Initiation of urate lowering therapies have been associated with an increased risk of gout flares. Hence, prophylaxis with either colchicine or naproxen has become routine in order to ameliorate this risk. Groups may vary on how long prophylaxis should be given but 6 months is generally recommended. Aside from prophylaxis, slow reduction of serum urate levels have also been advised as a means of minimizing flares (which is another reason why many groups still prefer allopurinol as first line therapy since following dosing guides result in a more gradual reduction of SUA compared to agents like febuxostat).
Some patients may be concerned with the number of pills they have to take when undergoing treatment for gout. So here is where arhalofenate may be an option. Arhalofenate is a novel uricosuric that blocks URAT1 mediated reabsorption of urate in the proximal tubules of the kidney. Similar to benzbromarone and lenisurad, it can be given as a single daily dose and does not share the need for frequent dosing seen with older uricosurics like probenecid and sulfinpyrazone. In mouse models, it has also been shown to inhibit activity of IL-1B – a key inducer of gout attacks – and also blocks neutrophil influx at the site of inflammation. In short, arhalofenate is a novel ULT with anti-inflammatory properties.
The randomized double blind placebo controlled Phase IIB study of Poiley J, et al. primarily explores this anti-inflammatory property of arhalofenate. 248 patients diagnosed with gout who had SUA levels between 7.5-12mg/dl and experienced 3 flares during the preceding year were randomized to receive either arhalofenate 600mg/d, arhalofenate 800mg/d, allopurinol 300mg/d, allopurinol 300mg/d + colchicine or placebo during the 12 week observation period in a 2:2:2:2:1 ratio.
Results in the primary endpoint of the study
After 12 weeks, patients on arhalofenate 800mg/d had significantly fewer flares of gout compared to those who were given allopurinol alone (0.66 vs 1.24, p=0.0056) and those who received placebo (0.66 vs 1.13, p=0.049) . However, the result was not statistically different when compared to those who received allopurinol + colchicine (0.66 vs 0.40, p=0.091). The number of flares in the arhalofenate 600mg and allopurinol arms were not statistically different. Flares were fewer in the allopurinol + colchicine than in the allopurinol group, expectedly. Duration of flares were not statistically different between the arhalofenate 800mg, allopurinol and allopurinol + colchicine arms but were longer in the placebo and arhalofenate 600mg groups. Flares also ceased to happen after 2 months of treatment with either arhalofenate 800mg or allopurinol + colchicine.
Unfortunately, it terms of the outcomes we actually target in gout treatment, i.e. achieving SUA <6mg/dl, only 11.8% of patients on arhalofenate 800mg met this endpoint compared to 48.1% receiving allopurinol alone. This endpoint is actually more important than short term reduction of flares as it has been shown in several studies to translate to fewer flares in the long run and is crucial in preventing or reversing some gout complications.
We still have to await formal phase III studies before fully appreciating the potential role arhalofenate can have in gout management. But additional options for our gout patients are always welcome news.
Reference: Poiley J, et al. A randomized double blind active and placebo controlled efficacy and safety study of arhalofenate for reducing flares in patients with gout. Arthritis & Rheum 2016; 68(8): 2027-34. (Read here)