Introduction

Mirikizumab, a monoclonal antibody targeting the p19 subunit of IL-23, was approved in Germany in May 2024 for the treatment of moderately to severely active ulcerative colitis (UC), following favorable results in clinical trials (1,2). We aimed to evaluate the effectiveness and safety of mirikizumab (MIRI) in a real-world setting, focusing on a population of patients with prior exposure to three or more advanced therapies.

Aims & Methods

​​​​​In October 2023, we initiated a prospective observational study, collecting clinical, biochemical, and endoscopic data from adult patients (n > 100) with moderate to severe UC who began MIRI treatment in our tertiary referral center in Munich, Germany. The primary endpoints were clinical remission, defined as a Clinical Activity Index (CAI, Lichtiger score) <4 and endoscopic remission, defined as an endoscopic Mayo score ≤1 at 12 months. Secondary outcomes included monthly (1-4 mo) and bimonthly (6-12 mo) trends in fecal calprotectin levels, CAI scores, urgency numeric rating scale (NRS), frequency of re-induction therapy (300 mg every 4 weeks for 3 doses), and steroid discontinuation during the observation period. Adverse events were systematically recorded. All statistical analysis was performed by SolidPulse Software in Phyton using pandas, scipy and statsmodels. This report presents the first key results from patients who have completed at least 6 months of treatment.

Results

To date, 73 patients have initiated MIRI therapy as approved; none have discontinued treatment. Of these, 55 patients have reached the 6-month follow-up. These 55 had a median disease duration of 11 years (range 3–43), and 55% were female. All 55 patients had been exposed to three or more advanced therapies before starting MIRI, and 23 patients (42%) received MIRI concomitantly in combination with another targeted therapy. Among the 55 patients, 29 (53%) had previously lost response to ustekinumab (90 mg every 8 weeks), and 19 (35%) were on concomitant corticosteroids at the start of MIRI therapy. At baseline, 36 patients had a Mayo endoscopic score of II or III, and 19 had a score of 0 or I.
Main results:

• The rates of clinical remission (CAI <4) increased from 36% (30/55) at baseline to 42% (23/55) at 1 month (p=0,6), 40% (22/55) at 2 months (p=0,8), 49% (27/55) at 3 months (p=0,09), 58% (32/55) at 4 months (p=0,008), and 58% (32/55) at 6 months (p=0.008, McNemar test).
• Median urgency NRS scores improved from 5 (range 0–10) at baseline to 1 (range 0–9) at 6 months (p<0.0001, two-sided Wilcoxon test).
• Median calprotectin decreased from 460 (range 20–2100) at baseline to 75 (range 20–2100) at 6 months (p<0.0001, two-sided Wilcoxon test).
• Among the 29 patients with prior ustekinumab use, clinical remission increased from 41% (12/29) at baseline to 55% (16/29) at 6 months, though this change did not reach statistical significance (p = 0.3, McNemar test), possibly due to the low number of patients.

Conclusion

Mirikizumab demonstrated clinical effectiveness and was well tolerated in a real-world UC cohort, including patients with longstanding disease and multiple prior treatments with advanced therapies.

References

1) D’Haens G, Dubinsky M, Kobayashi T et al. Mirikizumab as induction and maintenance therapy for ulcerative colitis. NEJM. 2023; 388: 2444–2455.
2) Dubinsky MC, Clemow DB, Hunter Gibble T et al. Clinical effect of mirikizumab treatment on bowel urgency in patients with moderately to severely active ulcerative colitis and the clinical relevance of bowel urgency improvement for disease remission. Crohn's Colitis 360. 2023; 360: 1–13.

Disclosure

This work has been funded by a grant from Eli Lilly

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.

Introduction

The International Microbiota Observatory aimed to measure awareness, knowledge and behaviors about the microbiome in general populations worldwide and in patients.

Aims & Methods

The survey was conducted among 7,500 individuals aged 18 years old and over in 11 countries (France, Spain, Portugal, Poland, Finland, Morocco, United States of America, Brazil, Mexico, China and Vietnam). Automated selection from the Ipsos online Panel ensured representative samples of general population fit the quotas method based on gender, age, employment status, and country regions. Participants were asked to fill out an online questionnaire with single- or multiple-choice questions. Demographics, microbiome awareness and knowledge, behaviors, information provided by healthcare professionals were documented and analyzed using descriptive statistics. Our focus is a self-reported patients’ sub-population that included 4,509 individuals with respiratory (n=888), cardiovascular (n=1,177), digestive (n=1,036), genitourinary and kidney (n=529), neurological (315), autoimmune (n=716), osteoarticular (n=1040), psychiatric diseases (n=652), diabetes (n=745), cancer (n=270) and allergies (n=2,097).

