Introduction

Patients with inflammatory bowel diseases often suffer from symptoms that are not directly linked to the intestine. Such symptoms frequently include fatigue, anxiety and depression. While these symptoms strongly reduce quality of life of persons with IBD, and while they are more frequent in active disease, they are not reliably resolved by successful antiinflammatory treatment. The underlying mechanisms of these extraintestinal symptoms are poorly understood, but a disturbance along the brain-gut-axis seems likely.

Aims & Methods

This study examined cerebral grey matter volume (GMV) differences between patients with Crohn's Disease (CD) in an active (aCD) or quiescent (qCD) state and healthy controls (HC) and analysed associations between GMV and fatigue, depressive and anxiety symptoms. Patients with CD (n=53, aCD=30, qCD=23) and HC (n=37) underwent structural MRI at 3T and completed questionnaires to assess fatigue (WEIMuS), depressive and anxiety symptoms (HADS). Patients also provided stool samples for analysis of faecal calprotectin (fCal). Whole-brain GMV was analysed using CAT12 in SPM12. We calculated group differences between CD and HC and performed Spearman correlation analyses to detect associations between anatomical regions with significant differences between the groups, fCal and symptoms of fatigue, depressive and anxiety symptoms.

Results

Patients had significantly higher mean scores than HC in all extraintestinal symptom scores: fatigue (WEIMuS) 25 vs 8.5, depression (HADS-D) 4 vs 1.9, anxiety (HADS-A) 5.5 vs 3.4, all p<.005. Patients with aCD hat numerically, but not statistically significantly higher mean scores than qCD in all domains.

	CD (n=53)	CD subgroups aCD (n=30)	qCD (n=23)	HC (n=37)	Statistics (CD vs HC) t df p
Age, mean (SD)	38.2 (13.5)	36.3 (12.7)	40.5 (14.4)	39.0 (13.7)
Sex, m/f	23/30	16/14	7/16	12/25
fCal (g/kg), mean (SD)	291 (307.6)	389 (313.9)	47 (45.2)	N/A
Depression					3.23	88	0.0017
HADS D, mean (SD)	4.0 (3.3)	4.4 (3.2)	3.3 (3.5)	1.9 (2.6)
Anxiety					3.03	88	0.0032
HADS A, mean (SD)	5.5 (3.5)	5.9 (3.5)	5.0 (3.5)	3.4 (2.8)
Fatigue					5.54	88	0.0001
WEIMuS, mean (SD)	25 (15.2)	28.4 (13.9)	20.5 (15.9)	8.5 (11.8)

Regionally reduced GMV in patients vs. HC was detected in the right cuneus, lingual and fusiform gyrus as well as the left precentral gyrus and cerebellum (all p<.0001). Depressive symptoms were associated with fCal (Spearman’s ρ = 0.37, p<0.05). Fatigue symptoms were negatively correlated with GMV in the left precentral cortex (Spearman’s ρ = 0.32) and right fusiform (ρ = 0.41) and lingual gyrus (ρ = 0.34). We detected no positive correlations between GMV and extraintestinal symptoms or fCal.

Conclusion

This study detected brain structural changes associated with CD that are partly related to fatigue, but not depressive or anxiety symptoms. These findings can help to increase our understanding of extraintestinal symptoms in CD, implicating disturbed brain-gut-interactions in their development.

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

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

OZA is approved in multiple countries for treatment of moderately to severely active UC in adults. In the phase 3 TN study, OZA was efficacious for up to 52 wk in pts with moderately to severely active UC. CRP is a widely used serum indicator of inflammation and prognosis in inflammatory bowel disease.

Aims & Methods

The effect of OZA on CRP levels and the association of CRP levels with OZA efficacy were assessed in all TN pts. During the 10-wk induction period, pts in Cohort 1 were randomized to OZA 0.92 mg or placebo (PBO) or received open-label OZA 0.92 mg in Cohort 2. Pts with clinical response to OZA at Week (W) 10 were rerandomized to OZA or PBO for maintenance through W52. Serum CRP levels were assessed at baseline (BL) through W52. Disease activity scores (rectal bleeding subscore [RBS], stool frequency subscore, Physician’s Global Assessment subscore, endoscopy subscore, and partial and total Mayo scores) were assessed at BL and W10. Efficacy endpoints (clinical remission, clinical response, endoscopic improvement, mucosal healing, and histologic remission) were assessed at W10. Associations of CRP levels with disease activity and efficacy endpoints were assessed using Spearman’s correlation and logistic regression, respectively.

