A review of the practical and clinical implications of the MIRROR study and consider the impact of pegloticase combined with an immunomodulator.
Gout affects an estimated 9.2 million people in the United States. It occurs when serum uric acid levels chronically remain above the solubility limit of 6.8 milligrams per deciliter (mg/dL). The following transcript focuses on a conversation between a clinical professor and a rheumatologist discussing the multicenter, open label MIRROR trial, which examined Krystexxa (pegloticase) in combination with methotrexate in patients with uncontrolled gout. They review the practical and clinical implications of the MIRROR study and consider the impact of pegloticase combined with an immunomodulator.
A brief background on gout
Orrin M. Troum, M.D.: Jeff, can you discuss some of the burden of gout on patients’ quality of life?
Jeff R. Peterson, M.D.: When patients have a flare of gout, they describe it as though somebody was tearing their skin off and putting acid on. I can’t imagine how terrible that it is, but I do know that it’s completely incapacitating to most patients during the flare. What we don’t recognize is that in chronic gout or uncontrolled gout, the tophaceous material builds up over time and that leads to a lot of other disability. Patients don’t even want to go for a walk with their family or play with their children because they can’t pick them up because their hand hurts too much. Sometimes they can’t work. In fact, many of the patients become disabled because of this. Quality of life issues are dramatic, and I’ve seen it. When we treat these patients well they get their life back and they’re so happy.
Troum: I think we’ve all found that as rheumatologists and other health care providers taking care of patients with gout, when their gout is controlled, they lead an otherwise normal life. The current landscape regarding management of gout really hasn’t changed much over the decades. Can you tell me what urate therapies you use?
Peterson: There are very few choices. They talk about using probenecid, which is a uricosuric agent, but we as rheumatologists almost never use the drug. Most of our patients have renal insufficiency, and uricosurics usually cause kidney stones, which is probably about as bad or worse than gout. Also there are a lot of drug interactions with probenecid.
Allopurinol is the classic one we always use. It’s inexpensive and it’s generally well tolerated. But what happens is a lot of the primary care doctors, or even rheumatologists, don’t push the dose up enough to get good adequate treatment from it. However, there are patients who just don’t respond or who have side effects. We also have Uloric (febuxostat), which is the other medication that we use. That’s basically it for medications in the past 10 years except for Krystexxa (pegloticase), and that has been a game changer especially now that we’re using immunomodulation.
Troum: One of the other caveats about using allopurinol is that we typically start at 100 milligrams and might go up to 200 or 300. Most of the patients who are referred to me have started on 300 milligrams. I’ve had a couple of patients who are on 800 or 900 milligrams of allopurinol. Once you get past 300 milligrams, you’re supposed to split the dosing to twice daily. The caveat is that some patients may not be able to tolerate that.
What treatment options are available for those who don’t achieve their target urate level?
Peterson: There are a lot of patients out there who are not being treated and the unmet need is really how to get them to us or to somebody who is comfortable managing gout. We have medications that work. Especially now that we have pegloticase, we can really debulk these patients and get their uric acid levels down very low and get rid of the tophaceous burden. Then we can reinitiate oral therapy at a much lower, more tolerable dose because, as you know, allopurinol has a ceiling effect.
In my patients, I try to get them down to approximately 4.5 mg/dL or even a little bit lower because that’s going to help get rid of the sodium urate burden quicker. The lower the uric acid, the faster the crystals will dissolve. However, it does increase risk for infusion reactions and gout flares. In essence, now that Krystexxa is out there and we’re using immunomodulation, we’re getting such a dramatic improvement in the response rate. I think that’s really where the unmet need lies, in getting those patients to us.
The MIRROR Trial
Troum: The guidelines, including the American College of Rheumatology guidelines, recommend maintaining the serum uric acid levels below 6 mg/dL and in patients with tophaceous gout it’s below 5 mg/dL.
Unfortunately, the urate lowering therapies are often underutilized, and a small subset of patients with gout cannot tolerate or do not respond to them. Pegloticase, or pegylated uricase, is highly effective in lowering serum uric acid. However, the clinical studies have shown that only 42% of patients maintain their serum uric acid below 6 mg/dL over six months of pegloticase therapy alone. We now know that that was due to anti-drug antibody production.
Dr. Peterson and his colleague Dr. John Botson came up with a pilot study to look at the effect of using immunomodulation along with pegloticase. This is not new; rheumatologists have been utilizing that for more than two decades and using our initial biologic therapies with anti-TNF therapies, such as infliximab. For example, although methotrexate is used to manage rheumatoid arthritis by itself, when in conjunction with the anti-TNF therapies it not only improved efficacy but also decreased the production of anti-drug antibodies.
(Dr. Peterson and Dr. Botson posed the question:) If it worked in those medicines, why shouldn’t it work with this medicine? Even though methotrexate is not indicated for use in gout itself or uncontrolled gout, they recognized the importance of inhibiting these anti-drug antibodies.
There was a screening period of less than two weeks. There was a four-week methotrexate run-in period to make sure that the patients were able to tolerate methotrexate. They were given the 15 milligram dose of oral methotrexate weekly and 1 milligram of folic acid daily, similar to what we do for our patients with other systemic diseases. (During the treatment period,) patients received 8 milligram of pegloticase intravenously every two weeks plus the 15 milligram of oral methotrexate weekly, with a maximum of 52 weeks.
