Introduction

Long-term data on bowel urgency (BU) in Crohn’s disease (CD) are limited, and the associations with other efficacy outcomes are not well studied.

Aims & Methods

Our aims were to examine the long-term efficacy of mirikizumab (MIRI) on BU remission and the associations between BU remission and clinical remission, endoscopic remission, and patient-reported outcomes (PRO) improvement at week (W) 104 in patients with moderately to severely active CD who were randomized to MIRI in the Phase 3 study VIVID-1 and continued into the long-term extension study VIVID-2. In VIVID-1, the MIRI group received induction with 900 mg intravenously (IV) at W0, W4, and W8, then 300 mg subcutaneously (SC) every 4W. W52 endoscopic responders (≥50% reduction from baseline in Simple Endoscopic Score for CD [SES-CD]) continued MIRI SC dosing in VIVID-2. Endoscopic non-responders received reinduction with MIRI IV (3x Q4W) at the start of VIVID-2 followed by SC dosing (IV-SC) as described. Patients that had an Urgency Numeric Rating Scale (UNRS) ≥3 (least to worst range 0-10) at baseline were included in these analyses. BU remission was defined as an UNRS score of ≤2. Associations between BU remission with clinical remission by Crohn’s Disease Activity Index (CDAI), endoscopic remission, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (range 0-52, higher is better), and Inflammatory Bowel Disease Questionnaire (IBDQ) remission, were assessed at W104, within the VIVID-1 W52 endoscopic response subgroups as well as the MIRI total group. Discontinuations or missing data were handled using modified non-responder imputation (mNRI) for categorical data. Missing values were imputed by multiple imputation and modified baseline observation carried forward for FACIT-Fatigue change from baseline.

Results

Over 50% of the MIRI total group, 56% of MIRI W52 endoscopic responders, and 43% of the MIRI W52 endoscopic non-responders achieved BU remission at W104. In the MIRI total group, a significantly higher percentage of patients achieved clinical remission, endoscopic remission and IBDQ remission at W104 in the BU remission group compared to those without BU remission. The improvement in fatigue by FACIT-Fatigue score was significantly more in the group with BU remission versus those without BU remission (p<0.0001). In both MIRI W52 endoscopic responders and non-responders, patients who achieved BU remission at W104, compared to those who did not, achieved significantly higher rates of clinical remission, greater improvements in FACIT-Fatigue, and higher rates of quality of life improvement measured by IBDQ remission (Table 1).

Table 1

Conclusion

Over 50% of patients with CD achieved BU remission at 2 years of treatment with MIRI. These results highlight that the achievement of BU remission corresponded with improvements to outcomes important to patients with CD, underscoring the importance of long-term management of BU in improving overall patient outcomes.

