Orrin M. Troum, MD, discusses methods and results of the MIRROR study in gout.
Orrin M. Troum, MD: As we discuss how this study came about, there was a screening period of less than 2 weeks. There was a 4-week methotrexate run-in period, which made a lot of sense because they wanted to make sure the patients were able to tolerate methotrexate. They were given 15 mg oral methotrexate weekly and 1 mg of folic acid daily, which is similar to what we do for our patients with other systemic traumatic diseases, like rheumatoid arthritis or other disease states that we use methotrexate for. The visits were followed by the pegloticase methotrexate treatment of 8 mg intravenously and of pegloticase every 2 weeks plus the 15 mg of oral methotrexate weekly, for a maximum of 52 weeks. There were visits on day 1 and biweekly after. The primary efficacy end point was during month 6 and then the end-of-treatment period.
Here are some baseline characteristics from the modified intent-to-treat population with 14 patients. The typical age that you might see for patients with gout was around 49.3; the male sex was 14%. There was a smattering of White and Asian patients but no African American or Native Hawaiian or other Pacific Islanders, which are an at-risk population. The BMI [body mass index] was as expected; these were obese patients. The eGFR [estimated glomerular filtration rate] was 84.6 mL/min. That may not be what most of your patients with chronic gout have. As Dr Peterson described earlier, some of these patients have significant renal insufficiency.
The time since the first gout diagnosis is a mean in years of 13.8. That’s not too different from the patients I see. The number of gout flares in the 12 months prior to screening is a mean of 10.8. That’s a significant number of gout attacks. As Jeff pointed out earlier, this has a major impact on patients. It’s affecting their lives, their psyche, and their family. To have that many gout attacks in a year is disabling. There are a significant number of tophi, and the baseline serum uric acid of 9.2 mg/dL.
Another important thing to remember is that although most laboratories have now adjusted to our recommendations and our guidelines of having a serum uric acid of less than 6 mg/dL, these patients come in and were entered into the study with a baseline serum uric acid around 9.2 mg/dL. It’s a significant load—and I’m sure with a significant serum urate load throughout their body—for patients who had tophi and chronic uncontrolled gout.
Here are the efficacy points for the modified intent-to-treat population. This is the percentage of patients who maintained a serum uric acid of less than 6 mg/dL and a serum uric acid less than 5 mg/dL for at least 80% of the time. You see in blue the number that remained less than 5 mg/dL, which was over 78%. Those who maintained less than 6 mg/dL was very close, both at months 3 and 6, showing significant ability—different from the initial clinical trials, which did not use methotrexate—of having patients with this efficacious medication be maintained.
Another mean serum uric acid change was from baseline to weeks 14 and 24. You see the differences here. There are significant reductions in the serum uric acid at week 12 and week 24. Your mean, median, and minimum and maximum numbers are on the right. We may come back to that. Dr Peterson, do you want to add anything to this aspect of this trial?
Jeff R. Peterson, MD: I’m all good with it.
Orrin M. Troum, MD: The changes in serum uric acid over 24 weeks was for the modified intent-to-treat [population]. What’s known and what we all see—for those of us who use this medication in our patients with uncontrolled gout or tophaceous gout—is a dramatic reduction. This happens almost immediately with the change of the monosodium urate into allantoin. Here you see the prior [uric acid level] to the left of 0. Starting at week 2, the dramatic reduction in serum uric acid is maintained all the way through week 24.
You can see changes in AST and ALT. One consideration and 1 of the potential problems with using methotrexate [is liver enzyme elevation]. We’ve always done monitoring for liver enzyme elevation. You can see the changes in ASD and ALT. That’s 1 of the important aspects of how this study led into that. These patients were given methotrexate first. It’s what I’ve been following since John Botson and Jeff Peterson had their pilot study using 15 mg weekly for the month prior to initiating pegloticase. Part of the reason I’ve done it is to check the liver enzymes and the CBC [complete blood count], which we’d do for patients who were on methotrexate for other reasons. The important point thing is that it did not rise past that over time.
Adverse events were observed during the methotrexate run-in and pegloticase-plus-methotrexate periods. Any serious adverse event is seen on the bottom left; there was 1. If somebody comes in and complains that they started sneezing right after the infusion—[for example] they sneeze 15 times and they’ve never done that in their life—they must report that. We have to do it as investigators because it’s something new. You see the typical adverse events: upper respiratory tract infections and sinus infections. Adverse events aren’t terribly surprising, as you see both in the methotrexate run-in and in the pegloticase-plus-methotrexate [period], and slightly higher in the combination group.
Gout fears are something you must tell your patients to expect when they get pegloticase. Anytime you mobilize these monosodium urate crystals in the body, you’re going to get a flare. Whether you get dehydrated and uric acid goes up quickly, or you give them pegloticase and there’s a dramatic precipitous decline in uric acid, the most common thing that happens is a gout flare. We try to mitigate that by using medications as they did in the trial. Diarrhea was seen, but it was infrequent. As you see here, there was upper respiratory tract infection, sinusitis, muscle strain, and hypertension. There was nausea abdominal discomfort—mainly in the methotrexate run-in period, more than with the pegloticase-plus-methotrexate period—but there were minimal adverse effects. That’s important, because besides the gout attack, patients are typically going to get 1, 2, or maybe 3 infusions; they typically dissipate after that. The dramatic benefit that patients will get by finally controlling their gout is significant, so it must be emphasized.
Here are the adverse events of special interest in the pegloticase-plus-methotrexate period—the modified intent-to-treat population. Those who had a gout flare were over 85% overall days 1 to 12. From 12 to 24, less so. This is important in inhibiting the production of antidrug antibodies, but also patients are able to stay on the drug longer because of the fewer adverse events.
Transcript edited for clarity