Alexandra S Steinberg1,2, Bradley D Vince1,2, Yun-Jung Choi1,2, Robert L Martin1,2, Charles A McWherter1,2, Pol F Boudes3,4. 1. From CymaBay Therapeutics Inc., Newark, California; Vince and Associates, Overland Park, Kansas, USA. 2. A.S. Steinberg, MD, PhD, CymaBay Therapeutics Inc.; B.D. Vince, DO, Vince and Associates; Y.J. Choi, PhD, CymaBay Therapeutics Inc.; R.L. Martin, PhD, CymaBay Therapeutics Inc.; C.A. McWherter, PhD, CymaBay Therapeutics Inc.; P.F. Boudes, MD, CymaBay Therapeutics Inc. 3. From CymaBay Therapeutics Inc., Newark, California; Vince and Associates, Overland Park, Kansas, USA. pboudes@cymabay.com. 4. A.S. Steinberg, MD, PhD, CymaBay Therapeutics Inc.; B.D. Vince, DO, Vince and Associates; Y.J. Choi, PhD, CymaBay Therapeutics Inc.; R.L. Martin, PhD, CymaBay Therapeutics Inc.; C.A. McWherter, PhD, CymaBay Therapeutics Inc.; P.F. Boudes, MD, CymaBay Therapeutics Inc. pboudes@cymabay.com.
Abstract
OBJECTIVE: Arhalofenate (ARH), in development for gout, has uricosuric and anti-flare activities. ARH plus febuxostat (FBX) were evaluated in subjects with gout for serum uric acid (SUA) lowering, drug interaction, and safety. METHODS: Open phase II trial in gout volunteers (NCT02252835). Cohort 1 received ARH 600 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 80 mg followed by 40 mg. FBX 40 mg was continued alone for 2 weeks. Cohort 2 received ARH 800 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 40 mg followed by 80 mg. FBX 80 mg was continued alone for 2 weeks. SUA, its fractional excretion (FEUA), and plasma oxypurines were assessed. Pharmacokinetics of FBX and ARH were determined alone and in combination for cohort 2. RESULTS: Baseline mean SUA was 9.4 mg/dl for cohort 1 (n = 16) and 9.2 mg/dl for cohort 2 (n = 16). The largest SUA decrease (63%) was observed with ARH 800 mg + FBX 80 mg, with all subjects reaching SUA < 6 mg/dl and 93% < 5 mg/dl. The area under the curve (AUC)(0-t) of ARH acid + FBX/ARH acid was 108%. The AUC(0-t) of FBX + ARH acid/FBX was 87%. As expected, FBX increased oxypurines and increases were unaffected by ARH co-administration. Baseline FEUA were low (3.5%-4.6%) and ARH increased them toward normal without overexcretion of UA. ARH was well tolerated and appeared safe. CONCLUSION:ARH and FBX lowered SUA by complementary mechanisms. The combination provided greater decreases than each drug alone. The combination was well tolerated and appeared safe. TRIAL REGISTRATION: NCT02252835.
RCT Entities:
OBJECTIVE:Arhalofenate (ARH), in development for gout, has uricosuric and anti-flare activities. ARH plus febuxostat (FBX) were evaluated in subjects with gout for serum uric acid (SUA) lowering, drug interaction, and safety. METHODS: Open phase II trial in gout volunteers (NCT02252835). Cohort 1 received ARH 600 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 80 mg followed by 40 mg. FBX 40 mg was continued alone for 2 weeks. Cohort 2 received ARH 800 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 40 mg followed by 80 mg. FBX 80 mg was continued alone for 2 weeks. SUA, its fractional excretion (FEUA), and plasma oxypurines were assessed. Pharmacokinetics of FBX and ARH were determined alone and in combination for cohort 2. RESULTS: Baseline mean SUA was 9.4 mg/dl for cohort 1 (n = 16) and 9.2 mg/dl for cohort 2 (n = 16). The largest SUA decrease (63%) was observed with ARH 800 mg + FBX 80 mg, with all subjects reaching SUA < 6 mg/dl and 93% < 5 mg/dl. The area under the curve (AUC)(0-t) of ARH acid + FBX/ARH acid was 108%. The AUC(0-t) of FBX + ARH acid/FBX was 87%. As expected, FBX increased oxypurines and increases were unaffected by ARH co-administration. Baseline FEUA were low (3.5%-4.6%) and ARH increased them toward normal without overexcretion of UA. ARH was well tolerated and appeared safe. CONCLUSION:ARH and FBX lowered SUA by complementary mechanisms. The combination provided greater decreases than each drug alone. The combination was well tolerated and appeared safe. TRIAL REGISTRATION: NCT02252835.
Authors: Caroline L Benn; Pinky Dua; Rachel Gurrell; Peter Loudon; Andrew Pike; R Ian Storer; Ciara Vangjeli Journal: Front Med (Lausanne) Date: 2018-05-31