newdrugs .EW DRUGS FOR GOUT IN THE PIPELINE that of the xanthine oxidase inhibitors. Data from the Phase II clinical trial program demonstrated that BCX4208 worked well as monotherapy and in combination with allopurinol to safely and effectively lower serum uric acid levels. In a Phase IIb, 12-week trial, the addition of BCX4208 at daily doses of mg, 10 mg, 20 mg, or 40 mg to allopurinol 300 mg/d approximately doubled the number of patients reaching a serum uric acid level of less than mg/dL compared with allopurinol monotherapy (33% 49% vs. 18%). The company recently announced that it is nearing the end of Phase II development and will be ready to start Phase III testing soon. Two biologic IL-1 inhibitors have been investigated for the management of gout: rilonacept and canakinumab Both agents are already approved by FDA for the management of cryopyrinassociated periodic syndromes. Data from a Phase II trial released in January of this year showed that rilonacept was effective at reducing gout Eighty-three patients with a history of two or more gout and elevated uric acid levels were randomized to treatment with rilonacept 320 mg as an initial dose, followed by 160 mg weekly via subcutaneous injection or placebo for 16 weeks. All patients received allopurinol 300 mg daily. At the 12-week endpoint, only 14.6% of patients given rilonacept experienced gout compared with 45.2% in the placebo group (P 0.004). No serious infections or deaths occurred in the trial. Studies have also been conducted with canakinumab for the management of acute gout in patients who failed to respond to NSAIDs or colchicine, and Novartis has applied for FDA approval for this indication. In June 2011, the FDA Arthritis Advisory Committee voted against approval of the drug for this indication, stating that it was effective for gout but had too many safety concerns. increased risk of infection, cardiovascular and renal function risks, and concerns about the pharmacokinetic of canakinumab in older patients were some of the safety concerns cited by the committee. Late last year, FDA followed the recommendation and declined to approve canakinumab for gout. The agency stated that it needed additional information, including clinical data to evaluate the in refractory patients. $ATA FOR ), BLOCKERS ,OOKING AHEAD Blockage of interleukin-1 (IL-1) has been investigated as a target for the management of gout Interest in IL-1 inhibition originated from the that urate crystals induce that leads to IL-1 production. Therefore, blockage of this pathway may result in improvements in gout Other drugs in development for gout include uricase-PEG (polyethylene glycol) 20 and apremilast. The management of gout can be expected to change dramatically in the coming years once new treatments with novel mechanisms of action reach the marketplace. Complementary mechanisms of action, novel targets Numerous investigational agents are in development for the management of gout. Some of these agents are in Phase II or III testing and some have submitted applications to FDA for approval. An overview of some key medications in the pipeline is presented here. demonstrate the of lesinurad in patients who have not achieved medically appropriate target serum uric acid levels with standard doses of xanthine oxidase inhibitors, in patients who cannot tolerate the current standard of care, and in patients with advanced disease. ,ESINURAD BCX4208 Ardea Biosciences is developing lesinurad, an oral, once-daily inhibitor of the urate transporter (URAT1). URAT1 is a transporter in the kidney that regulates uric acid excretion from the body. Data presented at the 2011 annual meeting of the European League Against Rheumatism showed that the addition of lesinurad to a regimen of allopurinol mg/d) in patients with gout resulted in reductions in mean serum urate levels. after weeks of treatment, lesinurad 200 mg plus allopurinol produced a reduction of 16%, lesinurad 400 mg plus allopurinol produced a reduction of 22%, and lesinurad 600 mg plus allopurinol produced a reduction of 30%, compared with a 3% increase in levels in patients on allopurinol alone (P 0.0001 for all comparisons). In addition, significantly more patients given combination therapy achieved serum urate levels less than mg/dL compared with allopurinol monotherapy. The investigator of this trial concluded that lesinurad appears to be a promising drug for the treatment of hyperuricemia in patients with gout who have an inadequate response to xanthine oxidase inhibitors. In December 2011, Ardea Biosciences announced that it has initiated the of four planned Phase III clinical trials for lesinurad for the management of chronic gout. The Phase III program is expected to involve approximately 2,000 patients from around the world and is designed to BioCryst is developing BCX4208, an oral, once-daily inhibitor of the purine nucleoside phosphorylase (PNP) enzyme. This enzyme functions in the purine salvage pathway and leads to formation of uric acid. As with lesinurad, BCX4208 has a mechanism of action that complements www.pharmacist.com ISSUE FOCUS: RHEUMATOLOGY 0HARM$ APRIL 2012 PHARMACY TODAY 45