2011: A Phase 1 Placebo Controlled, Single (SAD) and Multiple Dose Escalation (MAD) Safety and Pharmacokinetic (PK) Study of a Novel Colchicine Analogue ABP-745 in Healthy Volunteers (HV)

Background/Purpose: ABP-745 is a novel colchicine analogue in development as an anti-inflammatory agent for the treatment of acute gout and other chronic inflammatory conditions. In preclinical models, ABP-745 demonstrated comparable biological activity to colchicine with an improved safety profile including no significant drug-drug interactions.

Methods: Subjects were randomized to active drug or placebo in a 6/2 ratio. Subjects were dosed qd or bid in an ascending order (SAD). SAD Cohorts qd or bid of ABP-745 0.5 mg qd, 1.5 mg qd, 4 mg qd , 5 mg qd and 2.0 mg bid, 2.5 mg bid and placebo (N=32). Multiple ascending dose (MAD, 8 days) cohorts were ABP-745 0.5 mg qd; 1.5 mg qd; 4 mg qd; 2.5 mg bid; 2 mg bid (N=41). Single-dose food effect (ABP-745, 4 mg) was also studied (N=8). Safety was monitored until 3 days post last dose by clinical and laboratory methods. PK was followed over 36 hours (single dose) and on Day 1 (24 h) and Day 8 (36 h) of the MAD regimens.

Results: ABP-745 concentrations were detected 10 minutes post dose across all SAD levels. Maximum ABP-745 mean concentrations peaked between 1.50 h and 2.00 h with biphasic decline across all dose levels. Mean ABP-745 concentrations and exposure parameters (Cmax, AUClast, and AUC0-inf) increased over the 0.5 mg to 5 mg dose range. Mean Cmax ranged from 37.7 ng/mL to 216 ng/mL; mean AUClast ranged from 226 h*ng/mL to 1520 h*ng/mL. Mean ABP-745 Cmax, AUClast, and AUC0-inf increased in a less than proportional manner with increases in single ascending ABP-745 doses. MAD: mean ABP-745 concentrations and exposure parameters (Cmax and AUCτ on Day 1; Cmax,ss and AUCs on Day 8) increased with ascending multiple doses of ABP-745 across study days. On Day 8, mean Cmax,ss ranged from 34.0 ng/mL to 175 ng/mL, mean AUCτ ranged from 181 h*ng/mL to 1230 h*ng/mL. Accumulation ratios for Cmax,ss (RCmax) and AUCτ (RAUCτ) indicated no accumulation in ABP-745 exposure occurred during qd and bid 8-day dose regimens. RCmax values ranged from 0.944 to 1.13 for qd treatments and from 1.15 to 1.24 for bid treatments. On Day 8 approximately 20% of the administered oral dose was recovered in the urine. On Day 1 of MAD, maximum and total ABP-745 exposure (Cmax and AUCτ) generally increased in a less than proportional manner with an increase in multiple ascending QD doses. ABP-745 trough concentrations were higher for bid treatments compared to the qd treatment. Steady-state: Day 2 of dosing for both qd and bid dosing regimens. Food effect (fed/fasted) was studied (N=8). Mean ABP-745 Cmax and AUC0-inf were similar after administration of 4 mg ABP-745 under fed and fasted conditions. Median Tmax was delayed by @ 30 minutes under fed conditions (1.50 h vs. 0.988 h, respectively). Four treatment emergent AEs (TEAE) were reported in the SAD in the 5 mg single dose cohort as gastrointestinal symptoms (single events of diarrhea, nausea, abdominal pain, vomiting). In the MAD cohort 11 TEAE were reported in the 2 highest bid dose groups, such as single cases of nausea, constipation, headache, elevated blood lipase and amylase levels.

Conclusion: Safety and pharmacokinetics (PK) of ABP-745 following single, and multiple qd and bid oral doses in healthy volunteers under fasted and fed conditions further supports development of ABP-745 in an acute gout indication.