The FDA ( Food and Drug Administration ) has approved Krystexxa ( Pegloticase ), a PEGylated uric acid specific enzyme indicated for the treatment of chronic gout in adult patients refractory to conventional therapy. Chronic gout that is refractory to conventional therapy occurs in patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.
Krystexxa is not recommended for the treatment of asymptomatic hyperuricemia.

The recommended dose and regimen of Pegloticase for adult patients is 8 mg given as an intravenous infusion every two weeks.

The efficacy and safety of Pegloticase was studied in patients with chronic gout refractory to conventional therapy in two replicate, multicenter, randomized, double-blind, placebo-controlled clinical studies of six months duration. Patients were randomized to receive Pegloticase every 2 weeks or every 4 weeks or placebo in a 2:2:1 ratio. The primary endpoint in both trials was the proportion of patients who achieved plasma uric acid ( PUA ) less than 6 mg/dL for at least 80% of the time during month 3 and month 6.
The data in both clinical studies demonstrated that a greater proportion of patients treated with Pegloticase every 2 weeks achieved urate lowering to below 6 mg/dL than patients receiving placebo. During the first six months of treatment, 47% ( P<0.001 ) and 38% ( P<0.001 ) of patients in the Pegloticase arms of the two clinical studies achieved the primary efficacy endpoint, compared with 0% of patients in the placebo arm.

The effect of treatment with Pegloticase on tophi was a secondary efficacy endpoint of the clinical studies and was assessed using standardized digital photography, image analysis and a central reader blinded to treatment assignment. Tophi are deposits of monosodium urate crystals in people with longstanding high levels of uric acid in the blood and are commonly seen in conjunction with gout. Seventy one percent of patients had baseline tophi. A pooled analysis of data from both clinical studies at month 6 demonstrated that 45% ( P<0.02 ) of patients with tophi treated with Pegloticase every 2 weeks achieved a complete response, defined as 100% resolution of at least one target tophus, no new tophus appearing and no single tophus showing progression, compared to 8% of patients receiving placebo.

The full prescribing information for Krystexxa contains a boxed warning regarding anaphylaxis and infusion reactions. Anaphylaxis and infusion reactions have been reported to occur during and after administration of drug.
Krystexxa should only be administered in a healthcare setting and by healthcare providers prepared to manage anaphylaxis. Patients being treated with Krystexxa should be pre-medicated with antihistamines and corticosteroids prior to infusion and should be closely monitored for an appropriate period of time after administration. Since the risk of anaphylaxis and infusion reactions is higher in patients who have lost therapeutic response, patients' serum uric acid levels should be monitored prior to infusions and discontinuation of treatment should be considered if such levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed.

Krystexxa is contraindicated in patients with glucose-6-phosphate dehydrogenase ( G6PD ) deficiency due to the risk of hemolysis and methemoglobinemia. It is recommended that patients at higher risk for G6PD deficiency ( e.g., patients of African or Mediterranean ancestry ) be screened for G6PD deficiency before starting Pegloticase.

As with most uric acid lowering therapeutics, an increase in gout flare is frequently observed upon initiation of anti-hyperuricemic therapy, including treatment with Krystexxa. If a gout flare occurs during treatment, Krystexxa need not be discontinued, however, gout flare prophylaxis ( i.e., non-steroidal anti-inflammatory drugs or Colchicine upon initiation of treatment ) is recommended for at least the first 6 months of therapy unless medically contraindicated or not tolerated. In months 1 through 3, gout flares occurred in 74% of patients taking Pegloticase every 2 weeks and in 51% of patients who received placebo. During the next three months of therapy ( months 4 through 6 ), gout flares occurred in 41% of patients treated with Pegloticase every 2 weeks and in 67% of patients who received placebo.

Krystexxa has not been formally studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation. As such, caution should be exercised when using Krystexxa in patients who have congestive heart failure and such patients should be monitored closely following infusion.

As with all therapeutic proteins, there is a potential for immunogenicity with Krystexxa. Due to this, patients receiving re-treatment may be at increased risk of infusion reactions and should be monitored carefully for such reactions. The impact of anti-PEG antibodies on patients' responses to other PEG-containing therapeutics is unknown.

The most commonly reported adverse reactions ( occurring in at least 5% of Pegloticase-treated patients ) were gout flare, infusion reaction, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting.

Source: Savient Pharmaceuticals, 2010

XagenaMedicine2010


Link: Xapedia - Medical Encyclopedia