Several presentations during the American College of Rheumatology 2020 Convergence highlighted new findings in the treatment of gout. During an interview with DocWire News, John Botson, MD, RPh, CCD, discussed two of these abstracts: A Multicenter, Efficacy and Safety Study of Methotrexate to Increase Response Rates in Patients with Uncontrolled GOut Receiving Pegloticase (MIRROR): 12-Month Results of an Open-Label Study and Pharmacokinetics of Pegloticase and Methotrexate Polyglutamate(s) in Patients with Uncontrolled Gout Receiving Pegloticase and Co-treatment of Methotrexate.
DocWire News: What prompted you to undertake this study?
Dr. Botson: Well, this has been a passion of mine. In 2018, Dr. Jeff Peterson and I presented some data on some patients that we had that had gout that were being treated with pegloticase. We came up with an idea that if we could use another medication or something to help make the pegloticase work better, that this would be good for our patients.
Ultimately that’s it. We’re doctors on the ground, and we see patients every day, and this is just one way that we can hopefully help to treat our patients better. So that’s where the idea came from.
DocWire News: What are the key takeaways from the study?
Dr. Botson: There’s kind of two parts of the study that we’ve we brought out this year. The first one was basically the information regarding the MIRROR open-label [study]. This is an ongoing study that basically mirrored what we did as individual physicians, so essentially trying to create a way to make the pegloticase better.
Essentially in this study, this is called the MIRROR open-label, which the initial results for the first six months were actually previously presented, where basically we enrolled the patients that had gout, uncontrolled gout. We said [patients with] serum uric acids >6, that previously failed other treatments, so oral agents, etc.—these patients would get enrolled and receive methotrexate as a medication for a month before they received their first infusion of pegloticase. Basically, we saw when we did our initial case series where patients responded much better to the pegloticase versus the randomized controlled trial. So maybe a little background on that part.
The randomized controlled trials that got pegloticase approved [had] about a 42% response rate, so less than half of the patients actually responded to the medication or were able to complete full treatment. So by adding the methotrexate, what we saw with our 10-patient case series was that we had 10 out of 10 patients be able to complete the treatment.
So this is pretty exciting news obviously for us, and the MIRROR open-label is a way to reproduce that, in a more controlled fashion, the patients we’re seeing that way. So basically there [were] 14 patients that were in the MIRROR open-label. They received the methotrexate first for four weeks, then received the pegloticase.
At the primary end point, which was at six months, whether they had a serum uric acid >6, 11 out of 14, 79% of those patients were able to make it to have a complete treatment, or to be a responder at that point—nearly doubling the baseline rate, if you will, the rate from the randomized control trial.
This particular poster here presented the data basically for the 12 months, so the next six months primarily was being focused on what happened to these patients that were able to respond at the primary end point at six months and go out to 12. This is where this poster fell in. The key takeaways for this is of these patients that were considered responders, while there was one patient that couldn’t go on further because the trial actually changed.
There was originally only a six month trial, so one patient dropped out because of that. Then two patients actually met their treatment goals at six months, so they did not continue to receive pegloticase, but they also actually did get monitored. Of those two, one of them was still a responder—both were a responder at nine months—one was a responder at 12 [months] still.
But then of the eight patients that were left in that cohort, all of those patients remained responders at 12 months. I think that’s the biggest takeaway from this, is that these patients now are more likely to respond and they will remain responders throughout their treatment.
The other secondary takeaway was the gout flare. Obviously gout flares are our biggest issue when we’re treating these patients. It’s the number one sort of side effect, if you will, or adverse reaction, if you will. Those all reduced.
So in the first 12 weeks, we saw about 92.9% of patients have a gout flare. By weeks 37 to 52, sort of the end quartile of the treatment, that dropped to 25%. So now we’ve got patients that are maintaining a serum uric acid that’s low, their gout and tophi and outward clinical symptoms are improving, and their gout flares are improving—the best of all worlds there. That, I think, was the biggest takeaway.
