P572 Evaluation of safety, pharmacokinetics and efficacy of oral treatment with OST-122 in patients with moderate to severe ulcerative colitis: A Phase Ib/IIa, randomized, double blind, placebo controlled clinical trial

Abstract

Abstract Background OST-122 is an orally administered, GI-targeted and non-systemic JAK3/TYK2 inhibitor. In preclinical models and in healthy volunteers, OST-122 has demonstrated excellent safety and tolerability with minimal systemic exposure, thereby reducing the risk of causing serious systemic toxicities associated with current JAK inhibitors. The aim of this study was to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of OST-122 in moderate to severe ulcerative colitis (UC) patients. Methods This randomized, double blind, placebo controlled, multicenter proof of concept trial enrolled patients aged 18 to 75 years with moderate to severe UC (Total Mayo score 5-10, Endoscopic score ≥2) and with inadequate/loss of response, or intolerance to conventional (steroids and immunomodulators) and/or advanced therapy (ie. anti-TNFα, anti-integrin, anti-interleukin 12/23) in a 3:1 ratio to receive oral OST-122 400 mg (n=28) or placebo (n=9) for 28 days. The main objective of this study was to evaluate the safety and tolerability of OST-122 in patients with moderate to severe UC over 28 days by assessing the number, severity and type of adverse events. The pharmacokinetic profile was determined to confirm the compound’s low exposure in plasma (Cmax, AUC) previously observed in healthy volunteers and preclinical model. Another objective was to explore preliminary efficacy by assessing clinical parameters including rectal bleeding score and clinical response. Results A total of thirty-seven patients, 59.5% males, mean age of 44.8 years were included. The patients in the OST-122 group (n=28) had a mean Total Mayo Score at baseline of 8.1 compared to TMS = 6.7 in the placebo group (n=9). Safety analysis revealed no significant differences in the number of reported adverse events between the two treatment groups, nor did serious adverse events occur (Table 1). There were no clinically relevant changes in vital signs, laboratory values or ECG parameters which raise any safety concerns. After 28 days of treatment, 63% of patients taking OST-122 showed an improvement in rectal bleeding (vs 33% in the placebo group), 44% achieved a clinical response (vs 11% on placebo) and 22% reached clinical remission (Figure 1). Statistical significance was not achieved due to the small study size and patient variability. Pharmacokinetic data indicated minimal plasma concentrations (Cmax,ave. Day28 0.92 ng/mL) and therapeutically relevant levels in colon tissue (Cave.,Day28 15.5 ug/g tissue). Conclusion GI-restricted OST-122 was well tolerated during the 4-week treatment. Its excellent safety profile, limited systemic absorption and promising trends of clinical activity may provide a safer therapeutic option for patients with moderate to severe UC.