Background/Purpose: Arhalofenate is a novel Urate-Lowering Anti-Flare Therapy (ULAFT) to treat 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 primary objective was to evaluate the anti-flare activity of arhalofenate in gout patients in the absence of background colchicine treatment.

Methods: This was a randomized, double-blind, placebo- and active-controlled phase 2b (NCT02063997) at 54 centers. Male or female gout subjects with a sUA ≥ 7.5 mg/dL and ≤ 12 mg/dL were enrolled. Subjects experienced at least three flares during the previous year and could not have been using Urate Lowering Therapy (ULT) and colchicine two weeks before screening. Subjects were randomized 1:2:2:2:2 to placebo, arhalofenate 600 mg or 800 mg, allopurinol 300 mg or allopurinol 300 mg combined with colchicine 0.6 mg. Randomization was stratified on sUA levels and presence of tophi. Dosing was once daily, orally for 12 weeks.  Flares were recorded with an electronic diary. During study, flares were treated with non-steroidal or steroidal anti-inflammatory.

Results:

A total of 239 subjects were randomized and dosed, and constitute the efficacy (mITT) and safety population. The primary outcome of efficacy comparing flare rates between the arhalofenate 800 mg to allopurinol 300 mg groups was met with a 46% improvement (p = .0056). Additional key outcomes are presented in the table:

^a 46% reduction vs. allopurinol 300 mg (p = .0056) and 41% reduction vs. placebo (p= .049)

 ^b p = .0021 vs.placebo

 ^c p = .0059 vs. placebo

There were no SAEs related to arhalofenate. There was one SAE of a kidney stone in a patient on allopurinol 300 mg. There were no meaningful differences in the number of patients reporting Treatment Emergent AEs (TEAEs). The most frequent TEAEs were increases in creatine phosphokinase (4.6%), upper respiratory tract infections (3.8%), hypertension and headache (both 3.3%) with no relevant differences between groups. No subjects on arhalofenate who developed an abnormal serum creatinine value that was more than 1.5 times above pre-treatment values.

Conclusion:

Arhalofenate at 800 mg significantly decreases gout flares when compared to allopurinol 300 mg. There was no statistical difference in flares between arhalofenate 800 mg and allopurinol 300 mg combined with colchicine. Arhalofenate 800 mg also significantly decreased flares when compared to placebo. These results indicate that Arhalofenate has intrinsic anti-inflammatory activities clinically associated with improvement in gout flares.

Arhalofenate sUA lowering activity, while significant compared to placebo, was lower than in the allopurinol 300 mg groups. Arhalofenate was well tolerated and appeared safe.  

Arhalofenate is currently in development for the treatment of gout as a combination therapy with ULT, both to lower serum uric acid and prevent flares.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-study-to-evaluate-the-efficacy-and-safety-of-arhalofenate-for-preventing-flares-and-reducing-serum-uric-acid-in-gout-patients/