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* = Presenting author

P561 A first-in-human randomised double-blind placebo-controlled clinical trial of a novel narrow spectrum kinase inhibitor

A. Rowley1, A. Duggal1, M. Taylor*1, M. Foster1, Y. Solanke1, S. Sirohi1, C. Walshe1, S. Webber1, P. Irving2, S. Travis3

1Topivert Pharma Ltd, London, United Kingdom, 2Guy’s and St Thomas’ NHS Foundation Trust, Department of Gastroenterology, London, United Kingdom, 3Oxford University Hospitals Trust, Translational Gastroenterology Unit, Oxford, United Kingdom


TOP1288 is a novel narrow spectrum kinase inhibitor (NSKI) that selectively targets key kinases involved in signalling in inflammatory cells (p38-alpha mitogen activated protein kinase, Src family kinases [Src and Lck], and Syk), which are involved in both innate and adaptive immune responses. Through its synergistic effect on these kinases, TOP1288 is a potent inhibitor of the inflammatory cascade and, therefore, might have therapeutic potential in ulcerative colitis and Crohn’s disease patients. Non-clinical data indicate minimal systemic absorption is anticipated in humans, and, as such, this could provide a significant safety advantage over current therapies. This randomised, double-blind, placebo-controlled study was designed to evaluate the safety, tolerability, and pharmacokinetics of TOP1288 single and multiple ascending doses (SAD and MAD) in healthy volunteers, as well as exploratory markers of target engagement.


In total, 61 healthy subjects aged 18–55 years were randomised to receive single doses of 1, 10, 100, or 200 mg or 200 mg bid and multiple doses (once daily for 4 days) of 10, 50, or 200 mg or 20 0mg bid of TOP1288 or placebo administered as a rectal solution in successive cohorts (4 subjects TOP1288:2 placebo, per SAD cohort; 6:2, MAD). Safety parameters were assessed, and serial blood samples were collected for measurement of TOP1288 concentration in plasma. All subjects had a flexible sigmoidoscopy at baseline and at approximately 24 hours after final dose to obtain colon biopsies from the recto-sigmoid region for measurement of TOP1288 concentration and selected inflammatory biomarkers.


TOP1288 was well tolerated with no clinically significant findings of note. Plasma exposure occurred in only a minority of subjects, and measurable drug concentrations were very low (< 0.42 ng/mL 0–72 hours after first dose). Colon tissue exposure, approximately 24 hours following final dose, occurred in the majority of subjects in the higher dose cohorts (0.2–29.1 ng TOP1288/mg protein). Inhibition of IL-8 release was observed in ex-vivo biopsy analysis using isolated lamina propria mononuclear cells.


In this first-in-human study, TOP1288 was well tolerated with measurable levels of drug in colonic biopsies in a pharmacologically relevant range but with minimal systemic exposure. Positive signs for target engagement and biological effects were demonstrated, supporting future investigation of TOP1288 efficacy and safety in ulcerative colitis patients. ID: NCT02463045

Funding: Topivert Pharma Ltd