The second poster that was presented was also from the same cohort, from the same MIRROR open-label. This was maybe a little more basic, science-y, a little less clinical, but in this case, we also looked at, well, why is this happening? We’ve always had this suspicion that the reason that the medication methotrexate works so well with pegloticase [was that] it prevented these anti-drug antibodies that were attacking the medication, sort of neutralizing its effect, eliminating it quicker. We’ve always had this kind of thought that, well, this is probably what’s going on because we see this in other diseases and other rheumatologic processes. Actually, part of the reason we got to methotrexate [was] because we use methotrexate with some of our other diseases.
The theory was that in fact, we were probably helping to prevent these anti-drug antibodies from developing. The bottom line of the second poster was that we did see that. We did see the anti-drug antibody levels less. For comparison purposes in the randomized controlled trials, about 89% of patients developed anti-drug antibodies. Now some of those patients still responded, even though they had antidrug antibodies, but 89% had these antidrug antibodies.
In the MIRROR open-label study, the number was two patients out of 14 that had detectable antibodies. So percentage wise, you’re looking at about 14 or so percent that developed these antibodies. That data really helped to support what we saw clinically. It also supported that using methotrexate with pegloticase doesn’t cause a drug interaction, it doesn’t affect the mechanism otherwise of the pegloticase, except potentially through that anti-drug antibody mechanism.
Those are the biggest take-home points clinically of what we’re seeing an opportunity to treat these patients better. Some insight into why it’s happening, sort of verification of what our clinical theories were in the beginning, which is always nice in medicine. It’s always nice to have those things match.
DocWire News: Did any of the study’s findings surprise you?
Dr. Botson: Not really. I think it was encouraging because this was kind of what we were seeing clinically. This was a reproduction, if you will, of our original case series and there’s been multiple other case series presented too that really had similar findings. This was the most cohesive, sort of systematic way of looking at this, versus these case series that were presented. But it didn’t really surprise me because this is kind of what we expected to see. It was good to have the verification, though.
DocWire News: What limitations did the study have?
Dr. Botson: I think the biggest limitation to the study, like any open-label [study], is just not having a comparator group. It was also a small number of patients. I mean, 14 patients is a fairly small number to have in just a study. But I think the nice thing about this is it sort of did prove and support further that idea that this is the way to treat patients.
[This] actually leads to hopefully a more robust bit of data with a randomized controlled trial that’s actually enrolling right now and it’s under the same name, MIRROR open-label, or MIRROR randomized controlled trial. So I think we’ll see more data with that. But that’s always a limitation in these. It’s just a small sample size and how much of it you can actually … How much of the data and the results you can actually bring out to your full patient population, if you will.
DocWire News: My next question was if you have any future research plans for this area, and it sounds like you do. Do you want to maybe touch on that a little bit?
Dr. Botson: The one that’s exciting obviously is the MIRROR randomized controlled trial. Essentially [we] did the same study as the MIRROR open-label, but with a comparator group with a placebo, so essentially a group that received pegloticase monotherapy. That [study]’s enrolled fully now and [we] should see results early next year, so that’s pretty exciting.
The one other study is one that just was recently announced. That was the AGILE study, which is basically a similar study, but trying to make the infusions experience a little better for patients having a shorter duration of the infusion. That one will be enrolling its first patient really soon, so that’s also pretty exciting.
DocWire News: Is there anything else that you wanted to add that we didn’t cover in the questions so far?
Dr. Botson: I’m always really excited to talk about this; it’s kind of near and dear to my heart. The only thing I would add is just [that] we’re trying to do things that make the experience better for patients, that make their clinical response better.
This is a really tough population of patients that really has no other options. By the time they get to pegloticase, this is it, this is their last line of treatment. So the better we can do to make these medications work, the better it’s going to be for our patients.
I think, every day when we’re all seeing patients, that’s what motivates us to do this and what motivates us to come to work every day to see these good responses. That’s probably the takeaway I would leave at that, is just let’s keep our eyes open, keep our heads open, and try to get better results for these patients.