Introduction

Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator, is approved for the treatment of moderately to severely active ulcerative colitis (UC) and for the treatment of relapsing multiple sclerosis (RMS). Ozanimod is a first-in-class S1P receptor modulator approved for UC, and one of several S1P receptor modulators used for the treatment of RMS. Ozanimod has been extensively studied in RMS with large patient populations and long exposure times, which can provide more insight into the safety profile of ozanimod in UC.

Aims & Methods

This analysis evaluated the tolerability and safety of long-term ozanimod 0.92 mg/day treatment from clinical trial data in adults with moderately to severely active UC and from clinical trial data in adults with RMS. The UC population included patients pooled from phase 2 (NCT01647516), phase 3 (NCT02435992), and respective open-label extension (OLE; NCT02531126) trials through January 10, 2022. The RMS population included patients treated with ozanimod 0.92 mg in DAYBREAK (NCT02576717; October 16, 2015–February 1, 2022), an ongoing OLE trial of patients from phase 1‒3 ozanimod studies. Safety outcomes included treatment-emergent adverse events (TEAEs) and TEAEs of special interest based on association with S1P modulation. Exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) were calculated to adjust for time on study.

Results

Mean (SD) ozanimod exposure in 1158 patients with UC was 28.4 (23.3) months (2714.9 total PY exposure); ozanimod exposure in 2494 patients with RMS was 56.4 (15.9) months (11,732.2 PY; UC and MS combined: 14,447.1 PY). TEAEs occurred in 74.6% of UC and 88.2% of RMS patients. Serious TEAEs were reported in 17.3% of UC and 14.1% of RMS patients, and TEAEs leading to ozanimod discontinuation in 9.3% and 3.6%, respectively. The most common TEAEs were lymphopenia (12.3%; EAIR 5.6/100 PY), anemia (8.4%; EAIR 3.7/100 PY), lymphocyte count decreased (7.9%; EAIR 3.5/100 PY), and nasopharyngitis (7.9%; EAIR 3.5/100 PY) in patients with UC, and nasopharyngitis (20.6%; EAIR 5.1/100 PY), headache (16.9%; EAIR 4.0/100 PY), and upper respiratory infection (11.9%; EAIR 2.7/100 PY) in patients with RMS. In UC and MS, respectively, EAIR/100 PY were 20.2 and 22.9 for any infection, 1.6 and 0.8 for serious infection, 1.2 and 1.4 for opportunistic infection, and 0.6 and 0.3 for malignancy. Alanine aminotransferase levels ≥5 times the upper limit of normal occurred in 2.3% and 0.8% of UC and RMS patients, respectively.

Conclusion

Long-term ozanimod 0.92 mg/day was generally well tolerated and safe for most patients with moderately to severely active UC or RMS.

Disclosure

SD: received honoraria as a speaker, consultant, and/or advisory board member from AbbVie, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor.
BACC: received personal compensation for consulting for Alexion, Atara, Autobahn Therapeutics, Avotres, Biogen, EMD Serono, Gossamer Bio, Horizon Therapeutics, Neuron23, Novartis, Sanofi, TG Therapeutics, and Therini Bio; and received research support from Genentech.
DCW: received research honoraria as a speaker, consultant, and/or advisory board member from AbbVie, Arena, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, Janssen, Pfizer, and Takeda.
OA: received honoraria as a speaker from Janssen, Pfizer, and Takeda.
LC, AP, JKS, CYC, JVR, and DS: employees and/or shareholders of Bristol Myers Squibb.
FDL: participated in consulting agreements, advisory boards, and/or data and safety monitoring boards with Acorda, Actelion, Apitope, Atara, Biogen, BrainStorm Cell Therapeutics, EMD Serono, GW Pharmaceuticals, Immunic, Innate Immunotherapeutics, Jazz Pharmaceuticals, Mapi Pharma, MedDay, MedImmune/Viela Bio, Mylan, Novartis, Orion Biotechnology, Polpharma, Population Council, Receptos/Celgene, Roche/Genentech, Sanofi/Genzyme, Teva, and TG Therapeutics.
JAC: received personal compensation for consulting from Biogen, Bristol Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and Pharmaceutical Security Institute; speaking from H3 Communication; and serving as an editor of Multiple Sclerosis Journal.
DTR: received grant support from Takeda; served as a consultant for AbbVie, AltruBio, Arena Pharmaceuticals, Bristol Myers Squibb, Eli Lilly, Genentech/Roche, Gilead Sciences, Iterative Scopes, Janssen, Pfizer, Prometheus Biosciences, Takeda, and TechLab.

This study was sponsored and funded by Bristol Myers Squibb.

