FDA Approves Pegloticase for Refractory Gout

Yael Waknine

September 15, 2010

September 15, 2010 — The US Food and Drug Administration (FDA) has approved pegloticase (Krystexxa; Savient Pharmaceuticals, Inc) as the first and only treatment for chronic gout in adults refractory to conventional therapy.

"About 3 percent of the three million adults who suffer from gout are not helped by conventional therapy. This new drug offers an important new option for them," said Badrul Chowdhury, MD, director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA's Center for Drug Evaluation and Research, in an agency news release. Pegloticase is expected to be available by prescription in the United States later this year.

FDA approval of the pegylated uric acid–specific enzyme therapy was based on data from 2 replicate, multicenter, randomized, double-blind, 6-month studies in which 212 patients with baseline serum uric acid levels of 8 mg/dL or greater were randomly assigned in a 2:2:1 ratio to receive either 8 mg pegloticase every 2 weeks or 4 weeks or placebo.

All patients were prophylaxed with an oral antihistamine, intravenous corticosteroid, and acetaminophen. Unless medically contraindicated or not tolerated, patients also received prophylaxis for gout flares with nonsteroidal anti-inflammatory drugs and/or colchicine, beginning at least 1 week before pegloticase therapy.

Results from studies 1 and 2 showed that 47% and 38% of patients receiving 8 mg pegloticase on a bimonthly basis achieved plasma uric acid levels of less than 6 mg/dL for at least 80% of the time during months 3 and 6, compared with 0% of those given placebo (P < .001 for both comparisons). The difference between monthly pegloticase therapy and placebo only achieved statistical significance in 1 study (20% vs 0% [P = .044]; 49% vs 0% [P < .001]).

As a secondary endpoint, investigators also assessed the effect of pegloticase therapy on the tophi that were present in 71% of patients at baseline. A pooled analysis of data from both studies showed that 45% of patients receiving bimonthly pegloticase achieved a complete response at month 6, defined as 100% resolution of at least 1 target tophus, with no single tophus showing progression and no new tophi appearing (vs placebo, 8%; P < .02). The improvement in complete response rate was not statistically significant for patients receiving monthly pegloticase therapy.

"The clinical data have demonstrated that many patients treated with Krystexxa 8 mg administered every two weeks can experience within six months of treatment significant positive clinical improvement reversing the course of this severe, crippling and debilitating disease," said Paul Hamelin, RPh, president of Savient Pharmaceuticals, in a company news release.

Potential Adverse Effects

Despite premedication, bimonthly pegloticase therapy was associated with gout flares (77% vs placebo, 81%), infusion reactions (26% vs 5%), and anaphylaxis (5% vs 0%) that generally occurred within 2 hours of treatment. Nausea (12% vs 2%), contusion/ecchymosis (11% vs 5%), nasopharyngitis (7% vs 2%), chest pain (6% vs 2%), vomiting (5% vs 2%), and constipation (6% vs 5%) were also reported.

The recommended dose of pegloticase is 8 mg administered as an intravenous infusion over at least 2 hours, every 2 weeks. Because of the risk for anaphylaxis and infusion reactions, premedication with antihistamines and corticosteroids is advised, and patients should be closely monitored for an appropriate period of time after drug administration. In the event of a reaction, the infusion should be slowed, or stopped and restarted at a slower rate. Severe infusion reactions require discontinuation of therapy.

The FDA warns that the risk for infusion reactions is higher in patients who have lost therapeutic response; serum uric acid levels should be measured before infusions and discontinuation of therapy considered if levels increase to higher than 6 mg/dL, particularly if elevated levels are observed on 2 consecutive occasions. No controlled trial data are available on the safety and efficacy of reinitiating pegloticase therapy after more than 4 weeks; retreated patients may be at increased risk for anaphylaxis or infusion reactions and should be carefully monitored.

Because of these and other safety concerns, pegloticase has been approved with a risk evaluation and mitigation strategy that includes a patient medication guide and educational materials for clinicians.

Pegloticase therapy is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency because of the risk for hemolysis and methemoglobinemia. Patients at increased risk for the condition, such as those of African or Mediterranean ancestry, should be screened for G6PD deficiency before initiation of therapy.

As with other antihyperuricemic therapies, an initial increase in gout flares may occur. Gout flare prophylaxis with nonsteroidal anti-inflammatory drugs or colchicine is recommended for at least the first 6 months of treatment unless medically contraindicated or not tolerated.

Although pegloticase has not been formally studied in patients with congestive heart failure, 2 cases of exacerbation were reported in patients receiving bimonthly treatment. Caution and close monitoring is advised when administering pegloticase to patients with congestive heart failure.

According to the company news release, a 1-year postmarketing observational safety study is planned to further evaluate the frequency and severity of infusion reactions, anaphylaxis, and immune complex-related reactions and to identify serious adverse events related to pegloticase therapy.