Pegloticase plus mycophenolate mofetil yields 86% response rate in uncontrolled gout
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Concomitant use of mycophenolate mofetil with pegloticase demonstrated clinically meaningful improvement in 86% of patients with uncontrolled gout, compared with pegloticase alone, according to data published in Arthritis & Rheumatology.
Puja P. Khanna, MD, MPH, of the University of Michigan, Ann Arbor, co-author of the study, initially presented the study’s findings in November at ACR Convergence 2020.
“The response [to pegloticase] is limited in some patients due the development of anti-pegloticase antibodies,” Khanna told Healio Rheumatology at that time. “In the rheumatology space, we’re familiar with this concept and have used a variety of [disease-modifying antirheumatic drugs] to minimize the development of antidrug antibodies (ADAs) and increase the efficacy of therapies. Historically, we have used methotrexate to lower infliximab induced ADAs. Recently, there have been case series published on how methotrexate has successfully improved the response rate when used with pegloticase.”
“Gout patients often live with numerous comorbidities which can necessitate selecting a different immunomodulator than methotrexate, in addition with methotrexate use, side effects such as hematologic, hepatic and renal toxicities need to be carefully monitored,” she added. “With this in mind, we sought to explore other DMARDs that could be employed, and selected mycophenolate mofetil due to its known safety profile.”
To analyze whether mycophenolate mofetil could prolong the efficacy of pegloticase (Krystexxa, Horizon Therapeutics) in patients with uncontrolled gout, Khanna and colleagues conducted a phase 2, proof-of-concept, placebo controlled randomized trial. The researchers included a total of 32 adults — enrolled from five U.S. centers — with chronic refractory gout and serum urate levels of more than 6 mg/dL, and who had never received pegloticase or other uricase therapies.
Participants were randomized 3:1 to receive either 1,000 mg mycophenolate mofetil twice daily or placebo for 14 weeks, starting 2 weeks before, and while receiving, 8 mg of intravenous pegloticase biweekly for 24 weeks. The primary endpoint was proportion of patients who sustained a serum urate level of 6 mg/dL or less at 12 weeks. Secondary endpoints included 24‐week durability of the serum urate target, as well as the rate of adverse events. For their analysis, the researchers used Fisher’s exact test and Wilcoxon two‐sample test, as well as Kaplan‐Meier estimates and log‐rank tests.
According to the researchers, 86% of participants who received mycophenolate mofetil achieved the serum urate target of 6 mg/dL or less at 12 weeks, compared with 40% in the placebo group (P = .01). At week 24, 68% of participants in the mycophenolate mofetil group demonstrated the target serum urate level, compared with 30% in the placebo arm (P = 0.06).
Adverse event rates at week 24 were similar between the groups, with 30% of participants in the placebo arm experiencing more infusion reactions, compared with 0% of those who received mycophenolate mofetil.
“We know that when gout is left untreated, it causes severe disability in patients,” Khanna told Healio Rheumatology upon publication of the study in Arthritis & Rheumatology. “That boils down to higher numbers of hospitalizations that these patients incur, significant loss of work productivity, and ultimately contributes to the societal costs. So, I think it is time now for us to focus on gout.”
“With the RECIPE trial, we have a proof-of-concept study which is the first randomized controlled trial to demonstrate that mycophenolate mofetil mitigates the immunogenic response of pegloticase and patients are able to maintain a urate level of less than 6 mg/dL at 6 months without infusion reactions,” she added. “Our data adds to the growing body of evidence on the concomitant use of pegloticase with an immunomodulatory. This approach will help shift the treatment paradigm in uncontrolled gout so more patients can receive a full course of therapy and improve outcomes.”
Perspective
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After 3000 years of dealing with gout as primarily an inflammatory joint disease, we are beginning to understand the diffuse effects of an elevated uric acid and the potential implications of treatment. Studies have implicated high uric acid levels as affecting hypertension, diabetes, metabolic syndrome, and in a multitude of cardiovascular and renal issues.
Tophaceous gout might even be called uric acid deposition disease as crystals have been found in numerous tissues including muscles as well as heart muscle, kidneys, tendons and arteries. Consequently, the motivation to treat aggressively especially tophaceous or refractory gout has a strong medical basis.
One of the most effective treatments has been IV pegloticase, which lowers the serum uric acid much faster than other standard treatments. However, immunogenicity may, after a few doses, affect the response in as many as 40% of cases and increase the risk of infusion reactions. Case studies have shown that methotrexate before and after treatment with pegloticase can prevent the development of antibodies and thus maintain pegloticase’s effectiveness.
This double-blind study using mycophenolate mofetil confirms the effectiveness of an immunomodulator in maintaining the effectiveness of pegloticase in patients with refractory gout — and provides data for its use as an alternative to methotrexate or azathioprine.
Perspective
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There is no doubt that gout is a challenging disease to manage in many of our patients. There are a limited number of drugs that offer our gout patients a significant amount of hope and relief. This is particularly true for patients with kidney disease and for patients with heavy disease burden.
Pegloticase has offered a viable treatment option for these patients. However, it has presented several large challenges that must be addressed. It is an expensive drug that can be hard to obtain access to within the current payor landscape. It also has a reputation for being a drug with a high risk for adverse events.
I come from the infusion world of rheumatology and there is concern, from the providers to the nurses at the chair side, around the potential for significant AEs. The importance of close monitoring of serum uric acid is often not understood by the patient, adding to the challenges of infusing this drug.
As we see studies being done around the coadministration of DMARDs that can help to decrease the formation of anti-drug antibodies, it gives us hope that we will be able to more effectively and more safely administer a drug that has offered true relief to patients suffering with a painful, debilitating disease. If co-treating gout patients with mycophenolate mofetil allows us to give them even a few additional doses, then we have been able to give them more treatment than they would otherwise have received.
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