The Food and Drug Administration (FDA) has approved expanded labeling for Krystexxa® (pegloticase) to include concomitant use with methotrexate for the treatment of patients with uncontrolled gout to achieve a complete response to therapy.

The expanded approval was based on data from the double-blind, placebo-controlled phase 4 MIRROR trial (ClinicalTrials.gov Identifier: NCT03994731), which evaluated the efficacy and safety of Krystexxa plus methotrexate in 152 adults with uncontrolled gout. Patients were randomly assigned to receive methotrexate or placebo for 4 weeks, then Krystexxa in combination with either methotrexate (n=100) or placebo (n=52) for 52 weeks.

Results showed that 71% of patients treated with Krystexxa plus methotrexate met the primary endpoint achieving a complete serum uric acid (sUA) response, defined as sUA less than 6mg/dL at least 80% of the time during month 6, compared with 39% of those treated with Krystexxa plus placebo (P <.0001). Moreover, 60% of patients treated with Krystexxa plus methotrexate achieved a complete sUA response during month 12 compared with 31% of those treated with Krystexxa plus placebo (P =.0003).

Among patients with validated tophi at baseline, 54% of patients treated with Krystexxa plus methotrexate achieved a complete response at month 12, defined as 100% resolution of at least 1 tophus, no new tophi, and no single tophus showing progression, compared with 31% of patients treated with Krystexxa plus placebo (P =.048).

Clinical trial data showed no new safety concerns with the combination therapy. A lower incidence of infusion reactions was observed in the Krystexxa plus methotrexate arm vs the Krystexxa plus placebo arm (4% vs 31%, respectively). The most common adverse reactions reported with methotrexate coadministration included gout flares, arthralgia, COVID-19, nausea, and fatigue.

In the MIRROR trial, approximately 26% of patients had pre-existing antibodies to pegloticase. Findings showed that 30% of the Krystexxa plus methotrexate group and 51% of the Krystexxa plus placebo group had an increase in titer from baseline or were negative at baseline and developed an antipegloticase response at 1 or more post dose time points. Those with higher antibody titers were more likely to have faster clearance and lower efficacy.

“Immunomodulatory therapies like methotrexate are often used with biologics to reduce the development of antidrug antibodies and allow more patients to achieve a complete response,” said Elizabeth H.Z. Thompson, PhD, executive vice president, research and development, Horizon. “We anticipate this approval will encourage more physicians to recommend Krystexxa with methotrexate to help their patients with uncontrolled gout receive the full benefits of Krystexxa.”

Krystexxa, a PEGylated uric acid specific enzyme, is supplied as a single-dose vial containing 8mg of pegloticase (as uricase protein) per 1mL.

The recommended dosage is Krystexxa 8mg given as an intravenous infusion every 2 weeks, coadministered with weekly oral methotrexate 15mg and folic acid or folinic acid supplementation. Krystexxa alone may be used in patients for whom methotrexate is contraindicated or not clinically appropriate.

References

  1. FDA approves Krystexxa® (pegloticase) injection co-administered with methotrexate, expanding the labeling to help more people with uncontrolled gout achieve a complete response to therapy. News release. Horizon Therapeutics plc. Accessed July 8, 2022. https://www.businesswire.com/news/home/20220708005097/en/FDA-Approves-KRYSTEXXA%C2%AE-pegloticase-Injection-Co-Administered-With-Methotrexate-Expanding-the-Labeling-to-Help-More-People-with-Uncontrolled-Gout-Achieve-a-Complete-Response-to-Therapy
  2. Krystexxa. Package insert. Horizon Therapeutics plc; 2022. Accessed July 8, 2022. https://www.hzndocs.com/KRYSTEXXA-Prescribing-Information.pdf