Introduction

Volatile organic compounds (VOC) in stool samples may reflect functional activity of gut microbiome. Previous studies showed that gut flora may influence transient relaxations of lower esophageal sphincter through short-chain fatty acids production and thus - participate in pathogenesis of gastroesophageal reflux disease (GERD). However, the role of VOC in pathogenesis of GERD is poorly studied yet.

Aims & Methods

The aim of this study (FGMF-2025-0003) was to perform correlation analysis between concentrations of VOC in stool samples and GERD-Q score.
We enrolled willing to participate patients referred to perform multichannel 24-h pH-impedance recording (Ohmega, Laborie). According to the Lyon 2.0 criteria patients were allocated to the GERD or the control group. GERD-Q questionnaire was filled in by the participants on the same day as stool samples were collected. Thermo TSQ 8000 triple quadrupole mass-spectrometer (GC/MS) was used for the measurement of VOCs in stool samples were analyzed with. Correlation analysis (Spearman rank R) was performed between values of 80 VOCs in stool samples and the results of GERD-Q questionnaire.

Results

Data of 76 patients were eligible: 42 with GERD and 34 - of the control group. Participants in the GERD group were older (54.7±12.2 y.o. vs 46±14.9 y.o., P<0.05) and their BMI was greater (30.9±5.2 vs 27.2±6.5 kg/m², P<0.05). GERD-Q score was logically greater in GERD group (11.0±2.5 vs 5.2±1.2, p<0.01). Correlation analysis revealed significant correlations between GERD-Q score and concentrations of 2-methylbutyric acid (Spearman R =-0.31), caproic acid (0.34) and enantiic acid (0.396) in stool samples.

Conclusion

GERD-Q score positively correlates with concentrations of Caproic acid (0.34) and Enantiic acid (0.396) in stool samples and negatively – with 2-Methylbutyric acid. The data of this pilot study may serve as a basis for further research on the role of functional activity of gut microbiome in pathogenesis of GERD.

Clinical Case Summary

Immunotherapy with checkpoint inhibitors (CPI) has transformed oncology management, achieving durable remissions. However, its widespread has also led to significant immune-mediated side effects, whose treatment is a challenge in today's medicine.
We present the case of a 59-year-old man diagnosed with non-small-cell lung cancer who started treatment with Nivolumab(anti-PD1). After 6 months, the patient was admitted for 3 weeks diarrhoea(4 liquid stools/day).
A colonoscopy was done, identifying severe pancolitis with oedema, erythema, nodularity and superficial ulcers. PA revealed diffuse non-specific colitis with CMV IHC -. Given the suspicion of immune-mediated colitis vs de novo IBD, treatment was started with iv GCC, with no improvement.
Given the contraindication of long-term use of anti-TNF in IBD patients with active malignancies, induction with IV Ustekinumab (anti-IL12/23) was decided. Ustekinumab 390 mg iv was given, after which the patient showed clinical improvement until complete resolution. He continued with Ustekinumab 90 mg/8 weeks. A follow-up colonoscopy showed pancolic scarring with pseudopolyps and no inflammatory activity. Given these findings Ustekinumab was discontinued after 1 year, with the patient remaining asymptomatic and without oncologic progression.
Immune-mediated colitis is a common side effect, being mild in most cases. When severe cases occur, CPI should be discontinued indefinitely, and high-dose iv GCC (up to 2 mg/kg) should be initiated. Up to one-third of GCC-treated patients don't respond and are candidates for immunosuppressive therapy with biologic drugs.
Although clinical guidelines recommend Infliximab/Vedolizumab for induction as 2º line treatment, the therapeutic decision should be individualized, as they are contraindicated in IBD patients with active malignancies. Therefore, in this context of complex differential diagnosis, Ustekinumab (with lower rate of oncological side effects) appears to be an effective option.

References

Photo 1: Initial colonoscopy: severe pancolitis with erythema, oedema, superficial ulcers and mucosal nodularity.
Photo 2: Abdominal CT: Diffuse thickening of the colon with increased uptake of the wall.
Photo 3: Follow-up colonoscopy: Chronic scar changes without signs of acute activity.

Introduction

The estimated global prevalence of biopsy-confirmed celiac disease (CeD) is 0.7% and sero-positive prevalence is 1.4%. Differences in definitions of CeD cases and at-risk populations, as well as underdiagnosis, may affect accurate estimation of the size of the diagnosed CeD population. In this study, we calculated the 10-year prevalence of diagnosed CeD in the USA using different CeD case definitions and at-risk populations.