The modified intent-to-treat population (was) 14 patients. The mean age was approximately 50 years (49.3) and all were male. There was a smattering of White and Asian patients. There were no Black, native Hawaiian, or other Pacific islander patients. The body mass index would be as expected; these were obese patients. The mean time since the first gout diagnosis was 13.8 years. The mean number of gout flares in the 12 months prior to screening was 10.8, which is significant. As pointed out earlier, this has a major impact on patients. To have that many gout attacks in a year is disabling. There was a significant number of tophi and the baseline serum uric acid was 9.2 mg/dL.
Efficacy points were the percent of patients who maintained a serum uric acid of less than 6 mg/dL and serum uric acid of less than 5 mg/dL for at least 80% of the time.
There were significant reductions in the serum uric acid at week 12 and week 24. And this happens almost immediately with the change of the urates. At week two, there was already a dramatic reduction in serum uric acid, which is maintained through week 24.
There was one serious adverse event, and adverse events were slightly higher in the combination group. Diarrhea, upper respiratory tract infection, sinusitis, muscle strain and hypertension (were reported).
Gout flares, as expected, were greater than 85% overall day 1 to 12. But then from days 12 to 24, less so. Any time you mobilize these monosodium urate crystals in the body, you’re going to get a flare. We try to mitigate that by using medications as they did in the trial.
Challenges of Managing Gout
Troum: What challenges do we encounter through treatment?
Peterson: The first thing that’s important about patients with gout is that (they can be) terribly inconsistent with follow-ups and taking their medications. I try to impose on them the knowledge that gout is a chronic disease. Just because you’re not having a flare doesn’t mean it’s not there. But so many of my patients stop taking their allopurinol because they’re not having a flare. And then they come back a year later with a horrible flare, and they say, “Well, I didn’t fill it, because I didn’t think I had gout anymore.” A big problem for me is making sure those patients are educated, and that they stay on their oral medications. But we already know that many patients don’t. Having an intravenous medication that we can give them and knowing that they’re getting the medication is helpful.
Education is my main approach with my patients. I always start with oral therapies because that’s appropriate. Once I’m done with the oral therapies, if they require Krystexxa, then I have the discussion with them about why I’m using immunomodulation. We’re trying to prevent the antibody formation. The results have shown very clearly in the intent-to-treat population that we’re getting about double the efficacy if we use immunomodulation. And that’s huge. This is our last-ditch-effort drug; we want to make sure we’re going to keep those patients on for a complete course so that we can achieve our goals.
Troum: There are more than a dozen medications that can control rheumatoid arthritis, but only a few medicines that are used to manage gout.
Peterson: Right, and we’re working on that right now. And I think a lot of these patients are going to podiatry clinics, or they’re being seen in nephrology clinics. And so, educating those physician groups has been helpful in identifying these patients (with severe gout). I’m hoping that we can get in front of more primary care doctors as well, because patients with bad gout have a higher cardiovascular risk. We just need to get that message out there.
Troum: Approximately 25% of patients on pegloticase experience infusion reactions. What steps do you take to reduce the likelihood or manage the reactions effectively when they do occur?
Peterson: I want to point out that with the use of immunomodulation, the infusion reactions have gone from 24% to less than 4%. And in my practice, it almost never happens. I think I’ve gone to less than 1%. And so by using immunomodulation with Krystexxa, you get double the efficacy, and five times the safety. It’s a no brainer.
What I do for those patients before treatment is we always have them on antihistamines. We do use some steroids, although we’re trying to lower that dose so that our patients with diabetes aren’t overloaded with steroids. Dr. Botson and I are working on a protocol about how to get lower levels of steroid injection before the infusion. Also, if a patient’s had a problem with a slight infusion reaction in the past, we’ll go a little slower on the infusion. But generally, patients do well, especially using immunomodulation.
Troum: That’s an important point because when this medicine first came out, it was a big concern that patients could experience anaphylaxis. But, as you know, of the people who had those types of anaphylactic reactions, nobody was hospitalized, nobody was put on a respirator, nobody died. Three out of 4 kept using the drug, and they slowed the infusion.
But the message that got out was if you’re doing this in your own office, watch out. (Luckily,) that really is being mitigated by the fact that we’re using methotrexate now. Now the FDA has included it and allowed Horizon Therapeutics to include it in their label. So that was really a good thing, because now a lot of rheumatologists will have seen the data and will understand that this is an improved way to utilize this medicine. And as you pointed out, it is not just increasing efficacy by doubling it, but also decreasing the risk of infusion reactions, which is significant.
Are there any other take-home messages or other implications?
Peterson: It’s been really gratifying for me in this whole process, knowing that there was this problem with my patients and knowing that there’s a medication out there that we could do better with. The study was funded by the Alaska Rheumatology Alliance, which is a non-University, non-pharma company, just regular doctors in the trenches doing what they think is right for patients. And for me to see this label change is very gratifying. I would love for all patients with gout to get adequate therapy. I would like better education out there so that we know that patients with gout have opportunity to get full recovery of their life. I don’t want to see anybody disabled anymore. And I certainly don’t want to see any more patients die from comorbidities of gout.
Editor’s note: This transcript has been edited for length and clarity.