Combining Pegloticase With Methotrexate Bolsters Response Rate in Patients With Chronic Gout

John RP Tesser, MD, rheumatology specialist, Arizona Arthritis & Rheumatology Associates, and clinical adjunct professor, Midwestern University College of Health Sciences, discusses the MIRROR trial, a study which showed the addition of an immunosuppressant enhanced responses to pegloticase and reduced disease flares among patients with chronic gout.

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Welcome back to PopHealth Perspectives, a conversation with the Population Health Learning Network where we combine expert commentary and exclusive insight into key issues in population health management and more.

In the first part of this podcast, Dr John Tesser offers insight into the unmet need associated with chronic gout and the rationale behind the MIRROR trial.

Hi there, I'm John Tesser and I am a clinical adjunct professor at Midwestern University College of Health Sciences. It’s an osteopathic organization. I'm also a senior partner at Arizona Arthritis & Rheumatology Associates, which is a very large private practice of rheumatologists and advanced practice clinicians in Phoenix and throughout Arizona.

Can you discuss the symptom burden associated with chronic gout, and what unmet need led to the MIRROR study?

Gout is the most common inflammatory arthritis that exists in the United States, and probably the world. There are an estimated 8.3 million people with gout. Of those 8.3 million, maybe 5 million are receiving urate-lowering therapy. Of those 5 million, maybe 0.5 million are receiving adequate urate-lowering therapy. These numbers are based on data that was collected 10 to 12 years ago.

Of those approximately 4.5 million patients who are inadequately treated, there are a variety of reasons why. One is that they don't comply with treatment very well. Another is that physicians are not complying very well with guidelines. And then, of course, there's always the possibility of an incorrect diagnosis.

Of those patients who are being treated according to proper guidance, there is a population that is either treatment intolerant, which means they can't tolerate allopurinol or febuxostat, or true treatment failures, which means they’re just not responding to whatever treatment is used, even in very high concentrations and combinations. They have repeated gout episodes, they're not getting their serum uric acid level below the target of 6 mg per dL, or their tophi are not responding. 

This is a very large problem. Fixing it requires adequate treatment for the population of patients who might reasonably respond to a proper therapy. And there is this subpopulation which is otherwise an unmet-need population.

Thank you. And can you tell us about your study's design and the participants?

Just imagine, how would you design a study of those patients with unmet need if you had a medication approved by the FDA that, unfortunately, when utilized, was only successful in up to 40% of patients, give or take? That medication is pegloticase. It's a pegylated uricase, which is a polyethylene glycol (PEG) molecule attached to a uricase. And that combination of molecules is able to break down uric acid. 

With that being said, over the years that pegloticase was on the market (it was approved in 2010) there was a reluctance to use it. Patients sustained 1) that problem of up to 40% or so that would not be able to continue to take it because it would stop working; and 2) there would be infusion reactions. 

As more interest, study, and thought was given to this, the reasons revolved around the identification of antibodies against the pegloticase molecule. And there are 2 types of those: there are some antibodies that target the uricase aspect of the molecule, and then some antibodies that target the PEG portion. The latter turned out to be the more problematic antibody and was associated with the lack of response after a number of infusions given every 2 weeks, as patients would not maintain a consistent uric acid level below 6 mg per dL.

For those of you who have utilized or have read about pegloticase, you know that when the drug is given, the serum uric acid drops below detectable levels. It is important that it stays below detectable levels or at least below 6 mg per dL over time, as it's checked before each infusion, which is the correct way to monitor. In addition, you need to test glucose 6-phosphate levels and make sure patients have an adequate level, because they could have some adverse effect because of that. Assuming all of that's going well, there's no problem.

But 40% of patients saw their uric acid levels start to rise and not be less than 6 mg per dL after a series of infusions. It became a problem because it wasn't working. Some of those patients were having infusion reactions, even to the extent of having anaphylaxis, which, of course, is very scary.

With that understanding, several individual rheumatologists in small groups started to use immunosuppressive medications to suppress these antidrug antibodies. Over time, a number of strategies were utilized, including azathioprine and mycophenolate, but the big one is methotrexate. 

We, as rheumatologists, are very experienced in utilizing methotrexate to prevent the development of antidrug antibodies when we've been using tumor necrosis factor (TNF) inhibitor drugs. Methotrexate became part of our armamentarium in the sense that it enhanced the efficacy of drugs and prevented the development of antibodies which contributed to lack of response over time. It also reduced the potential for infusion reactions or other types of hypersensitivity reactions when the drug was given.

So, with that experience, there was an open label small study looking at methotrexate for this purpose. That led to the idea of doing a larger, double-blind, placebo-controlled trial, and that's where the MIRROR trial came in.

These were patients who had ongoing serum uric acids above 7 mg per dL, at least 2 attacks of gout in the past year, and tophaceous deposits, and they were not responding to at least 1 hypouricemic agent at a reasonably safe maximum dose. Patients who fell into those parameters were able to be included in the trial. But, of course, they could not be intolerant to methotrexate, and there was a run-in period to determine that where patients had to have their glucose 6-phosphate levels checked.

Can you next walk through the major findings for MIRROR and any outcomes that stood out to you in particular?

Obviously, the main goal of this study was to determine whether more patients were able to successfully maintain their response on pegloticase at month 6 with methotrexate. Almost 80% of patients were able to achieve maintained response, compared to the other arm which was randomly assigned to receive placebo. The placebo group was getting pegloticase, they were being treated, but they were not being given the methotrexate. Approximately 40% of patients were unable to maintain their response at that 6-month timepoint.

In addition to that primary endpoint, there were a couple of other things we looked at in the trial. One was the ability of methotrexate to maintain the serum uric acid below 6 mg per dL. It’s very important to point out that some patients have ongoing gout in terms of gouty episodes; ongoing tophi; potentially the development of renal stones, which is another problem with hyperuricemia and gouty disease; etc. Normal uric acid ranges go up to 7 to 8 mg per dL in laboratory evaluations, but some patients continue to have active disease even if their uric acid levels are between 7 and 8 mg per dL. So, the target is less than 6 mg per dL. In the trial, the addition of methotrexate allowed patients to maintain uric acid levels of less than 6 mg per dL throughout the study period.

The other things that were important were to try to reduce the number of gouty episodes that would occur during the trial period, which were considered flares of the disease. And the final thing we studied was the ability of methotrexate plus pegloticase to achieve the resolution of tophi. With methotrexate, tophi were less prominent and were resolved in about one-third of patients at 6 months and more than half of the patients at 12 months. It was a differential of about 20% between the methotrexate group and the placebo group.

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This transcript has been edited for clarity.