Results

645 pts were randomized to OZA (n=429) or PBO (n=216) and 367 pts received open-label OZA for 10 wk; 230 and 227 OZA-treated pts who responded were rerandomized to OZA and PBO, respectively, for maintenance through W52 (69 PBO-treated pts who responded continued on PBO). Pts on OZA showed reductions from BL in CRP levels at W10, which was significant vs PBO (P<0.001, both cohorts) (Table). Reductions in CRP levels were significantly greater in pts with vs without clinical response at W10 in all treatment groups (P<0.001, all groups) (Table). Significantly greater reductions in CRP levels occurred with OZA vs PBO at W10 regardless of prior biologic or anti–tumor necrosis factor exposure (P<0.05, all groups). Reductions in CRP levels were maintained through W52; pts who continued OZA had similar reductions at W52 as pts who switched to PBO (Table). Decreases in CRP levels in W52 responders were maintained through W52 of treatment, while W52 nonresponder CRP levels started to rise following induction toward BL values (Table). BL CRP levels were significantly positively correlated with most BL disease activity scores (Spearman’s rho 0.2–0.3, P<0.05, all scores) except RBS. BL CRP levels and change in CRP levels at W5 were prognostic for W10 response. Higher BL CRP levels were associated with lower endoscopic improvement, mucosal healing, and histologic remission at W10 and greater reductions in CRP levels at W5 were associated with better clinical response at W10, independent of treatment. Change in CRP levels at W10 was significantly positively correlated with change in most disease activity scores at W10 with OZA and PBO (Spearman’s rho 0.1–0.3, P<0.05, all scores in both groups) except endoscopy with PBO.

Adjusted mean percent change from BL in CRP levels (95% CI)	Induction (Week 10)			Maintenance (Week 52)
	PBO (C1) (n=216)	OZA (C1) (n=429)	OZA (C2) (n=367)	OZA/PBO (n=227)	OZA/OZA (n=230)​​​​​​​​​
All pts	–1.2 (–13.3, 12.7) n=192	–26.8 (–33.3, –19.8) n=407	–25.7 (–32.7, –18.1) n=336	–19.9 (–30.9, –7.1) n=125	–23.5 (–32.7, –13.0) n=181
Respondersa	–39.9 (–52.5, –24.0) n=55	–45.9 (–52.2, –38.9) n=204	–40.4 (–47.5, –32.3) n=189	–33.1 (–44.1, –20.0) n=91	–30.9 (–40.4, –20.0) n=135
Nonrespondersb	12.0 (–3.5, 29.9) n=137	–10.7 (–20.9, 0.9) n=203	–7.4 (–19.8, 7.0) n=147	3.1 (–20.3, 33.4) n=34	–2.9 (–23.0, 22.6) n=46
aResponders are pts who achieved clinical response at W10 for the induction period and at W52 for the maintenance period. bNonresponders are pts who did not achieve clinical response at W10 for the induction period and at W52 for the maintenance period. C1, Cohort 1; C2, Cohort 2.

Conclusion

In moderately to severely active UC pts, OZA led to reductions in CRP levels. Higher BL CRP levels were associated with worse disease outcomes and greater reductions in CRP levels were associated with better disease outcomes regardless of treatment, supporting CRP levels as a prognostic biomarker for UC.

Disclosure

This study was funded by Bristol Myers Squibb, Princeton, NJ, USA
SH, RM, CW, YH, and AP: employees and/or shareholders of Bristol Myers Squibb.
DTR: received grant support from Takeda; consulted for AbbVie, AltruBio, Aslan Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chronicles, ClostraBio, Connect BioPharma, EcoR1, Eli Lilly, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen, Kaleido Biosciences, Pfizer, Prometheus Biosciences, Reistone, Seres Therapeutics, Syneos, Takeda, Target RWE, and Trellus Health.

Introduction

Therapeutic progress in inflammatory bowel disease (IBD) is limited by the lack of understanding of the pathophysiology and the mechanisms involved in response or lack/loss of response to treatments. IBD patients are treated with anti-inflammatory drugs, including biologics such as anti-tumor necrosis factor (TNF) agents, which have been crucial in achieving steroid-free remission and prevention of long-term complications. However, a significant subgroup of patients becomes refractory to these biologicals due to the development of immunogenicity, characterized by the presence of anti-drug antibodies (ADAs). The antibody production and peripheral tolerance are initiated and maintained within lymphoid organs, such as the peripheral lymph nodes, but the exact role of immune cells in these lymphoid structures and whether they are involved in anti-drug antibody (ADA) formation is unknown.

Aims & Methods

We aimed to unravel the pathophysiology behind the development of anti-drug antibodies. Therefore, we performed ultrasound-guided inguinal lymph node needle biopsies from which we isolated leukocytes along with PBMCs from the same patients. Leukocyte populations were analyzed at single cell level via high dimensional phenotyping through mass cytometry (CyTOF).

