Introduction

Current IBD therapy regimens are still frequently inefficient, can exert severe side effects, and loss of treatment response is common. Thus, the development of novel therapeutic approaches is an unmet clinical need – especially for patients featuring a primary non-response, refractory disease and/or severe side effects. Here we assessed novel small molecule inhibitors targeting a4b7 integrin or IRAK4 regarding their efficacy to relieve colitis in a model of spontaneous intestinal inflammation either as a stand-alone treatment or in combination.

Aims & Methods

IL-10 knockout (IL-10KO) mice, which develop spontaneous immune-driven intestinal inflammation resembling human IBD, were used for all studies. Mice with established disease were fed for three weeks ad libitum with control chow or chow containing the inhibitors at two previously defined concentrations: a higher concentration intended to induce optimal treatment response or a lower, sub-optimal concentration that did not induce therapeutic effect as stand-alone therapy.

Results

When administered as stand-alone treatment at the higher dose, a4b7 and IRAK4 inhibitors both significantly reduced colitis severity (reduced endoscopic and histological colitis scores [p<0.001 and p<0.01], reduced disease activity index scores [p<0.001]). This effect was accompanied by a normalization of immune cell populations in the colonic lamina propria. Particularly, we found reduced numbers of granulocytes, Th1, Th17, and cytotoxic T cell sin a4b7 and IRAK4 treated mice. Furthermore, mRNA and protein levels of inflammatory cytokines (IFNg, IL17, TNFa and IL-1b) were normalized in intestinal tissue of a4b7 and IRAK4 inhibitor-treated mice (p<0.01, each). When administered in lower concentrations, however, the a4b7 and IRAK4 inhibitors were not able to reduce disease activity as a stand-alone treatment. Of note, a combination of the low doses of the a4b7 inhibitor and the IRAK4 inhibitor significantly reduced the disease severity as evidenced by reduced endoscopic and histologic colitis scores [p<0.001, each], reduced disease activity scores [p<0.01] and a normalization of immune cell infiltrates (reduced levels of granulocytes [p<0.001], Th1 cells [p<0.001], Th17 cells [p<0.001] and less IFNg+ CD8 T cells [p<0.001]). Furthermore, while low doses of anti-IL12/23 p40 antibody were not able to reduce disease severity as a stand-alone treatment, combination of low-dose anti-IL12/23 p40 with the low dose of the a4b7 inhibitor resulted in amelioration of colitis (normalized endoscopic [p<0.001] and histologic [p<0.01] colitis scores, reduced infiltration of granulocytes, Th1, Th17 and IFNg+ CD8 T cells [p<0.01, each], normalization of IFNg, TNFa and IL-1b protein and mRNA levels in the intestine).

Conclusion

Our results demonstrate that small molecule inhibitors for a4b7 and IRAK4 were efficient in reducing colitis in a model of spontaneous immune-cell driven intestinal inflammation. Combination of the a4b7 inhibitor with low doses of the IRAK4 inhibitor or sub-optimal doses of an anti-IL12/IL23 antibody was effective to relieve the disease in the IL-10-KO model. This indicates that combination treatment of a4b7 inhibition with other immune-modulatory drugs, such as IL12/23 neutralization or IRAK4 inhibition might be a promising approach for patients that do not respond to single therapies. Furthermore, our results indicate that combination therapy is able to induce significant disease-relieving effects when the drugs are administered in low concentrations what could minimize side effects without interfering with treatment response.

Introduction

The LIR!C trial demonstrated that laparoscopic ileocaecal resection (ICR) is a cost-effective alternative to infliximab therapy (IFX) in patients with uncomplicated ileocaecal Crohn’s disease (CD), with comparable quality of life outcomes. The aim of this study was to assess the 10-year follow-up of patients enrolled in the LIR!C trial.

Aims & Methods

This retrospective follow-up study included patients from the original LIR!C trial, a multicentre randomized controlled trial comparing ICR to IFX treatment in patients with ileal CD. Long term follow-up data were collected between February 3 and April 14, 2025. Data extraction was focused on initiation or switch of IBD treatments (corticosteroids, immunomodulators and/or advanced medical therapies) and (re)-resections. The follow-up period ranged from trial enrolment to the last visit with the gastroenterologist or surgeon. Primary outcomes were: (1) proportion of patients in clinical remission without therapy switch (no medical therapy or re-resection in the ICR group, and continuation or the cessation of IFX in case of remission in the IFX group), and (2) therapy-free remission, defined as clinical remission without IBD medication and (re)resections.

