Background/Purpose: Arhalofenate is a novel Urate-Lowering Anti-Flare Therapy (ULAFT) for the treatment of gout.  It lowers serum uric acid (sUA) by blocking URAT1, a tubular UA transporter, and reduces gout flares by blocking the local release of IL-1β. The study evaluated the serum uric acid (sUA) lowering effect of arhalofenate when combined with febuxostat, the potential for drug-drug interaction and safety.

Methods: This was a single-center, open label Phase 2 (NCT02252835) with two cohorts of volunteer gout subjects (n = 16 each). Subjects were treatment naïve or willing to discontinue urate 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 co-administration of febuxostat 80 mg and 40 mg. During the final 2 weeks, febuxostat 40 mg alone was continued. The second cohort received arhalofenate 800 mg for 2 weeks, followed by sequential one-week co-administration of febuxostat 40 mg and 80 mg. During the final 2 weeks, febuxostat 80 mg alone was continued. sUA and oxypurines (xanthine, hypoxanthine, guanine) were assessed at multiple time-points.  Arhalofenate (800 mg) and febuxostat (80 mg) pharmaco-kinetics were determined in the second cohort.

Results:

Thirty-two subjects were enrolled. Baseline mean sUA were 9.4 and 9.2 mg/dL, respectively. The largest decrease in sUA (63%) was seen in the arhalofenate 800 mg plus febuxostat 80 mg combination. With this treatment, 100% of subjects achieved a goal of < 6 mg/dL, 93% < 5 mg/dL and 79% < 4 mg/dL.

The mean ± SD arhalofenate acid AUC_(0‑τ) was 2,960 ± 730 and 3,190 ± 871 µg·h/mL in the absence and presence of febuxostat, respectively.  The ratio of AUC_(0‑τ)geometric means of the combination to arhalofenate alone was 108% (90% CI 89-131%).

The mean ± SD febuxostat AUC_(0‑τ) was 11,100 ± 2,940 and 9,590 ± 2,270 ng·h/mL in the absence and presence of arhalofenate, respectively. The ratio of AUC_(0‑τ)geometric means of the combination to febuxostat alone was 87% (90% CI 74-103%).

As expected from its mechanism of action, febuxostat alone dramatically increased the plasma levels of oxypurines. These levels were unchanged, or even slightly increased, by the co-administration of arhalofenate.

Arhalofenate, either alone or in combination, was well tolerated and appeared safe. No subjects had >1.5X elevation in serum creatinine or any value above normal.

Conclusion: The combination of arhalofenate with febuxostat was well tolerated, appeared safe and was more efficacious in decreasing sUA than both drugs alone. Arhalofenate decreased the AUC of febuxostat when compared with febuxostat alone, however this was not clinically relevant as this was not associated with a decrease of oxypurines levels. Arhalofenate in combination with febuxostat is now in phase 3 to reduce sUA and prevent gout flares.

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ACR Meeting Abstracts - http://acrabstracts.org/abstract/a-study-to-evaluate-the-pharmacodynamics-pharmacokinetics-and-safety-of-arhalofenate-in-combination-with-febuxostat-when-treating-hyperuricemia-associated-with-gout/