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A look down the gout Tx pipeline.

Allopurinol should, for now, remain the standard hyperuricemia treatment for gout, despite the approval of febuxostat and pegloticase and ongoing development of other pharmaceuticals.

The reason is that allopurinol - if adequately dosed - works for most patients. And after decades on the market, its safety profile is well known; it's also the least expensive option.

But even with adequate dosing, allopurinol does not work for everyone. For some, renal problems or previous hypersensitivity reactions make its use problematic.

That's where the newer options come in. For physicians and patients alike, they mean that allopurinol is not the end of the line anymore.

Soon, there will likely be enough options to treat every gout patient.

We recently reviewed febuxostat and pegloticase, as well as other drugs in the gout pipeline (Lancet 2010 Aug. 17 [doi:10.1016/S0140-6736(10)60665-4]). Our conclusion: Recent developments signal a new era in the treatment of gout.

Febuxostat (Uloric), which was approved by the Food and Drug Administration in February 2009, is already making a difference in clinical practice. Patients who have had trouble with allopurinol often respond to febuxostat. The first dose can quickly drop urate levels down to 5 mg/dL or so, without side effects or rash. It's a great drug that is here to stay.

Like allopurinol, febuxostat is a xanthine oxidase inhibitor, but a more selective one that does not inhibit other enzymes in the purine and pyrimidine metabolic pathways.

Febuxostat dosing is easier, too. There are two options in the United States: 40 mg and 80 mg/day. The allopurinol dosing range is 100-800 mg/day, depending on patient's renal history and response.

Even with those advantages, febuxostat should be seen as a second-line agent, considered mainly for patients who are intolerant to allopurinol.

Febuxostat just has too many unknowns that are awaiting further information. For instance, it is not known if it is more effective than allopurinol. Febuxostat was better at dropping uric acid levels in trials, but it was compared with a suboptimal allopurinol dose (300 mg), and about 50% of gout patients need a higher dose to control hyperuricemia.

Also, febuxostat's cardiac safety is a concern. Cardiac events were more common in febuxostat patients during trials, although the implications of that are not yet clear. Takeda Pharmaceutical Co., the drug's maker, is investigating the matter further.

Finally, although no hypersensitivity reactions were attributed to febuxostat during trials, the FDA had received reports of 11 as of last May, including 2 anaphylactic reactions, 1 case of angioedema, and 2 of Stevens-Johnson syndrome.

Given the unknowns, clinicians need to use their judgment whether to push allopurinol to the therapeutic level rather than use febuxostat.

Patients who have mild or moderate renal insufficiency might be an exception, however. Adjustments in febuxostat dosage are not needed as long as patients' creatinine clearance is higher than 30 mL/min, according to the review article. Allopurinol is typically adjusted downward for diminished renal function.

Most people who have renal insufficiency do fine even on allopurinol, as long as they are started on a low dose that is titrated upward to therapeutic effect, and they are monitored for kidney function.

Febuxostat is making inroads in the United States: Some 139,565 prescriptions were written for it during its first 6 months on the market, according to health care market analytics firm SDI Health LLC.

One should expect ther to be a more modest reception for the next gout treatment - pegloticase (Krystexxa) - which is manufactured by Savient Pharmaceuticals Inc and which was approved by the FDA last month. Pegloticase's strength is rapid reduction of uric acid levels, to about 1 mg/dL within 24 hours in most cases, according to data presented before the FDA's arthritis advisory committee.

Its market will be among patients who need that kind of power: those with severe tophaceous gout whose urate loads are so high that there is an urgent clinical need to lower it.

Having a "big gun" for those situations would be a major advance, especially when allopurinol and febuxostat don't work or can't be used.

But pegloticase is destined to remain in the hands of subspecialists because it's tricky to use. The drug is a biologic that is administered intravenously a few times a month. In trials, at least 25% of patients developed antibodies to it, with subsequent infusion reactions, diminished effects, and treatment withdrawals, according to our review article.

Anaphylaxis developed in 7.3% of those who were infused every other week. The rapid uric acid reduction also led to frequent and sometimes severe gout flares.

Safe use is possible if rising concentrations of serum urate - a sign of antibody development and impending infusion reaction - are caught in time. But the use issues mean that pegloticase will have a limited audience. It is unlikely to be something that is used freely.

Other drugs intended for the management of gout are in early development. But, like febuxostat and pegloticase, they may help to plug gaps in current therapy if they are approved for gout.

Already approved for cryopyrin-associated periodic syndromes, the anti-inflammatory interleukin-1 inhibitors rilonacept (Arcalyst) and canakinumab (Ilaris) are being studied both for acute gout and for prophylaxis. Conceivably, they could find a home among gout patients who have relative contraindications to steroids or cannot use colchicine or NSAIDs because they have heart failure, kidney disease, peptic ulcers, or some other problem.

The gout pipeline also contains the uricosuric RDEA594. It is thought to be more selective than probenecid and benzbromarone, leading to the possibility that it would be a candidate for concomitant use with other urate-lowering treatments. However, findings from a small phase II trial show that RDEA594 was less effective than 300 mg allopurinol in lowering serum urate.

And combination therapy is already an option with allopurinol and probenecid.

It is too early in development to predict whether RDEA594 itself will make it through the FDA approval gauntlet, but a more selective uricosuric would be a useful addition to the expanding gout armamentarium.

ROBERT L. WORTMAN, M.D.,

CHRISTOPHER M. BURNS, M.D.

DR. WORTMANN is professor of medicine in the division of rheumatology at the Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and reports that he is a paid consultant for Takeda Pharmaceutical Co. and Savient Pharmaceuticals Inc. DR. BURNS is assistant professor of medicine in the rheumatology division of Dartmouth-Hitchcock, and reports no conflicts.
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Title Annotation:COMMENTARY
Author:Wortmann, Robert L.; Burns, Christopher M.
Publication:Internal Medicine News
Date:Oct 1, 2010
Words:1062
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