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Rheumatology Network interviewed Puja Khanna, MD, MPH, Associate Professor of Medicine from the University of Michigan, about her study that evaluated how patients with poorly controlled gout fared when they were treated with pegloticase and mycophenolate mofetil combination therapy.
Rheumatology Network sat down with Puja Khanna, MD, MPH, Associate Professor of Medicine from the University of Michigan, to discuss her study titled, “Reducing Immunogenicity of Pegloticase (RECIPE) with Concomitant Use of Mycophenolate Mofetil in Patients with Refractory Gout—a Phase II Double Blind Randomized Controlled Trial.” The study evaluated how patients with poorly controlled gout fared when they were co-treated with pegloticase and mycophenolate mofetil.
Rheumatology Network: What sparked your interest in this study?
Puja Khanna, MD, MPH: Gout is a disease of abnormal uric acid production and metabolism. So there is an overabundance of urate in the body and, as a result, in order to lower the urate levels which cause chronic inflammation, we have to use certain medications. Unfortunately, we have limited options in terms of approved medications for lowering this burden. Pegloticase, an intravenous medication, is a very powerful drug that can lower the urate and actually dissolve all the tophi (deposits of urate) that occur in these patients. However, the use of pegloticase is limited because the body develops high levels of anti-drug antibodies and, as a result, patients have infusions reactions. The solution to lower this immunogenic response is to utilize disease-modifying agents, which rheumatologists commonly use for various rheumatic disease. So, our main rationale to do this study was to prove that if we used specific disease-modifying agents, we could lower the immunogenic potential of pegloticase and make it more effective.
RN: What key takeaways did you observe?
PK: The main takeaways were that treating patients on an immunomodulatory therapy does in fact reduce their likelihood of developing antibodies to pegloticase. When we use mycophenolate mofetil (MMF) alongside pegloticase, we improved the response and prolonged the durability of urate lowering in these patients. There were no infusion reactions noted. That essentially tells us that disease-modifying antirheumatic drugs in patients who are going to undergo IV pegloticase therapy can be used to mitigate that immunogenic response. We saw this effect not only at 12 weeks, we also saw it at the 24-week mark, which is the completion of the 6-month course of pegloticase.
RN: Were there any limitations or strengths of the study that you'd like to highlight?
PK: Our primary limitation was the sample size. This was a proof of concept study where we were looking to see the signal that MMF indeed mitigated that immunogenic response of pegloticase. The biggest strength meanwhile was that it is the first randomized control trial to look at this issue of immunogenicity. We enrolled 32 patients; 22 received mycophenolate with pegloticase and 10 received matching placebo and pegloticase. Given the large difference in response rate, we deemed the statistical power to be appropriate.
The other issue that can be considered is generalizability and to counter that we recruited patients from non-academic sites. But, unless randomization failed, we did not expect this to have caused problems. When we recruit patients from academic sites, for instance, you are biasing results to the more severe population. But we actually had a nice mix of patients from both academic and non-academic sites.
Finally, the study was only a 6-month study. So one could think that if we really wanted to assess the durability of response and complete resolution of urate burden, which presents itself as tophaceous deposits, it would be helpful to do the study maybe over a year or maybe longer. So there are questions to consider in the design of future studies.
RN: Does your team plan on doing any further research on this topic?
PK: We would definitely want to consider a longer study with a larger number of patients. We also want to look at things like verifying that the antibody levels of the patients who responded to the pegloticase versus those who did not. It would be beneficial to create a profile of the patient who was likely to respond to the IV infusion and avoid infusion reactions preemptively. That piece of information will be clinically more meaningful.
Other aspects would be study what minimal dose of MMF and duration of use would be sufficient to control adenosine deaminase (ADA) production and the spectrum of side effects of using disease-modifying antirheumatic drugs (DMARDs) long term.
Longitudinal follow-up would allow us the ability to also assess the burden of disease. So if we performed imaging for instance, dual energy CTs, it would be able to provide us information on whether the patient has urate deposits in their joints or not. If we did these studies prior to starting the drug with mycophenolate and a year after we stopped the drug, and saw a reduction in the size of these tophi, that also provides us additional long-term evidence that indeed suppressing the immunogenic potential of pegloticase with mycophenolate does actually benefit the patients in the long term.
RN: Is there anything else you’d like our audience to know?
PK: We as rheumatologists have historically done a fantastic job in terms of treating rheumatoid arthritis (RA). And as you have seen in the market, there are multiple biologics which are effective therapies for treatment of RA. But the challenge is that with gout we do not have these options. And gout, as you know, is far more prevalent when compared with RA. Since we know that oral uric lowering therapies are not able to address uncontrolled gout and oral options are limited, it would be truly beneficial if we could utilize and optimize existing therapies such as pegloticase to address this large burden of disease.
We know that when gout is left untreated, it causes severe damage and disability to patients. That boils down to the number of hospitalizations that these patients incur, loss of work productivity, and contributes to the societal costs. So I think it is time now for us to focus on gout. And we are really pleased that we have this randomized controlled trial to prove the point that mycophenolate can mitigate that immunogenic response of pegloticase. This opens up the possibility to use pegloticase in patients who have not been able to control their gout with oral urate lowering therapies and improve their outcomes. There is hope for patients with gout!