Gout, Tophi and the Kidneys (PRA 2011 Presentation Part 4)

Febuxostat is a non-purine xanthine oxidase inhibitor – similar in action to that of Allopurinol. Although the first trial (FACT) was published in 1995, Febuxostat was only approved for commercial use in Europe in 2008 and in the US in 2009. Three randomized clinical trials and one open-label extension study had been done involving >4,000 patients with gout. The  FACT study enrolled gout patients with normal renal function while the APEX study attempted to involve patients with renal insufficiency. Unfortunately, this subgroup was under-represented enrolling only 10 patients with renal impairment. The CONFIRMS study had 65% of enrolled patients having either mild or moderate renal impairment. All three RCTs had treatment duration of <52 weeks. The FOCUS study is an open-label extension phase of an initial Phase II trial that evaluated the 5 year efficacy of Febuxostat.
When the biochemical endpoint of achieving a target SUA <6mg/dl was looked into, all three RCTs were consistent in showing superiority of Febuxostat over Allopurinol in gout patients with either normal or impaired renal function. Interestingly, the CONFIRMS trial showed that Febuxostat 40 mg was as effective as Allopurinol 300 mg as far as reducing SUA is concerned. The higher the dose of Febuxostat, the more patients achieving SUA<6 mg/dl were reported. Moreover, a significant proportion of patients in the Febuxostat arms were able to achieve SUA<4 or <5 mg/dl – a target shown to promote more rapid tophus resolution.

If we were to follow the results of other observational studies, we should expect less reports of flares among patients receiving Febuxostat. Unfortunately, there was no significant difference between groups. In fact, more patients in the Febuxostat arms experienced flares during the first 8 weeks – something attributed to the drug’s more dramatic effect of lowering SUA. And when comparing resolution of tophi in the APEX and FACT studies (CONFIRMS did not look into this), there was no significant different in mean resolution of tophi (number and % reduction) between groups. However, this may be a limitation of the study design as both trials involved giving the study drug <52 weeks. But with the results of FOCUS, there were only 31% of patients with persistent tophi after 5 years of Febuxostat use.
Adverse events occurred in similar proportions between the groups receiving Allopurinol and Febuxostat. The most commonly reported AE’s were those of abnormal LFTs and diarrhea (which occurred more in the Febuxostat 240 mg group). Something that must be followed up is the tendency to increase CV events among patients febuxostat.
Pegloticase is a uricase agent derived from porcine-baboon models. It is able to convert uric acid to soluble allantoin – generating peroxide and carbon dioxide in the process. The concept for uricase had been presented as early as 1981. However, drug development had been limited by the following concerns: (1) drug’s short half-life warranting infusion every 1-2 weeks, (2) tendency to develop drug antibodies which significantly reduces its therapeutic effects, (3) caution for use in patients with G6PD deficiency. Patients enrolled in the Gout outcomes and urate therapy (GOUT) trials were all treatment failures to allopurinol. And based on data, 34-42% of patients were able to achieve SUA<6 mg/dl. But the good news about pegloticase is its impact on tophus reduction. In the 26 weeks trials, 20-40% of patients reported target tophus resolution – some occurring even as early as 13 weeks.
If subgroup analyses were to be performed comparing persistent (able to maintain SUA<6mg/dl) vs transient (after an initial response, treatment response diminishes) responders, the latter group was associated with more infusion reactions occurring between the 3rd and 4th infusion. This observation was related to development of anti-pegloticase antibodies. If antibody production could be suppressed, uricase could be more freely used to reduce tophi.
Another new drug for gout, is RDEA594 – a novel uricosuric drug which selectively inhibits URAT1 transporter in the kidneys. Phase II trials have shown that it has additive benefits when given with either Allopurinol or Febuxostat and, so far, with no reported AEs. RDEA594 is able to maintain its efficacy even in patients with moderate renal insufficiency.
References
  1. Becker M, Schumacher HR, Wortmann R, et al. Febuxostat compared with Allopurinol in patients with gout and hyperuricemia. NEJM 2005; 353: 2450-61.
  2. Schumacher HR, Becker M, Wortmann R, et al. Effects of Febuxostat versus Allopurinol and Placebo in reducing SUA in subjects with hyperuricemia and gout. Arth Rheum 2008; 58: 1540-8.
  3. Becker M, Schumacher HR, Espinoza L, et al. The urate lowering efficacy and safety of Febuxostat in the treatment of gout and hyperuricemia, Arth Res Ther 2010; 12: R63.
  4. Schumacher HR, Becker M, Lloyd W, et al. Febuxostat in the treatment of gout: CONFIRMS trial. Rheum 2009; 48: 188-94.
  5. Reinders M, Jansen T. New advances in the treatment of gout: review of pegloticase. Ther Res Clin Risk Mngt 2010; 6: 543-50.
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