2012: A Phase 2a Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of ABP-671 in Subjects with Hyperuricemia or Gout in China

Background/Purpose: ABP-671 is a novel, selective and potent URAT1 inhibitor in development for the treatment of elevated serum uric acid (sUA) levels and gout.

Methods: Subjects (N=45) ≥18 and ≤ 55 years, without clinically significant kidney abnormalities on renal ultrasound and non-symptomatic hyperuricemia or gout (two separate fasting sUA results of >7 mg/dL and >24 hours apart) were enrolled. Subjects were randomized to 5 multiple ascending oral dose groups including 1, 2, 4, 6, 12 mg of ABP-671 and placebo in a 7/2 ratio. All subjects underwent a dose escalation dosing period starting from 0.2 mg to 1 mg over a 9-day or 10-day period to mitigate any renal uUA overload. A 7-day dosing period of ABP-671 or placebo followed. The groups were enrolled separately and conducted sequentially (Table 1).

TEAEs were reported in 24 (53.3%), including 5 (71.4%), 4 (57.1%), 6 (85.7%), 4 (57.1%), 1 (14.3%), and 4 (40%) in the 1, 2, 4, 6, and 12 mg and placebo groups, respectively. There were no SAEs, grade >3 TEAEs, or deaths. The incidence of AEs was not found dose dependent.

Group	Dose Escalation Period	Target Dose Period
1	d1 - d3: 0.2 mg, QD d4 - d10: 0.5 mg, QD	d11 - d17: 1 mg, QD
2	d1 - d3: 0.2 mg, QD d4 - d6: 0.5 mg, QD d7 - d9: 1 mg, QD	d10 - d16: 2 mg, QD
3		d10 - d16: 4 mg, QD
4		d10 - d16: 6 mg, QD
5		d10 - d16: 12 mg, QD

Table 1: Schedule for dose initiation and target dosing phase

Results: Serum UA (sUA) levels decreased in a dose dependent manner. The max median decrease of sUA occurred at 3.00-9.00 h post dose. For placebo, 1, 2, 4, 6 and 12mg dose groups, the maximum mean sUA decrease in gout subjects was 17.7%, 56.4%, 58.1%, 69.4%, 77.0%, and 79.2% from baseline, and in hyperuricemia subjects, they were 19.9%, 50.1%, 64.1%, 73.2%, 81.2%, and 82.1%. Subjects (%) with sUA levels lower than 6.0, 5.0, and 4.0 mg/dL 24 h post dose were 85.7%, 57.1%, and 14.3% for 1 mg, 100%, 85.7%, and 14.3% for 2 mg, 100%, 85.7%, and 14.3% for 4 mg, 100%, 100%, and 57.1% for 6 mg, and 100%, 100%, and 100% for 12 mg.

Table 2. Response rate (N/%) at selected categories 24 h post dose

24 h post dose	1 mg (n=7)	2 mg (n=7)	4 mg (n=7)	6 mg (n=7)	12 mg (n=7)	Placebo (n=10)
sUA < 6.0 mg/dL	6 (85.7)	7 (100)	7 (100)	7 (100)	7 (100)	0
sUA < 5.0 mg/dL	4 (57.1)	6 (85.7)	6 (85.7)	7 (100)	7 (100)	0
sUA < 4.0 mg/dL	1 (14.3)	1 (14.3)	1 (14.3)	4 (57.1)	7 (100)	0

Conclusion: ABP-671 has acceptable safety and tolerability in Chinese subjects with hyperuricemia or gout. ABP-671 reduced the sUA in a dose-dependent manner.