Advances in Urate-Lowering Therapy: Time to Revisit High-Dose Febuxostat

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Successful gout treatment depends almost entirely on lowering serum urate levels.1 Over the last decade, the Food and Drug Administration (FDA) approved 3 new urate-lowering medications: febuxostat, pegloticase, and lesinurad (joining the long-ago-approved drugs allopurinol and probenecid). Despite these therapeutic advances, gout remains an often difficult-to-treat disease.2 Barriers to successful treatment include patient comorbidities that pose relative contraindications to gout treatments, limited treatment options, health care providers who are unaware of “treat-to-target” recommendations, and patient noncompliance.3,4 Aggressive treatment can overcome many of these barriers, but even with the introduction of newer therapeutics, a number of patients are still unable to achieve adequate disease control.
When the FDA gave the nod to febuxostat (like allopurinol, a xanthine oxidase inhibitor) in 2009, it approved the drug at daily doses of 40 and 80 mg,5 diverging from the European Medicines Agency's decision the year before to approve 80 and 120 mg doses.6 The company filing for FDA approval did not, in fact, submit the 120 mg dose for review in 2009, despite the fact that the higher dose was more effective in clinical trials, and did not seem to confer serious safety concerns.
In the first published febuxostat phase 3 trial, 47% of subjects (118/249) taking 80 mg daily achieved a uric acid <5 mg/dL at their final visit, versus 66% (160/242) on 120 mg daily.7 Similar findings resulted from a more recent phase 3 study comparing the uricosuric agent lesinurad (200 mg) combined with febuxostat (80 mg) with febuxostat 80 mg: at the end of the double-blinded portion of the trial (6 months), 50.4% (66/131) of those on febuxostat monotherapy lowered their uric acid to <5 mg/dL, whereas combination therapy reached this target in 65% (85/131).8 In a separate study looking specifically at a population with tophaceous gout, 200 mg lesinurad plus 80 mg febuxostat yielded a serum urate <5 mg/dL in 57% of subjects, vs. 47% on febuxostat 80 mg alone.9 From these data, although febuxostat 80 mg plus lesinurad 200 mg outperforms febuxostat 80 mg monotherapy, the combination seems equivalent to febuxostat 120 mg daily.
The combination of allopurinol plus lesinurad, recently approved by the FDA, seems inferior to febuxostat 80 mg monotherapy. In the phase 3 Combining Lesinurad with Allopurinol Standard of Care in Inadequate Responders (CLEAR) 1 study, allopurinol 300 mg plus lesinurad 200 mg daily brought serum uric acid to less than 6 mg/dL in 54% of patients10 [by comparison, 74% on febuxostat 80 mg daily (and 80% on 120 mg) reached this target at the final visit in an earlier trial].7 In CLEAR 1, less than 30% of patients lowered their uric acid levels to <5 mg/dL. It must be noted that in the CLEAR 1 trial, average baseline serum uric acid levels were considerably lower than in all published febuxostat studies (6.9 mg/dL, vs. a range from 8.7 to 9.8 mg/dL), making the target uric acid of <6 mg/dL considerably easier to reach. Additionally, there is no evidence that lesinurad added to 300 mg allopurinol is more effective than judiciously titrating allopurinol to higher doses. That is, the allopurinol-plus-lesinurad trial used allopurinol 300 mg daily as an active comparator, although allopurinol is FDA approved up to 800 mg/d. Although another uricosuric drug, probenecid, has been available for decades, there are no data comparing the relative efficacy and safety of lesinurad with probenecid.
Lesinurad is additionally associated with renal toxicity. In a published phase 3 trial combining lesinurad with allopurinol, lesinurad 200 mg plus allopurinol caused a greater than 50% rise in baseline creatinine in 12 (6%) study patients (vs.
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