The safety, PK and PD profile of ADC3680, a potent and selective CRTh2 antagonist, in healthy volunteers and partly controlled atopic asthmatic subjects

ADC3680 is a potent and selective CRTh2 antagonist whose efficacy is currently being evaluated in subjects with uncontrolled asthma on ICS. In Phase I, 88 healthy volunteers were exposed to ≥1 dose of ADC3680 (1 – 200 mg as single doses; 10, 30 and 90 mg once daily for 7 days; and 10 mg daily for 14 days). 24 further subjects with partly controlled atopic asthma on ICS, received a 22.73 mg ADC3680 once daily for 28 days. ADC3680 is relatively rapidly absorbed (t max 2.5 hrs) and suitable for once-daily oral dosing (t 1/2 11–15 hrs). Total plasma clearance of ADC3680 is low with little evidence of accumulation on repeat dosing. ADC3680 was safe and well-tolerated at single doses up to 200 mg, at doses up to 90 mg administered once daily for 7 days and in post-menopausal female volunteers at a single dose of 25 mg. ADC3680 was also well-tolerated in atopic asthmatics (22.73 mg once daily for 28 days). Most adverse events reported were mild or moderate and were considered to be unrelated to treatment and there were no clinically significant changes in laboratory safety parameters. ADC3680 blocked PGD 2 mediated eosinophil shape change response (ESC) ex-vivo in blood from healthy and asthmatic subjects. >90% inhibition of ESC was observed with ADC3680 at single (1 to 200 mg) and multiple ADC3680 doses (10, 30, and 90 mg once daily for 7 days). In asthmatic subjects, ADC3680 (22.73 mg daily) blocked ESC by >95% 24 hours post-dose on Day 1, and at 24 and 48 hours post-dose after 28 days9 treatment. The overall PK, safety and PD profile of ADC3680 support its further development as a low dose (