Results

4,509 people with various chronic diseases from 11 countries completed the questionnaire (52% female, mean 47,7 years). 70% of these patients have heard of the term “microbiome”, with 24% knowing exactly what it is. However, patients' awareness varies according to the disease they have: people with diabetes are less aware (65%; (p<0.001) and people with digestive diseases are more aware (79%; (p<0.001) of this term compared to all patients. For patients with cardiovascular disease, awareness is not statistically different compared to all patients (68%). In their daily lives, 61% of patients have changed their behaviors to keep their microbiome as balanced and functional as possible. This proportion varies according to the disease they have: patients with cardiovascular diseases are less likely to change their behaviors (57%; p=0.001) while patients with digestive diseases are more likely to change them (73%; p<0.001). And among patients with diabetes, the proportion who have changed their behaviors (59%) is not statistically different compared to all patients. Only 48% of patients had received from a healthcare professional an explanation of what a microbiome is, its role and function. But, compared to all the patients, people with cardiovascular disease (43%; p<0.001) were the patients the least likely to have received this piece of information and those with digestive diseases were more likely to have received it (61%, p<0.001). Finally, 78% of patients would trust healthcare professionals as the first source of relevant and trustworthy information.

Conclusion

This survey provides insights into the need for additional education in patients. Healthcare professionals could play a crucial role in providing information about the role and functions of the microbiome, more precisely tailored to each chronic disease that patients suffer from.

References

https://www.biocodexmicrobiotainstitute.com/en/international-microbiota-observatory

Disclosure

The survey was sponsored by the Biocodex Microbiota Institute.

Introduction

Colorectal endoscopic submucosal dissection (ESD) is not widely performed in western countries due to technical complexity, risk of adverse events, and procedure time. Hybrid ESD (H-ESD) - partial submucosal dissection followed by snare-assisted resection – may be useful to achieved endoscopic resection in difficult situations. In our center we use H-ESD as rescue therapy during conventional ESD in case of unstable position, inability to achieving appropriate and safe knife angle, advanced submucosal fibrosis or thin submucosal layer and patient instability.

Aims & Methods

We retrospectively analyzed colorectal ESD performed in our centre between January 2014 and March 2023, colorectal lesions in inflammatory bowel diseases were excluded. Univariate and multivariate analyses were conducted to examine factors that may have influenced switch to H-ESD.

Results

A total of 281 colorectal ESDs for superficial neoplasms in 276 patients were considered. 160 patients (58%) were male with an average age of 68,9 years. In 55 (19,6%) cases ESD was switch to H-ESD.. 171 lesions were located in the colon (60.8 %) and 110 (39.1%) in the rectum; mean maximum diameter of the neoplasms was 35,9 mm (SD 18,4 mm). En bloc resection and complete resection (en bloc resection and R0) were achieved in 259 (92 %) and 245 (86 %) cases respectively.
On univariate analysis, the use of waterjet system-assisted knife (OR 0,3; 95% CI 0,17-0,57), underwater-ESD (OR 0,24; 95% CI 0,09-0,63), rectal localization (OR 0,17; 95% CI 0,07-0,40) and granular laterally spreading morphology (OR 0,40; 95% CI 0,21-0,75) were significantly associated to the achievement of complete ESD. Proximal colon localization (OR 3,9; 95% CI 2,08-7,30), severe submucosal fibrosis (OR 4,9; 95% CI 2,51-9,63), non-granular laterally spreading morphology (OR 2,31; 95% CI 1,27-4,21) and maximum diameter < 40 mm (OR 3,91; 95% CI 1,83-8,38) were related to the switch to H-ESD. On multivariate analysis only waterjet system-assisted knife use and U-ESD were significantly correlated with achievement of complete ESD; severe submucosal fibrosis and proximal colon localization resulted significantly related to the switch to H-ESD.

Conclusion

The use of waterjet system-assisted knife and underwater technique reduce the need to switch to H-ESD during endoscopic submucosal dissection of superficial colorectal lesions. Severe submucosal fibrosis and proximal location are risk factors for the need for the H-ESD switch.

