During the American College of Rheumatology (ACR) Convergence 2020, Puja Khanna, MD, MPH, Associate Professor of Medicine from the University of Michigan, presented a 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 (MMF). Dr. Khanna spoke with DocWire News about the results of the study during an interview.
DocWire News: What prompted you to undertake this study?
Dr. Khanna: Gout is a disease of abnormal uric acid production and metabolism. So there is an overabundance of urate in the body as a result, and in order to lower the urate levels that 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 (IV) 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 infusion reactions. The solution to lower this immunogenic response is to utilize disease-modifying agents, which rheumatologists commonly use for various rheumatic diseases. So, our main rationale to do this study was to prove that yes, if we used particular disease-modifying agents, we could lower the immunogenic potential of pegloticase and make it more effective.
DocWire News: What were the key takeaways of the study?
Dr. Khanna: The main takeaways were that treating patients on an immunomodulatory therapy does in fact reduce their likelihood of developing antibodies to pegloticase. When we used 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 (DMARDs) 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 six-month course of pegloticase.
DocWire News: What were the limitations and strengths of the study?
Dr. Khanna: 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 controlled trial to look at this issue of immunogenicity. We enrolled 32 patients, 22 of whom received mycophenolate with pegloticase and 10 of whom 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 you 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 six-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.
DocWire News: Do you have any future research plans pertaining to this, maybe something longer or larger?
Dr. Khanna: 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 to study what minimal dose of MMF would be sufficient to control ADA production and the spectrum of side effects of using 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, which are able to provide us information of 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 gives us additional long-term evidence that indeed suppressing the immunogenic potential of pegloticase with mycophenolate, does actually benefit the patients in the long term.
DocWire News: Any last comments?
Dr. Khanna: I think 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 a much more prevalent disease as compared to RA. Since we have limitations with options in terms of oral uric lowering therapy, it would be really beneficial if we could utilize pegloticase to address this large burden of disease, especially since we know that oral uric lowering therapies are not able to address uncontrolled gout.
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 actually mitigated 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.
Credit: Original article published here.