Disclosure

SRV: has received consulting fees, speaker’s honoraria and unrestricted research grants from Abbott, Alfasigma, Amgen, Arenapharm, BMS, Falk Pharma GmbH, Ferring Pharmaceuticals, Gilead, iQuone, Janssen, MSD, Permamed, Pfizer, Sanofi-Aventis, Schwabe Pharma, Takeda, Tillotts, UCB and Vifor
DTR: receives grants or contracts from Takeda, and discloses consultancy fees with AbbVie, Altrubio, Apex, Avalo Therapeutics, Bristol Myers Squibb, Buhlmann Diagnostics Corp, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Janssen Pharmaceuticals, Lilly, Pfizer, Samsung Neurologica, and Takeda. He serves on the Board of Directors for Cornerstones Health.
JW, GY, AV, REM, and RRH: Employees and stockholders of Eli Lilly.
GD-H: Has received research grants from: Alimentiv BV, Bristol Myers Squibb, Eli Lilly and Company, Pfizer, and Takeda; and consulting fees from: AbbVie, Alimentiv, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, GSK, Merck Sharp & Dohme, Pfizer, Sorriso Pharmaceuticals, Takeda, Tillotts Pharma AG, and Ventyx Biosciences
ST: has received grants from: AbbVie, BUHLMANN Diagnostics, ECCO, Eli Lilly and Company, Ferring Pharmaceuticals, International Organization for the Study of Inflammatory Bowel Disease, Janssen, Merck Sharp & Dohme, Norman Collison Foundation, Pfizer, Procter & Gamble, Schering-Plough, Takeda, UCB Pharma, Vifor Pharma, and Warner Chilcott; and reports other disclosures from: Abacus Pharma, AbbVie, Actial Farmaceutica, ai4gi, Alcimed, Allergan, Amgen, Aptel, Arena Pharmaceuticals, Asahi Kasei Pharma, Aspen Pharmacare, Astellas, AstraZeneca, Atlantic Pharmaceuticals, Barco, Biocare Medical, Biogen, BL Pharma, Boehringer Ingelheim, Bristol Myers Squibb, BUHLMANN Diagnostics, Calcico Therapeutics, Celgene, Cellerix, Cerimon Pharmaceuticals, ChemoCentryx, Chiesi, Cisbio, Comcast, Coronado Biosciences, Cosmo Pharmaceuticals, Dr. Falk Pharma, Ducentis BioTherapeutics, Dynavax Technologies, Elan Pharma, Eli Lilly and Company, Enterome, Equillium, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Genzyme, Gilead Sciences, GlaxoSmithKline, Glenmark Pharmaceuticals, Grünenthal, GW Pharmaceuticals, Immunocore, Indigo Biosciences, Janssen, Lexicon Pharmaceuticals, Medarex, MedTrix, Merck, Merrimack Pharmaceuticals, Mestag Therapeutics, Millennium Pharmaceuticals, Neovacs, Novartis, Novo Nordisk, NPS Pharmaceuticals/Nycomed, Ocera Therapeutics, OPTIMA Pharma, Origin Pharma, Otsuka, Palau Pharma, Pentax Medical, Pfizer, PharmaVentures, Phesi, Phillips Pharma Group, Procter & Gamble, Pronota, Proximagen, Resolute Pharma, Robarts Clinical Trials, Sandoz, Santarus, Satisfai Health, Sensyne Health, Shire, Sigmoid Pharma, Sorriso Pharmaceuticals, Souffinez, SynDermix, Synthon, Takeda, Theravance Biopharma, TiGenix, Tillotts Pharma AG, Topivert, Trino Therapeutics with Wellcome Trust, TxCell SA, UCB Pharma, Vertex Pharma, VHsquared, Vifor Pharma, Warner Chilcott, and Zeria Pharmaceutical
AW: reports consulting and/or speaking fees from Abbvie, Bristol-Myers Squibb, Ferring, Galapagos, Janssen, Pfizer, and Takeda.

Clinical Case Summary

Aims: We report 3 cases of new inflammatory bowel disease (IBD) which occurred in multiple sclerosis (MS) patients undergoing ocrelizumab therapy over last year in Irish Teaching Hospital setting.
Background: Ocrelizumab, a monoclonal antibody targeting CD20-positive B cells, is an established treatment for MS. While it is generally well-tolerated, emerging reports suggest a possible link to gastrointestinal complications, including IBD.
Methods: Three MS patients presented after starting ocrelizumab with gastrointestinal symptoms suggestive of inflammatory bowel disease. They were fast-tracked for endoscopic evaluation by an experienced gastroenterologist specializing in IBD. Diagnosis was based on clinical presentation, endoscopic findings, and histological analysis. Data regarding symptom onset, disease severity, colitis grade, inflammation distribution, and treatment response were assessed.
Results: A temporal relationship was observed between ocrelizumab initiation and IBD onset in all three cases, with symptoms emerging after 4-6 infusions. Reported symptoms included diarrhoea, nausea, urgency, and abdominal pain. Faecal calprotectin levels at time of referral ranged from 900 to 1800 µg/g. Endoscopy confirmed mild colitis and terminal ileitis, while histology revealed active colitis with cryptitis, acute terminal ileitis, or normal colon findings. Treatment with steroids, Mesalazine, and antibiotics led to symptom resolution in all cases. Discontinuing ocrelizumab resulted in recovery within 4-6 weeks, with no relapse over an average follow-up of two months.
Conclusion: These cases suggest a potential association between ocrelizumab and IBD onset or exacerbation in MS patients. Symptom resolution upon drug withdrawal supports a possible causal relationship. Clinicians should be aware of this risk to facilitate early detection, management, and patient education.

