Background: TOP1288 a novel narrow spectrum kinase inhibitor (NSKI), selectively targets key kinases fundamental to inflammatory cell signalling in innate and adaptive immune responses: p38-alpha MAP kinase, Src family kinases (Src and Lck) and Syk. Through synergistic effects on these kinases TOP1288 is a potent inhibitor of the inflammatory cascade and offers therapeutic potential in ulcerative colitis and Crohn's disease with minimal systemic absorption which could provide a significant safety advantage over current therapies. In healthy subjects TOP1288 (evaluated up to 400mg total daily rectal dose for 4 days) is well tolerated, with measurable drug levels in colonic biopsies in a pharmacologically relevant range but with minimal systemic exposure. Positive signals for target engagement and biological effects were seen. The present phase 1b study was designed to evaluate TOP1288's safety, tolerability, PK and PD in ulcerative colitis patients.
Methods: Subjects (n=6) aged 18–55 years with moderate ulcerative colitis (total Mayo Clinic Score 5–10; sigmoidoscopy subscore ≥1) experiencing rectal bleeding and receiving oral 5-ASA (<2.4g/day) were randomized double blind to TOP1288 200mg or placebo rectal solution once daily for 4 days. Subjects were resident in a phase 1 accredited clinical trials' unit for assessments. Safety parameters were assessed and serial blood samples collected to measure TOP1288 plasma concentrations. Subjects had sigmoidoscopy at baseline and approx. 24 hours after final dose to obtain recto-sigmoid biopsies to measure TOP1288 concentration and selected inflammatory biomarkers.
Results: TOP1288 was well tolerated with no clinically significant adverse events. Plasma exposure occurred in a minority of subjects (below quantification limit in 3/5 TOP1288 subjects by Day 4) and measurable drug concentrations were very low (<0.134 ng/mL). Colon tissue exposure approx. 24 hours after final dose occurred in most (4/5) subjects (0.2–1.2 ng TOP1288/mg protein). TOP1288 inhibited IL-8 and IL-6 release from unstimulated whole colonic biopsies: IL-8 was reduced from 110647 pg/mL pre-dose to 62429 pg/mL post-dose (placebo 84971 pg/mL pre-dose; 90079 pg/mL post-dose) and IL-6 from 8247 pg/mL pre-dose to 4341 pg/mL post-dose (placebo 7423 pg/mL pre-dose; 7400 pg/mL post-dose).
Conclusions: In this first study in ulcerative colitis the NSKI TOP1288 was well tolerated with measurable drug levels in colonic biopsies in a pharmacologically relevant range, but with minimal systemic exposure. Positive signs for target engagement and biological effects were demonstrated suggesting a normalization of dysregulated cytokine pathways.