Concomitant injection Pegloticase with Methotrexate therapy Improves uncontrolled gout

DUBLIN: A phase 4 trial to evaluate the efficacy and safety pegloticase injection in combination with methotrexate to increase response rates in patients with chronic gout refractory to conventional therapies has yielded positive results.

The topline results from MIRROR randomized controlled trial (RCT) met the primary endpoint, showing a significant increase in efficacy using Pegloticase with the immunomodulator methotrexate as compared to the response rate of Pegloticase with placebo for people with chronic gout refractory to conventional therapies – also known as uncontrolled gout.

Pegloticase is marketed under the brand name Krystexxa® and is currently approved as monotherapy for the treatment of chronic gout in adults refractory to conventional therapy.

"It is rare that you can improve a response rate so substantially for patients; by 30 percentage points in this case based on the results of our trial," said Elizabeth H.Z. Thompson, Ph.D., executive vice president, research and development, Horizon. "These results reinforce what we have seen from published case series as well as our open-label trial evaluating KRYSTEXXA with methotrexate. Horizon has invested significantly over the last several years to ensure more uncontrolled gout patients are able to benefit from KRYSTEXXA and we continue to develop new approaches that target the underlying cause of gout."

In the MIRROR randomized controlled trial, 152 adults living with uncontrolled gout were randomized to receive methotrexate or placebo for four weeks and then treatment with KRYSTEXXA and methotrexate or KRYSTEXXA and placebo for 52 weeks. This trial was designed to evaluate the concomitant use of KRYSTEXXA with methotrexate, an immunomodulator commonly prescribed by rheumatologists, to help more patients achieve a complete and durable response to therapy. The primary endpoint was defined as the proportion of serum uric acid (sUA) responders defined as sUA <6 mg/dL at least 80% of the time during Month 6.1

Results show that 71% (71 of 100) of patients who were randomized to receive KRYSTEXXA with methotrexate compared to 40% (21 of 52) of patients who were randomized to receive KRYSTEXXA with placebo achieved the primary endpoint (p<0.001). No new safety concerns were identified. These results are aligned with published literature and the prior original pivotal clinical trials of KRYSTEXXA monotherapy which showed 42% (36 of 85) of dosed patients had a complete sUA response and met the primary endpoint of maintaining sUA <6 mg/dL at least 80% of the time in Months 3 and 6.2,3

"The impact of uncontrolled gout cannot be overstated; in addition to its effect on the patient's quality of life, research underscores the systemic burden and increased risk of morbidity and mortality," said John K. Botson M.D., R.Ph., C.C.D., president, Alaska Rheumatology Alliance and rheumatologist, Orthopedic Physicians Alaska. "Effectively attenuating the development of anti-drug antibodies often seen in biologics, like KRYSTEXXA, has been central in our approach to reduce the burden of urate and address the long-term consequences of systemic uric acid deposition."

The MIRROR randomized controlled trial follows the MIRROR open-label trial (NCT03635957), which showed a 79% (11 of 14 patients) response rate (sUA <6 mg/dL) at Month 6 when KRYSTEXXA was used with methotrexate.4 Separately, two independent, in-practice case series showed 805 and 100%6 of patients (8 of 10 patients and 10 of 10 patients, respectively) were able to receive a full course of treatment with the concomitant use of KRYSTEXXA and methotrexate. No new safety concerns were identified in these studies, but the findings are limited by the small sample sizes.

"These results reinforce trends seen in clinical practice and illustrate that the use of an immunomodulator, such as methotrexate, with KRYSTEXXA can help more uncontrolled gout patients complete a full course of therapy," said Jeff R. Peterson, M.D., president, Washington Rheumatology Alliance and a director at Northwest Rheumatism Society and Western Washington Medical Group Arthritis Clinic's clinical research department. "Taken together with the open-label trial and published literature, the MIRROR randomized controlled trial results highlight an evolution of care for people living with uncontrolled gout and shift in approach to addressing the underlying burden of disease."

Data from the trial are expected to be presented at an upcoming medical congress. Horizon plans to submit a Supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) in the first quarter of 2022.