Pegloticase is effective for lowering serum urate patients with uncontrolled or refractory gout, although more than half of patients experience anti-drug antibody development which limits its efficacy.1 Administering pegloticase in conjunction with an immunomodulating therapy has been shown to improve sustained urate reduction while on treatment.2 Very little data is available pertaining to who might be the best candidate for this approach, as well as which immunomodulation agent should be used. The data presented by Dr Broadwell reflected the experience from two community rheumatology practices where immunomodulating therapy is routinely prescribed in patients undergoing pegloticase treatment. Rheumatologist Dr Aaron Broadwell (Shreveport, Louisiana) presented the results of the study during the annual American College of Rheumatology Convergence of 2021,3 which was more or less simultaneous with the a related systematic review presented at the Kidney Week of the American Society of Nephrology, which was held virtually November 4-7, 2021.4


 

A total of 34 patients were included, of whom 79% were male and the median age was 62.4. All participants had uncontrolled gout, with median serum urate at 9.1±2.0 mg/dL, with median 14.7±13.4 years of gout history; 91% had tophi. Comorbidities were common: hypertension (76%), obesity (71%), osteoarthritis (68%), and chronic kidney disease (47%). Most patients achieved the goal of 12 infusions, with a mean of 14.6±7.1 pegloticase infusions administered over 28.5±14.9 weeks. Immunomodulator co-therapy was initiated prior to (5.3±3.0 weeks, n=32) or concomitant (n=2) to initial pegloticase infusion and included subcutaneous methotrexate (n=20), oral methotrexate (n=9), oral mycophenolate mofetil (n=3), and oral azathioprine (n=2). Response to pegloticase treatment was defined as ≥12 pegloticase infusions and serum urate levels < 6 mg/dL at infusion 12. All patients received pre-infusion prophylaxis (methylprednisolone, hydrocortisone, fexofenadine, or diphenhydramine).

The findings showed that treatment responder rate was 89.3% (n=28). When looking at response per immunomodulatory agent Response rates were 93% for subcutaneous methotrexate (n=14), 89% for oral methotrexate (n=9), 100% for mycophenolate mofetil (n=3), and 50% for azathriopine (n=2). eGFR remained essentially unchanged during therapy and CKD stage remained stable or improved in 85%. 19 patients (56%), no infusion reactions or infections were noted, and no new safety concerns were identified.

The authors concluded that these data provide further support for concomitant immunomodulator/pegloticase therapy, showing similar efficacy rates to both an open-label trial with oral methotrexate (79%) and a systematic literature review of all immunomodulators (83%).2,5

Physician’s Weekly spoke with study author Dr. Brian LaMoreaux, MD, MS, Medical Director at Horizon Therapeutics, Chicago, IL, to discuss the results.

 

PW: Why are these studies important?

BL: Gout is of particular importance, and a longstanding topic of passion of mine. There is a lot to be done, not only to prevent gout, but to modulate the disease state of gout itself. The molecule pegloticase, which is an infusion medicine for severe or uncontrolled gout, is effective in severe uncontrolled gout, which is refractory to standard oral medication.

Clinical doctors have just become aware of the value of immunomodulation to improve pegloticase efficacy, and we worked with the doctors to evaluate their databases. One such project, which was very successful, was presented here in this study.3 Dr. John Albert (Milwaukee) and Dr. Aaron Broadwell from Louisiana have both been using a variety of immunomodulators in uncontrolled gout and wanted to capture that data to share. They are both passionate to make sure they never see one of their gout patients lose response to pegloticase. They were really committed to this idea even before there was a lot of data. We (Horizon) partnered with them and collected the data. Impressively, these two rheumatology clinics enrolled a considerable number of patients in a short period, and 89% of those were full responders. They had considerable experience with subcutaneous methotrexate and some with oral methotrexate, three mycophenolate patients who were all responders, and a couple patients received azathriopine.

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The data shows that there is a clear preference for methotrexate, given the comfort most rheumatology practices have with it and awareness of it, but when the need arises, for example due to a comorbidity, there appear to be several options available that work very well. Methotrexate is a good drug, and it has been around a long time. Rheumatologists are extremely familiar and comfortable with methotrexate. And there is also analogous data from the rheumatoid arthritis and sero-negative spondyloarthropathy world, where using methotrexate with a biologic helps the biologic work better for longer in those patients.

There were also no infusion reactions seen in this dataset. We have observed a very strong link between pegloticase efficacy and safety; if you are a responder and achieve rapid reduction of uric acid, you are very unlikely to have an infusion reaction, because we know that those patients do not have anti-drug antibodies. That is the point of immunomodulation, to prevent that from happening, and secure the long-term response to that medicine.

One other interesting observation was that there were no infections seen in this group of 28 patients. Because these are immunomodulating agents, it is theoretically possible that we would see increased infections, but we have simply not seen that clinically in any of the datasets combining immunomodulation with pegloticase. These data collectively are really encouraging; it means that there is a relatively safe and predictable way to combine 2 therapies and make the pegloticase course really work for almost all patients.

 

What are the challenges for patients?

We understand that the logistics of pegloticase therapy remain a challenge, when you have to come in to the clinic every 2 weeks, and the infusion takes a couple of hours, you have to be watched a little bit after. In addition, this remains a challenge also for the clinicians and scheduling.

We all agree it would be much, much easier to have oral therapy or subcutaneous options for pegloticase. Orally, this medicine would not work because it is an enzyme and so if you were to consume it, your first-pass hepatic metabolism would break down the enzyme. We are looking at a couple of things to really help make this easier and one is shorter infusions: instead of the 2 hours, we have a clinical study looking at 60 minutes and even 30 minutes. If that one goes well, then we are actually have underway a 4 week study, where patients only get treatment every 4 weeks instead of 2, in combination with immunomodulation.

Fortunately, we have good, robust data sources with mycophenolate mofetil, especially, and even more still with leflunomide, another agent that does not have the renal considerations that methotrexate might. So, it is nice to have a bunch of different data sources here so clinicians can tailor for each individual uncontrolled gout patient which immunomodulating therapy makes the most sense for that patient. Lastly, the effects in patients with chronic kidney disease in this study were promising.