Aims & Methods

A prevalence analysis of CeD cases was conducted using data collected from the Optum Clinformatics^® Data Mart, a US claims database. Prevalence calculations were based on two different definitions of CeD cases. Case definition 1 included any of the following: 1) International Classification of Diseases (ICD)-9/-10 diagnostic codes for CeD (≥ 1 inpatient or ≥ 2 outpatient codes), 2) tissue transglutaminase immunoglobulin A (tTG-IgA) positive serology or 3) biopsy-confirmed CeD (defined as esophagogastroduodenoscopy [EGD] followed by an ICD diagnostic code for CeD used as proxy). Case definition 2 was defined as the first ever positive tTG-IgA test followed by biopsy-confirmed CeD. The prevalence of diagnosed CeD was estimated for each study year from 2013 to 2022. Prevalence estimations were age- and sex-standardized using 2022 US Census data.

Results

The total population (denominator) comprised ~81 million individuals; of whom, 110,140 had ≥ 1 inpatient or ≥ 2 outpatient diagnostic codes for CeD, 41,184 had ≥ 1 positive tTG-IgA test and 44,641 had biopsy-confirmed CeD. Among all individuals that were tested for tTG2-IgA, 0.85% (95% confidence interval [CI]: 0.82, 0.89) were positive for CeD. The age- and sex-standardized prevalence of diagnosed CeD according to case definition 1 modestly increased from 0.27% (95% CI: 0.27, 0.27) in 2013 to 0.35% (0.34, 0.35) in 2022. Over the same time period, the age- and sex-standardized prevalence of diagnosed CeD according to case definition 2 increased from 0.01% (0.01, 0.01) to 0.03% (0.03, 0.03), respectively.

Conclusion

The overall prevalence of diagnosed CeD in the USA modestly increased from 2013 to 2022. During this same time period, the proportion of patients who underwent an EGD after a positive tTG-IgA test steadily rose. Validation of the CeD case definitions used in this study will be important to enable these results to be replicated or refuted. Furthermore, a standardized and validated CeD case definition will support comparisons between studies and inform better clinical care/disease management.

Disclosure

MA, SM, NC, KG and DAL are employees of Takeda Development Center Americas, Inc. and receive stock or stock options.

Introduction

Infliximab is an important treatment option in the management of inflammatory bowel disease (IBD). It has traditionally been administered as an intravenous(IV) infusion but is now available as a subcutaneous (SC) injection. There is limited real world data around SC infliximab use and drug levels. In Ireland, IV medications are paid for from the hospital budget and SC medications are paid for from the community health budget.

Aims & Methods

This study aims to assess the trough levels of infliximab when given in SC formulation compared to IV formulation, to assess faecal calprotectin pre and post switching drug route, to assess patient’s attitudes to SC therapy and to examine the cost savings associated with switching to SC infliximab. Proactive therapeutic drug levels are routinely performed in our clinic and we routinely offer SC switch to patients on IV infliximab. Patients currently receiving infliximab were identified using the departmental IBD database. Inclusion and exclusion criteria were applied. Infliximab trough levels from when the patient was receiving IV infliximab were compared to the most recent trough level while using SC infliximab. Response to SC infliximab was assessed using faecal calprotectin. Health related quality of life was also measured using the IBD Disk Questionnaire. A subset of patients completed a questionnaire about attitudes to SC therapy. The financial cost of providing IV infliximab to each patient was assessed.

Results

In total 103 patients receiving SC infliximab for >3 months were identified. 0 were excluded. 55 (53%) were female and 48 (47%) were male. The median age was 39 (19-79). 57 (55%) had Crohn’s disease (CD), 46 (45%) had ulcerative colitis (UC). Infliximab trough levels improved by an average of 14.98ug/mL (188.6%) after switching to SC (P<0.05). Faecal calprotectin fell by an average of 74.45ug/g (-18.8%) after switching from IV to SC formulation (P<0.05). Average IBD disk score while on SC infliximab was 36.96/100 reflecting that the included patients have ongoing disease activity. The IBD disk score correlated with faecal calprotectin r 0.22 (P<0.05). In a subset of patients surveyed, 90% (n=10) preferred SC to IV infliximab. Switching from IV to SC infliximab for the 103 patients included in this study has saved our department 523,137 euro per annum. There are also significant savings in terms of infusion suite capacity. In total our unit saves 670 infusion suite appointments per year due to these patients switching to SC therapy.

Conclusion

Switching from IV to SC Infliximab is not associated with a deterioration in infliximab drug levels or faecal calprotectin levels. Switching from IV to SC infliximab saved significant amounts of money for our hospital budget and has improved our infusion suite capacity. Patients expressed a preference for SC administration over IV. In summary switching from IV to SC infliximab may be considered for patients with Crohn's disease and ulcerative colitis.