Results

Follow-up data were available from 60 ICR patients and 57 IFX patients (87% of 134 patients originally included). The median follow-up time was 12 years (IQR 9-14). The clinical remission rate without therapy switch was 40% in the ICR group compared to 26.3% in the IFX group (p=0.117). Of the 60 ICR patients, 24 (40%) had no additional therapy, 13 (21.7%) received an immunomodulator, 18 (30%) biological therapy and 5 (8.3%) underwent a second resection after biological treatment. In the IFX group, 33 (57.9%) required an ICR of whom 25 (75.8%) had previously received second-line biological treatment. Additionally, 7/57 patients (12.3%) were therapy free, 8 (14%) continued IFX treatment, 6 (10.5%) received other biological treatment, and 3 (5.3%) switched to an immunomodulator. Therapy-free remission was significantly higher in the ICR group when compared to the IFX group (40% vs 12%, p < 0.001).

Conclusion

After 10 years of follow-up, the clinical remission rate without therapy switch was comparable between both groups, highlighting the long-term durability of both treatment approaches. The majority of IFX patients needed ICR within 10 years of follow-up. 40% of the ICR group did not require any additional therapy further supporting ICR as first-line treatment option in ileal CD.

References

Ponsioen, C. Y., de Groof, E. J., Eshuis, E. J., Gardenbroek, T. J., Bossuyt, P. M. M., Hart, A., Warusavitarne, J., Buskens, C. J., van Bodegraven, A. A., Brink, M. A., Consten, E. C. J., van Wagensveld, B. A., Rijk, M. C. M., Crolla, R. M. P. H., Noomen, C. G., Houdijk, A. P. J., Mallant, R. C., Boom, M., Marsman, W. A., Stockmann, H. B., … LIR!C study group (2017). Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: a randomised controlled, open-label, multicentre trial. The lancet. Gastroenterology & hepatology, 2(11), 785–792. https://doi.org/10.1016/S2468-1253(17)30248-0

Disclosure

GD'H served as a consultant for AbbVie, Alimentiv, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Exeliom Biosciences, Johnson & Johnson, Pfizer, and Takeda; and has received speakers bureau fees from AbbVie, Eli Lilly, Pfizer, Bristol Myers Squibb, and Takeda.

Introduction

Crohn's disease (CD) location would influence the risk of complications and therapeutic strategies. The objective of this study was to compare the clinical presentation at diagnosis and the natural history of colonic CD in comparison to ileal CD and ulcerative colitis (UC) in pediatric-onset IBD.

Aims & Methods

All children (< 17 years) with a diagnosis of CD or UC made between 1988 and 2011 in a population-based registry were followed retrospectively until 2013. The presentation at diagnosis, the risks of complications, surgery, hospitalization and exposure to different treatments in ileal CD (L1), colonic CD (L2) and UC were compared. Disease location was defined at diagnosis. In case of extension of the disease (L1 or L2 to L3), follow-up was censored.

Results

A total of 215 L1 patients, 234 L2 patients and 337 UC patients were included. At diagnosis, the proportion of male (L1 53.5%; L2 53.4%; UC 42.7%; p=0.012), age at diagnosis (15.0; 13.7; 14.0 years; p=0.003), family history of IBD (12.6%; 12.7%; 5.0%; p=0.005), diagnostic delay (3.0; 3.0; 2.0 months; p=0.001) and smoking prevalence (11.6%; 8.1%; 5.6%; p=0.041) were different between the three groups. Over the study period, incidence of L1, L2 and UC were 0.65 [0.57-0.74], 0.71 [0.62-0.81] and 1.02 [0.92-1.14] per 100,000 person-years, respectively. Bloody stool and diarrhea at diagnosis was observed in 14.9% respectively; 44.4%; and 91.1% (p < 0.001) and 47.0%; 71.8%; and 65.0% (p < 0.001) of L1, L2 and UC. At diagnosis, granuloma was identified in 12.6% of L1 patients and 31.2% of L2 patients (p<0.001). The risk of extension to L3 was significantly higher in the L2 group than in the L1 group (at 5 years - 37% vs. 14%, p<0.001). L2 location was associated with a lower risk of luminal fistula (HR 0.41 [0.21-0.79], p=0.008) but a higher risk of anoperineal lesion (HR 2.11 [1.29-3.45], p=0.003). The prevalence of extra-intestinal manifestations, articular (p<0.001) and cutaneous (p<0.001) was higher in L2 CD. While the risk of surgery was significantly higher in case of L1 location (at 5 years - 37%, 13% and 13%; p<0.001), the risk of hospitalization (at 5 years - 22%, 39% and 33%; p=0.01), exposure to corticosteroids (at 5 years - 55%, 69% and 67%; p<0.001), immunosuppressants (at 5 years - 47%, 61% and 42% - p<0.001) and anti-TNF (at 5 years - 16%, 35% and 22%; p<0.001) were higher in case of L2 location.