Results

Using this unique approach, we have so far results from 4 Crohn’s Disease (CD) patients with ADAs (75% females, 50% active disease) and 4 without ADAs (50% females, 75% active disease). Active disease was defined, as an observation of an elevated CRP (c-reactive protein) (>5 mg/L) and/or calprotectin >250 (mg/kg), including symptoms (Harvey-Bradshaw index score > 4 or disease activity index score-CDAI >150).
The proportion of CD4⁺ TEMRA (terminally differentiated effector memory T-cells), CD4⁺ effector and central memory T-cells were increased in the peripheral lymph nodes of patients that developed immunogenicity. Mature NK cells, classical and non-classical monocytes were also increased. Furthermore, the levels of the alpha-4 integrin expression were higher in the lymph node T-lymphocytes, as well as, in the lymph node naïve and memory B-cell subsets in the patient group with ADAs.

Table: Cytometry and Biochemical Characteristics.

Parameters	ADAs (n=4)	no ADAs (n=4)	p-value
Proportion of Lymph Node CD4+ TEMRA T-Cells; median (Range)	5.3 (1.05-16.5)	0.16 (0.1-0.39)	0.02
Proportion of Lymph Node CD4+ Effector Memory T-Cells; median (Range)	3.2 (0.64-7.2)	0.5 (0.14-1.37)	0.049
Proportion of Lymph Node Mature NK-Cells; median (Range)	4.04 (0.49-5.17)	0.08 (0.05-0.2)	0.029
Proportion of Lymph Node Classical Monocytes; median (Range)	4.8 (1.47-16.9)	0.8 (0.91-1.1)	0.027
Proportion of Lymph Node Non Classical Monocytes; median (Range)	6.9 (0.99-9.4)	0.9 (0.68- 0.99)	0.026
Mean alpha-4 Integrin Expression Levels (Effector T-cells)	1.61	0.87	0.03
Mean alpha-4 Integrin Expression Levels (Memory B-cells)	1.58	0.94	0.03
CRP (c-reactive protein) (mg/l); median (Range)	2.85 (0.5-8.5)	3.90 (0.7-14.75)	0.396
Calprotectin (mg/kg); median (Range)	650 (228-1130)	1007 (476-2037)	0.17

Conclusion

Lymph node T-helper cells, monocytes and NK cells potentially play a role in the development ADAs in IBD patients treated with biologics. Although, there was no significant difference in the proportion of naïve and memory B-cells, our findings concerning the alpha-4 integrin expression levels also indicate that both lymph node T and B-lymphocytes, are possibly characterized by a higher migratory potential during immunogenicity conditions.

References

1. Stein RE, Lee DY, Leonard MB, et al. The association between drug levels, anti-drug antibodies, and therapeutic response during infliximab therapy in pediatric Crohn’s disease. J Crohns Colitis 2014; 8: S434.
2. Bodini G, Savarino V, Dulbecco P, et al. The influence of anti-adalimumab antibodies on adalimumab trough levels, TNF-alpha levels and clinical outcome. J Crohns Colitis 2014; 8: S42
3. Stefan S, Sandborn WJ, Choi J, et al. Anti-drug antibodies separate responses of markers of inflammation (c-reactive protein, fecal calprotectin) in Crohn’s disease patients treated with certolizumab pegol. Inflamm Bowel Dis 2014; 20: S68.
4. Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review. BioDrugs. 2017;31(4):299-316. doi:10.1007/s40259-017-0231-8.
5. Brun MK, Goll GL, Jørgensen KK, et al. Risk factors for anti-drug antibody formation to infliximab: Secondary analyses of a randomised controlled trial. J Intern Med. 2022;292(3):477-491. doi:10.1111/joim.13495.

Disclosure

The authors state no conflict of interest.

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

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

Patient No	Tmax (h)		Cmax (ng/mL)		AUClast (h*ng/mL)		Tlast (h)
	Week 0	Week 6	Week 0	Week 6	Week 0	Week 6	Week 0	Week 6
101*	1	0.5	165.0	6.4	371.6	11.7	4	4
102	1	-	17.0	-	28.1	-	4	-
103*	2	0.5	19.9	24.5	71.7	36.4	8	4
105*	2	1	51.9	9.4	192.5	18.9	8	4
106	2	-	43.8	-	149.7	-	8	-
107*	1	0.5	20.0	21.6	29.2	66.7	4	4
108	0.5	-	21.7	-	25.6	-	4	-

*Patients in clinical remission at week 6 received a 3^rd dose of cobitolimod for a 2^nd PK analysis.

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.