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S804 Pilot Study to Assess Pharmacokinetic and Pharmacodynamic Markers Following Enema-Dosing With Adalimumab in Patients With Active Ulcerative Colitis (UC)

Introduction: The local delivery of drug at the desired site in the gastrointestinal (GI) tract has been a longstanding goal of IBD therapy. Data from topical administration of anti-TNFa antibody in chronic colitis mouse models are promising and show significant efficacy when compared to systemic administration. Here, we investigate the effects of topical dosing of adalimumab in active ulcerative colitis patients. Methods: Up to 12 eligible patients with active Ulcerative Colitis (fecal calprotectin $ 250 ug/g or serum C-reactive protein $ 2) received adalimumab enema daily (160mgs/50ml or 80mgs/50 ml) on day 1, 2 and 3 and underwent sigmoidoscopy with biopsy on day 0, 4, 5 and 8. Serum samples were collected on Days 1,2,3,4,5,8 and 30. The endpoints of the study were safety, tissue and blood PK/PD assessment. Tissue, serum, and fecal samples were collected as defined in the protocol. PK and PD were analyzed after each patient has completed dosing. Adalimumab dose were adjusted based on initial PK and PD data for previous subjects. Results: Administration of adalimumab by enema was well tolerated and did not give rise to any safety concerns. PD data from the initial cohort of patients are presented. All the patients with a Day 0 tissue TNFa measurement and treated with adalimumab enema demonstrated decrease in tissue TNF (average of 6 biopsies) levels at Day 8. The 2 patients who benefited from treatment (patient reported outcomes) also had decrease in tissue IL-6, Oncostatin M, and Phospho/Total STAT 3. Serum (CRP) and fecal markers (Calprotectin) also decreased along with mayo score. The 2 patients who did not report benefit from treatment had increase in tissue IL-6 and Oncostatin M on Day 4 and 8. (Table) Conclusion: Topical treatment with adalimumab may be beneficial in patients with Active UC. Target engagement and modulation was demonstrated in at least 2 patients. Monitoring tissue TNFa, IL6 and Oncostatin M might be useful in understanding pathway redundancy or feedback loops. Available data from the literature, and the results of our current work indicate that the topical route of administration has the potential to provide higher exposures of adalimumab in the target tissue in comparison to plasma exposures. In addition, there is lower risk of overexposing the patient systemically while providing expected tissue exposure. These data suggest that targeted administration of adalimumab has the potential to result in pharmacologically relevant tissue levels while reducing systemic side effects.