General Information

Krystexxa is a uric acid specific enzyme, a recombinant uricase, achieves its therapeutic effect by catalyzing the oxidation of uric acid to allantoin, thereby lowering serum uric acid. Allantoin is an inert and water-soluble purine metabolite. It is readily eliminated, primarily by renal excretion.

Krystexxa is specifically indicated, as monotherapy or co-administered with methotrexate, for the treatment of chronic gout in adult patients refractory to conventional therapy.

Krystexxa is supplied as a solution intended for intravenous infusion after dilution. The recommended initial dose is 8mg (uricase protein) given as an intravenous infusion every two weeks.

Mechanism of Action

Krystexxa is a uric acid specific enzyme, which is a PEGylated product that consists of recombinant modified mammalian urate oxidase (uricase) produced by a genetically modified strain of Escherichia coli. It achieves its therapeutic effect by catalyzing the oxidation of uric acid to allantoin, thereby lowering serum uric acid. Allantoin is an inert and water-soluble purine metabolite. It is readily eliminated, primarily by renal excretion.

Clinical Trial Results

FDA approval of Kyrstexxa was based on two replicate, multicenter, randomized, double-blind, placebo-controlled studies of six months duration: trial one and trial two. The trials enrolled adult patients with chronic gout refractory to conventional therapy, who were randomized to receive Krystexxa 8 mg every two weeks or every four weeks or placebo. The studies were stratified for the presence of tophi: 71 percent of patients had baseline tophi. 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 percebt of the time during month three and month six. Data showed that a greater proportion of patients treated with Krystexxa every two weeks achieved urate lowering to below 6 mg/dL than patients receiving placebo. Although the four week regimen also demonstrated efficacy for the primary endpoint, this regimen was associated with increased frequency of anaphylaxis and infusion reactions and less efficacy with respect to tophi.

Trial One

Pegloticase 8 mg every two weeks: 47 percent responders; Pegloticase 8 mg every four weeks: 20 percent responders and placebo: zero percent responders.

Trial Two

Pegloticase 8 mg every twp weeks: 38 percent responders; Pegloticase 8 mg every four weeks: 49 percent responders and placebo zero percent responders.

The effect of treatment on tophi was a secondary efficacy endpoint. A pooled analysis was conducted. At month six, the percentage of patients who achieved a complete response (defined as 100 percent resolution of at least one target tophus, no new tophi and no single tophus showing progression) was 45 percent, 26 percent and 8 percent, with Krystexxa 8 mg every two weeks, Krystexxa 8 mg every four weeks and placebo, respectively. The difference between Krystexxa and placebo was statistically significant for the every-two-week dosing regimen, but not for the every-four-week dosing regimen.

The FDA approval for Krystexxa with methotrexate is based on the results from the MIRROR randomized controlled trial in which adults living with uncontrolled gout were randomized to receive methotrexate (15 mg/week) or placebo for four weeks, and then treatment with Krystexxa with methotrexate or Krystexxa with placebo for 52 weeks. The primary endpoint was defined as the proportion of serum uric acid (sUA) responders during Month 6 (defined as sUA less than 6 mg/dL at least 80% of the time. 71% (71 of 100) of patients randomized to receive Krystexxa with methotrexate vs 39% (20 of 52) of patients randomized to receive Krystexxa with placebo achieved the primary endpoint. 60% (60 of 100) of patients randomized to receive Krystexxa with methotrexate achieved a complete response during Month 12 compared to 31% (16 of 52) of patients randomized to receive Krystexxa with placebo. Complete response is defined as sUA less than 6 mg/dL at least 80% of the time during Month 12. among patients with validated tophi at baseline, 54% (28 of 52) of patients randomized to receive Krystexxa with methotrexate had complete resolution of at least one tophus, no new tophus and no single tophus showing progression at Week 52 vs 31% (9 of 29) of patients randomized to receive Krystexxa with placebo.