Conclusion

The clinical presentation and evolution of ileal and colonic CD at diagnosis differ significantly. Colonic location is associated with a high risk of perianal CD, extra-intestinal manifestations, hospitalization and exposure to steroids, immunosuppressants and anti-TNFs. These differences could justify different therapeutic approaches in the future.

Introduction

Cobitolimod (MW 5925.18 Da) is a DNA-based oligonucleotide functioning as an immunomodulatory Toll-like receptor 9 agonist. Cobitolimod is in phase III clinical development as a new therapy for moderate to severe left-sided ulcerative colitis (UC). This phase Ib study aimed to evaluate the pharmacokinetics (PK), safety and tolerability of rectally administered cobitolimod in patients with moderate to severe UC.

Aims & Methods

The phase Ib open-label study was conducted at a single center in Sweden (NCT05404074). The patients had moderate to severe UC defined by a 3-component Mayo score of 5 to 9, with an Investigator read endoscopic subscore ≥2, and with stool frequency and rectal bleeding subscores each ≥1. Patients received one cobitolimod enema (500 mg/50 ml) at week 0, and blood samples for PK analysis were collected pre-dose, 15 min, 30 min, 1h, 2h, 4h, 8h, 12h and 24h after dosing. Patients received a second cobitolimod enema (500 mg/50 ml) at week 3, and at week 6 the degree of clinical remission was evaluated. Clinical remission was defined by the 3-component Mayo score with a rectal bleeding subscore = 0, a stool frequency subscore ≤1 (≥1 point decrease from baseline), and an Investigator read endoscopic subscore ≤1. Patients in clinical remission at week 6 received a third cobitolimod enema (500 mg/50 ml), and blood samples were collected for a second PK analysis as described above. The primary endpoint was PK parameters: maximum plasma concentration (C_max), time to C_max (T_max), area under the curve from 0 to timepoint t (AUC_t) and half-life (T_1/2). Secondary endpoints included safety and tolerability.

Results

Eight patients with active disease were enrolled in the study and included in the safety analysis set. One patient was excluded from the pharmacokinetic analysis set (PKAS) due to an immediate bowel movement following administration. Of the 7 patients included in the PKAS, 4 patients achieved clinical remission at week 6. Rectal administration of 500 mg cobitolimod at week 0 resulted in median C_max of 21.7 ng/ml, median T_max of 1h, median T_last of 4h, and median AUC_0-last of 71.7 h*ng/ml (n=7). For the 4 patients in remission at week 6, corresponding numbers were: median C_max of 15.5 ng/ml, median T_max of 0.5h, median T_last of 4h and median AUC_0-last of 27.6 h*ng/ml. T_1/2 was <2.5h both at week 0 and week 6.
In total, 24 adverse events occurred in the study, out of which the majority was mild and judged as unlikely related to study drug. No serious adverse events were reported.

Table 1. PK parameters per patient

Conclusion

The study demonstrates that rectally administered cobitolimod results in a low systemic exposure of short duration both in patients with active disease and in clinical remission. Cobitolimod was safe and well tolerated at a dose of 500 mg.

Disclosure

Thomas Knittel is a consultant for and a shareholder in InDex Pharmaceuticals, Sweden. Pernilla Sandwall is a former employee and a shareholder in InDex Pharmaceuticals, Sweden. Christine Dieterich Johansson is employed by InDex Pharmaceuticals, Sweden. Arezou Zargari is employed by and a shareholder in InDex Pharmaceuticals, Sweden. Johan Bring is a consultant for InDex Pharmaceuticals, Sweden. Per Hellström receives consultancy fees from: Clinical trial consultants, Sweden; ROSE pharma, USA; Pharmanovia, Denmark; Swedish Agricultural University, Uppsala; Pharmacosmos, Denmark; Stockholm Diabetes Association, Sweden; Celltrion, Finland; Mag-tarmförbundet, Sweden; Karolinska Institutet, Sweden; Bristol-Myers Squibb, Sweden; ClinSmart, Sweden; InDex Pharmaceuticals, Sweden; Takeda pharmaceutical company; Mediahuset, Sweden; Bonnier Healthcare Sweden; Folkuniversitetet, Stockholm, Sweden; Biogaia, Stockholm, Sweden; Norgine, Denmark; Nanologica AB, Södertälje, Sweden.