Introduction

We have previously described the conserved butryophilin-like (BTNL)-γδ axis in health, whereby human intestinal Vγ4 intraepithelial lymphocytes (IEL) are regulated by local, epithelial-restricted proteins BTNL 3/8¹. Mice lacking key Btnls have demonstrable absence of mature Vγ7 IEL, suggesting a T cell selection and maintenance function of these proteins². Furthermore it has previously been described that the BTNL gd axis is dysregulated in coeliac disease³. However this axis and its potential dysregulation has yet to be elucidated in IBD.

Aims & Methods

We aim to compare the status of BTNL dependent γδ T cells in IBD and in healthy tissue, and to assess the potential impact of the BTNL-γδ IEL axis on IBD incidence and progression.
Biopsies obtained at endoscopy from non-IBD controls and patients with IBD with and without inflammation were analysed by flow cytometry and RNA sequencing. We then undertook a large-scale case control study investigating whether there was an association between IBD and a previously described BTNL variant allele. These studies were performed in a test set and findings were replicated and validated using the UK IBD bioresource.

Results

RNA sequencing of colonic γδ cells demonstrated that a subset expressing the integrin α_Εβ7 (CD103) have an intraepithelial transcriptomic programme. Moreover, CD103 expression was reversibly downregulated in gut inflammation. Complete restoration of γδ CD103 expression in IBD patients on treatment (n=7) was associated with significantly lower relapse over 5 years follow up than those who demonstrated an ongoing γδ CD103 dysregulation despite therapy (n=12) (HR 6.54 (1.86 – 22.9) p=0.027). Conventional CD8 T cells also express CD103 which is downregulated by inflammation, but restoration of CD8 CD103 phenotype was not associated with sustained remission (HR 0.72 (0.2 to 2.5) ns).
It was noted that a number of patients and non-IBD controls demonstrated low levels of Vγ4 cells. We investigated whether there may be genetic factors which disrupt communication between Vγ4 IEL and the BTNL3/8 complex. A common 56kb copy number variant (CNV) has previously been described (minor allele frequency 0.310)⁴, and we showed that this polymorphism is hypomorphic in that it disrupts Vγ4-BTNL3 interactions. By phenotyping our local cohort we found that homozygous carriage of this CNV leads to lower proportions of Vγ4 IEL, and those Vγ4 IEL which remain demonstrated an altered phenotype.
To investigate the effects of this on IBD we performed a large case-control study. While there was no association between this CNV and the development of IBD, there was a significant association between the CNV and the development of penetrating Crohn’s disease (CD) in a test set (n=1817), which was subsequently replicated in an independent cohort from the UK NIHR IBD bioresource (n=4491) (OR 1.38 (1.13-1.68) p=0.0015).

Conclusion

This multi-faceted study demonstrates that γδ IEL are an hitherto undescribed marker of inflammation resolution in IBD and may be a useful biomarker of treatment response and restoration of a functioning epithelium. Furthermore, our genetics data clearly implicate the BTNL-Vγ4 axis in regulating CD severity. Only a few genes are associated with IBD prognosis, and for most, the biological pathway involved remains uncertain. By contrast, our study strongly implicates Vγ4 IEL as regulators of IBD pathobiology, possibly by driving wound healing and tissue repair, as has been implied by murine studies. Practical diagnostic and therapeutic applications of this protective pathway should be further investigated.

References

1. Melandri et al Nature Immunology 2018; 19: 1352-1365
2. Di Marco Barros et al Cell 2016; 167: 203-218
3. Mayassi et al Cell 2019; 176: 967-981
4. Aigner et al BMC genetics 2013; 14: 61
   

Disclosure

R.J.D., I.Z., P.V., N.J.P. and A.C.H. have filed provisional patent applications for work described herein. R.J.D. has received speaking/consulting fees from Janssen, Takeda, Tillotts. All unrelated to this manuscript., C.A.L. declares research support and/or fees for development and delivery of non-promotional education from Janssen, Dr Falk, Takeda, Abbvie, AstraZeneca, Eli Lilly, Orion, Pfizer, Roche, Sanofi Aventis, Ferring, UCB, Biogen and Genentech Inc. All unrelated to this manuscript. P.M.I. declares research support and/or fees for development and delivery of non-promotional education from AbbVie, Arena, Boehringer-Ingelheim, BMS, Celgene, Celltrion, Falk Pharma, Ferring, Genentech, Galapagos, Gilead, Hospira, MSD, Janssen, Lilly, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Tillotts, Topivert, Sapphire Medical, Shire, VH2, Vifor Pharma, Warner Chilcott. A.C.H. is a scientific consultant for Prokarium and eGenesis and receives research funds from Takeda Pharmeceuticals. All other authors report no conflict of interest.