Part A: randomized, double-blind, placebo-controlled, single-ascending dose phase
PD
ADVERSE EFFECT
A starting dose of 5 mg was chosen as this was approximately twofold lower than the maximum recommended starting dose (MRSD) in humans of 9.6 mg determined from the results of a murine PD study, and was therefore not expected to have any pharmacological activity. This dose was also more than 30-fold lower than the MRSD of 162 mg calculated from the no observed adverse effect level in the toxicology species (mouse and dog). It was therefore considered to be a well tolerated and pharmacologically inactive starting dose allowing a wide dose escalation range.Participants in Part A were sequentially assigned to 1 of 5 cohorts (cohorts A1–A5; 5 mg, 20 mg, 50 mg, 100 mg or 200 mg; 