References

https://journals.lww.com/acgcr/Fulltext/2022/01000/Severe_Ocrelizumab_Induced_Enterocolitis_Treated.31.aspx
https://pubmed.ncbi.nlm.nih.gov/32198886/

Disclosure

No Conflict of Interest

Introduction

Ulcerative colitis (UC) is a progressive disease and associated with reduced quality of life.¹ Treatment goals for patients with UC are to induce and maintain clinical remission, and avoid or delay the need for surgery.^2,3 Increasing number of advanced treatment options have been approved in recent years for patients with UC. However, the optimal treatment pathway is not well understood. Guselkumab, a dual-acting IL-23 inhibitor, has demonstrated clinical remission as high as 50.0% at maintenance Week 44 in the Phase 3 QUASAR study, suggesting the potential of guselkumab to provide durable clinical remission.⁴ A disease model was developed to identify the optimal treatment sequence with guselkumab for patients with moderate-to-severe UC.

Aims & Methods

A hybrid decision tree/Markov disease model was developed to project rates of clinical remission, response and active disease for patients with UC over five years. Patients were first distributed into health states representing remission, response without remission, and active UC (no response) based on the rates of clinical remission and response reported in the induction phases of Phase 2 and Phase 3 trials. Over time, loss of response and transition to the next line of therapy is derived based on loss of response rates in the trial data. Up to three treatment lines were modelled, and patients who lose response after third-line treatment are categorized as in active disease state where they can receive surgery. Age- and sex-adjusted mortality rates obtained from the US population life table were applied in the model. Three treatment sequences were assessed, where guselkumab was placed in first-line, second-line, and third-line, respectively. A treatment basket was used for the other lines of therapy, informed by 2024 market share data from MarketScan. We report the predicted average proportion of time spent in each health state for each of the three treatment sequences over five years.

Results

Over a 5-year period, the predicted average proportion of time patients spent in active disease is consistently lower for patients treated with guselkumab as a first-line therapy compared to those receiving it in later lines. In the first year, patients receiving first-line guselkumab spent 28% of time in active disease, while those treated with guselkumab in the second or third line spent 33%. This difference becomes more pronounced over the 5-year period, with proportion of time in active disease at 36% for first-line guselkumab use versus 48% and 51% for second- and third-line use, respectively. The reduction in time in active disease with earlier use of guselkumab infers that patients are asymptomatic, as patients are also projected to experience longer time in remission. The model predicts that, over 5 years, patients treated with first-line guselkumab spend an average of 52% of their time in remission, in contrast to 40% and 38% for those treated with guselkumab in the second- or third-line, respectively.

Table 1: Projected average proportion of time spent in each health state over a 5-year period

Conclusion

Model projections suggest that using guselkumab in first line is associated with long-term sustained remission for patients with UC, compared to using guselkumab in later lines of treatment.

References

1. Armuzzi A, Liguori G. Quality of life in patients with moderate to severe ulcerative colitis and the impact of treatment: A narrative review. Dig Liver Dis. 2021;53(7):803-808.
2. Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG Clinical Guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114(3):384-413.
3. Feuerstein JD, Isaacs KL, Schneider Y, et al. AGA clinical practice guidelines on the management of moderate to severe ulcerative colitis. Gastroenterology. 2020;158(5):1450-61.
4. Rubin DT, Allegretti JR, Panes J, et al. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. Lancet. 2025;405(10472):33-49.

Disclosure

Mariya Dimova, Mi Jun Keng, Dominik Naessens, Sumesh Kachroo, Shashi Adsul, Mario Gomez, and Elise Wu are employees of and may hold stock/stock options in Johnson & Johnson.