after the procedure, suggesting a sustained effect of microbiome modulation in the medium term. One patient died during follow-up for reasons other than ICI-colitis.

Conclusion

Our preliminary findings suggest that FMT may be a promising therapeutic strategy for refractory ICI-colitis. Further, larger and randomized studies are warranted to confirm our data.

References

1. Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021;160(4):1384-1393. doi:10.1053/j.gastro.2020.08.063
2. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(12):1217-1238. doi:10.1016/j.annonc.2022.10.001
3. Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24(12):1804-1808. doi:10.1038/s41591-018-0238-9
4. Cammarota G, Ianiro G, Kelly CR, et al. International consensus conference on stool banking for faecal microbiota transplantation in clinical practice. Gut. 2019;68(12):2111-2121. doi:10.1136/gutjnl-2019-319548
5. Ianiro G, Rossi E, Thomas AM, et al. Faecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma. Nat Commun. 2020;11(1):4333. doi:10.1038/s41467-020-18127-y
6. Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr. 2021;112(1):90-92. doi:10.1016/j.ad.2019.05.009

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.

Introduction

The Phase 3 QUASAR induction study (NCT04033445) was a randomized, double-blind, placebo-controlled study that evaluated guselkumab (GUS), an interleukin-23 p19 subunit antagonist, in patients with moderately to severely active ulcerative colitis (UC) who had an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants and/or advanced therapy (ADT, i.e., tumor necrosis factor antagonists [anti-TNFs], integrin receptor antagonists [vedolizumab], and/or Janus kinase [JAK] inhibitors [tofacitinib]). Here we report induction efficacy results for GUS compared with placebo by history of inadequate response, loss of response, or intolerance to ADT (ADT-IR).

Aims & Methods

Patients were randomized in a 3:2 ratio to receive IV GUS 200 mg or placebo at Weeks (Wks) 0, 4, and 8. The primary analysis population included patients with a baseline modified Mayo score of 5 to 9, inclusive, and a centrally reviewed endoscopy subscore ≥ 2. The primary endpoint was clinical remission at Wk 12. Symptomatic remission, clinical response, endoscopic improvement, histo-endoscopic mucosal improvement (HEMI), and endoscopic normalization were assessed at Wk 12.

Results

Of the 701 patients in the primary analysis population, 357 (50.9%) had no history of ADT-IR (of which 95.0% were ADT-naïve) ; 344 (49.1%) had a history of ADT-IR. Among the ADT-IR patients, the proportions with a history of inadequate response/loss of response/intolerance to TNF antagonists , vedolizumab, tofacitinib, and multiple ADT classes were 87.5%, 54.1%, 18.0% and 47.4%, respectively. At baseline, patients with a history of ADT-IR had longer disease duration (mean 8.9 vs 6.2 yrs), more severe endoscopic disease (endoscopy subscore of 3, 78.5% vs 57.7%), higher CRP (median 5.3 mg/L vs 3.4 mg/L and proportion of patients >3mg/L 64.1% vs 53.7%) and higher fecal calprotectin (median 1647 mg/kg vs 1589 mg/kg and proportion of patients >250 mg/kg 92.3% vs 86.9%) compared with patients without a history of ADT-IR. Greater proportions of patients treated with GUS vs placebo achieved primary and key secondary endpoints at Wk 12 in both subgroups of patients with and without a history of ADT-IR, including clinical remission, symptomatic remission, clinical response, endoscopic improvement, HEMI, and endoscopic normalization (Table 1). The treatment differences for GUS vs placebo were generally greater among patients without a history of ADT-IR compared with those with such a history.

Table 1. Primary and key secondary endpoints by history of inadequate response/loss of response/intolerance to advanced therapy (ADT-IR)

Conclusion

Induction treatment with GUS 200 mg IV resulted in greater improvements compared with placebo across key clinical, symptomatic, and endoscopic/histologic outcomes at Wk 12 among moderately to severely active UC patients with and without a history of ADT-IR.

Disclosure

Brian Bressler is an advisor/speaker and has received research support from Janssen. Steering Committee member for Janssen.
Laurent Peyrin-Biroulet reports personal fees and serves as a Steering Committee member for Janssen.
Jessica R. Allegretti is a consultant and Steering Committee member for Janssen.
Kuan-Hsiang G. Huang is an employee of Johnson & Johnson and owns company stock/stock options.
Matthew Germinaro is an employee of Johnson & Johnson and owns company stock/stock options.
Nicole Shipitofsky is an employee of Johnson & Johnson and owns company stock/stock options.
Ye Miao is an employee of Johnson & Johnson and owns company stock/stock options.
Hongyan Zhang is an employee of Johnson & Johnson and owns company stock/stock options.
Martin Bortlik is a clinical investigator and consultant for Janssen.
Tibor Hlavaty is a clinical investigator and consultant for Janssen.
Toshimitsu Fujii has received research grants and speaker’s fees from Janssen.
Brian G. Feagan received grant/research support from Janssen Research & Development LLC.; a consultant for JnJ/Janssen; a member of the speakers bureau for JnJ/Janssen; a member of the scientific advisory board for JnJ/Janssen. Steering Committee member for Janssen.
Bruce E. Sands reports grants, consulting and speaking fees and other support from Janssen, and is a Steering Committee member for Janssen.
Axel Dignass reports fees for participation in clinical trials, review activities such as data monitoring boards, statistical analysis and end point committees from Janssen; consultancy fees from Janssen; payment from lectures including service on speakers bureaus from Janssen. Steering Committee member for Janssen.