Introduction

Inflammatory bowel disease (IBD) is an idiopathic and chronic disorder that includes ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases are different but show an uncontrolled intestinal immune response that generates tissue inflammation. Dendritic cells (DC) are phagocytic professional antigen presenting cells that link the innate and adaptive immune systems. Indeed, they are the only cell type able to stimulate naïve T cells generating an antigen-specific immune response. In humans, DC can be divided into plasmacytoid (pDC) and c conventional type 1 and 2 (cDC1, cDC2). Although cDC migration towards the GI mucosa is enhanced in IBD, the mechanisms underlying these migrations and whether biological drugs can modulate them are currently unknown.

Aims & Methods

This study aimed to analyze DC migratory capacity towards the GI mucosa, and whether biological drugs with different mechanisms of action can modulate this process in health and IBD.This is a cross-sectional observational postmarketing study where the modulatory effect of different biological treatments on samples from patients with an endoscopic diagnosis of IBD and healthy controls was studied ex vivo. Peripheral blood mononuclear cells (PBMC) were obtained from 15 patients per group and were cultured in presence of golimumab or ustekinumab. Following culture, surface markers expression was determined, assessing the differential effect of biological drugs (if any) over the DC subsets in the different groups. After that, the migratory capacity of circulating DC towards CCL2, CCL25, and MadCam1 from the different study groups was determined. Finally, we evaluated the DC migratory capacities in presence of biological drugs or with culture media alone.

Results

The cDC2 subset showed higher expression levels of β7 and CCR5 compared to cDC1. Golimumab and ustekinumab did not modify the expression of the homing markers in any studied subset in pDC and cDC2.On the contrary, in cDC1 both golimumab and ustekinumab increased CCR6 expression in qCD patients and CCR9 in aUC patients. Regarding to the migratory capacities of the different DC subsets toward intestinal chemoattractants ustekinumab decreased the migratory capacity of cDC2 from CD patients towards a medium supplemented with MadCam1 and increases toward CCL2 in case of cDC1 from CU. In the case of migratory capacities of cDC2 from HC were increased by ustekinumab and golimumab toward CCL2 and CCL25 just in case of golimumab.

Conclusion

cDC2 showed more migratory profile markers than other DC populations. Golimumab and ustekinumab modify the expression of the homing markers just in cDC1 subset. Nevertheless, ustekinumab and golimumab modify the migratory capacities of cDC in IBD patients and HC, but do not exert any effect on pDC. These effects occur in a different manner in CD and UC indicates that the behavior of cDC is different in CD and UC, and that the migration capacity of this subset is not dependent exclusively on homing markers.

Introduction

During and following the COVID-19 pandemic, there has been a major expansion of self-administered subcutaneous biologics for the management of inflammatory bowel disease. These agents are more difficult to monitor since patients do not need to attend the Biologics infusion unit and there is no audit trail to confirm administration of the drug at the scheduled time points.

Aims & Methods

Following a successful NHS D&I bid for funding, a pilot proof of concept project to assess the feasibility and uptake of a digital technology (Health Beacon Digital Sharps Box®) to record and monitor subcutaneous injectable pen use was implemented in 50 consecutive IBD patients who were being treated with subcutaneous infliximab (Remsima®), Adalimumab (Amgevita®) or Vedolizumab (Entyvio®), on a 2-weekly schedule. The Health Beacon ICMS is comprised of a Smart Sharps Bin, pre-programmed with a patient’s individual treatment schedule. The bin electronically captures each time a used injection is disposed of, to create a time-stamped record as a proxy for medication adherence. This is accompanied by Health Beacon’s Companion App and Care Team support. Patients were also sent electronic dose reminders if they failed to dispose of a scheduled injection within certain time periods. Adherence data from the HealthBeacon ICMS, as well as patient satisfaction, transmission reports of data to

Results

Of 50 patients invited to join the programme, 45 registered patients had complete record of 6 months follow up; 4 patients deactivated recruitment and 1 left the programme. 21 patients were on Vedolizumab, 18 on Adalimumab and 8 on Infliximab, all 2-weekly SC injection. 45% patients were in the 36-50year age group, with the remaining spread between 18-75 years. M: F=21:24. Of 418 scheduled drops, 360 were made, with overall adherence being 86%. On time adherence was 76%. The study showed that up to 24% pts on SC Biologics at home delay their scheduled drug administration. Patient satisfaction was high. Reasons for delay in administration included forgetting, being away from home and being busy. Reminders were acknowledged.

Conclusion

This is the first study to our knowledge exploring adherence to subcutaneous biologics at home for IBD. It showed that a digital injection monitoring and support system is useful and acceptable to track adherence. Of the patients involved in the study there is an overall adherence of 90%, with up to 24% patients delaying their scheduled administration. Further studies are needed to analyse patient behaviour and impact on disease course.

Disclosure

Anjan Dhar has been paid an honorarium as a Speaker for presenting this abstract the a Health Beacon Meeting