Background Arhalofenate is a novel uricosuric drug that blocks URAT1, a tubular uric acid transporter.

Objectives The study evaluated the serum uric acid (sUA) lowering effect of arhalofenate when combined with febuxostat and the potential for a drug-drug interaction. The effect of arhalofenate on the fractional excretion of uric acid (FEUA) was also assessed as well as safety. Pharmacokinetic data will be reported elsewhere.Arhalofenate is a novel uricosuric drug that blocks URAT1, a tubular uric acid transporter.

Methods This was an open label Phase 2 study (NCT02252835) at a single center with two cohorts of volunteers gout patients (n=16 each). Subjects were treatment naïve or willing to discontinue uric acid lowering therapy. Dosing was once daily oral including flare prophylaxis with colchicine. One cohort received arhalofenate 600 mg for 2 weeks followed by sequential one week periods of co-administration of febuxostat 80 mg and 40 mg. During the final two weeks, febuxostat 40 mg alone was continued. The second cohort received arhalofenate 800 mg for 2 weeks, followed by sequential one week periods of co-administration of febuxostat 40 mg and 80 mg. During the final two weeks, febuxostat 80 mg alone was continued. sUA was assessed at multiple time points. FEUA was assessed over three intervals (9 am-3 pm, 3 pm-9 pm and 9 pm-9 am) at multiple time points. Eight subjects on arhalofenate 800 mg alone had FEUA measured at baseline and days 3, 7 and 14.

Results Thirty-two subjects were enrolled. Baseline mean sUA were 9.4 and 9.2 mg/dL, respectively. The responder rates (percentages of subjects reaching different sUA targets) are shown below:

Treatment with arhalofenate 800 mg monotherapy gradually decreased sUA with approximately half of the decrease on day 7. Intraday variations in sUA were <10%. FEUA values increased from ∼4.6 (9 am -9 pm) and ∼3.5% (9 pm-9 am) at baseline to ∼5.8% (9 am -9 pm) and ∼4.7% (9 pm-9 am) on day 14 (p<0.001), respectively.

There were no serious adverse events and only one severe event of uncontrolled hypertension not related to study drugs. There was one case of elevated transaminases that emerged after the initiation of febuxostat. No subjects had >1.5X elevation in serum creatinine or any value above normal.

Conclusions The combination of febuxostat with arhalofenate was well tolerated, appeared safe and was more efficacious in decreasing sUA than febuxostat alone. With the 800 mg combinations, 100% of subjects achieved sUA <6 and 93% <5 mg/dL, recommended treatment goals, and 79% of subjects achieved <4 mg/dL, a more ambitious goal for patients with high urate crystal burden. On arhalofenate alone, sUA slowly decreased over 2 weeks with small intraday variations in both sUA and FEUA. Low FEUA, a hallmark of gout, was restored toward normal levels. These data are consistent with the long half-life of arhalofenate (∼50 hours). Arahlofenate is currently in development as a monotherapy and in combination therapy for the treatment of gout.

Disclosure of Interest A. Steinberg Shareholder of: cymabay therapeutics, Employee of: cymabay therapeutics, B. Vince: None declared, Y.-J. Choi Shareholder of: cymabay therapeutics, Employee of: cymabay therapeutics, R. Martin Shareholder of: cymabay therapeutics, Employee of: cymabay therapeutics, C. McWerther Shareholder of: cymabay therapeutics, Employee of: cymabay therapeutics, P. Boudes Shareholder of: cymabay therapeutics, Employee of: cymabay therapeutics