MIRROR RCT (NCT03994731) phase III data support the combination of immunosuppression with pegloticase treatment for uncontrolled gout in all patients, raising the response rate from 40-42% to 71%. Physician’s Weekly spoke with Dr. John K Botson, (Orthopedic Physicians Alaska, Anchorage).
PW: How did you think about combining immunomodulation agents to improve response with pegloticase?
JB: This is a great story, a real journey. About 3 years ago, we were treating some of the most refractory gout cases and thinking about how to do it better so that patients could benefit and stay on therapy.
The burden on quality of life that gout imposes is substantial. While gout is a disease that has been around forever, contrary to popular belief, it is largely determined by genetic factors, not only lifestyle choices. Beyond the impact of gout itself, there is an association with higher morbidity and mortality in patients with cardiovascular disease and an association with higher risk of metabolic syndrome and diabetes. Addressing gout in patients has both short-term and long-term benefits.
We considered that the underlying pathophysiology driving uncontrolled gout is likely a chronic inflammatory process, perhaps similar to rheumatoid arthritis, lupus or other diseases that we deal with daily in rheumatology. It occurred to me and my colleagues that gout is a systemic disease causes by an imbalance between uric acid production and excretion. You can tip the scale favorably, by decreasing nitrogen input through reduced dietary protein intake, but that is riddled by variables you can’t control, such as the patient’s genetic makeup. The other option is increasing excretion. Ultimately, we realized, it is a better idea to get rid of the excess uric acid that is causing the problem.
What really got us thinking about new approaches was that we have this great medicine, pegloticase which literally dissolves uric acid. The medication has been around now about 9 years; however, is underutilized as it works effectively for less than half of patients. The clinical trials data inform us that as a monotherapy, pegloticase is roughly 42% efficacious. We know that even good responders may need 6-9 months of this treatment to achieve the threshold levels of serum uric acid because their disease can be so extensive.
Pegloticase is given as an infusion every 2 weeks, and typically used as a later-line therapy to patients with refractory gout, where every oral medicine does not work sufficiently. Quite frankly, the oral agents that we use are not that good. The cut-off for acceptable serum uric acid is 6 mg/dL, but we prefer to get our patients under 5 mg/dL. If you have a patient with a serum uric acid of 11 mg/dL and they have tophi coming out of their fingers and toes, you are not going to be able to bring them below the cut-off with oral medication. Remember, it takes years, even decades, for these folks to build up that much uric acid. You cannot turn that off overnight, especially, with oral agents.
These are the rare and extreme cases, people who are so burdened by gout that they have to call off a lot of days of work. These are the folks who are miserable, literally bed-ridden from the disease.
More than half of the patients, the other 58% of the patients in those trials, find after 1 or 2 doses of pegloticase, despite observing interval improvement, that the medication would just stop working. Those people are stuck at that point because they have no other treatments. We would have to say, “Mr. Smith, I’m sorry. That is it. We do not have anything else.”
Dr. Jeff Peterson in the Seattle area in Washington and myself asked ourselves about 3 years ago whether we could add other medicines onto pegloticase to improve outcomes. Immunomodulation, for example using methotrexate, is a standard practice in rheumatology, and we decided to try a pilot. We agreed that the next 10 patients we put on pegloticase; we would start them with a run-in period of methotrexate before their first pegloticase treatment and keep them on methotrexate during the course of their treatment. At the end of 6 months, after we met each other every month to check in on all the patients, we were amazed. All of the patients responded, it was 10 out of 10 patients.1 This initial data led up to the MIRROR trial. MIRROR started as an open-label study combining methotrexate treatment with pegloticase, and 79% of the patients had a response.2 Although this data was certainly promising, we really needed data from the gold standard, a randomized controlled trial, to change the recommendations.
We just received the results from MIRROR-RCT in the last 2 weeks; 71% of patients randomized to receive methotrexate and pegloticase had a response. The placebo arm showed a response of 40%, which is exactly what we see in everyday practice for patients on pegloticase monotherapy. Based on these results, you are looking at nearly twice as many patients who responded. We are confident that these data represent real-world patients, and that these numbers are really solid and consistent across all studies.
With regard to safety, was the most common adverse event in the RCT as well, was it gout flares?
Gout flares happen all the time, and even in these in these trials about 71% or so of patients have a gout flare, generally in the first 3 months. We observed that the longer the subject stayed on the medication, the number of gout flares significantly reduced. We do things to try to help prevent flares, such as prophylaxis with anti-inflammatories, corticosteroids or colchicine. Some patients also received IV corticosteroids, such as methylprednisolone at the time of their infusion. Initially, we were using corticosteroids to prevent infusion reactions, but currently we think of it more of a gout flare prophylaxis or gout flare treatment.
Once normal serum uric acid levels have been achieved after induction therapy with pegloticase, can you re-challenge with an oral drug for maintenance therapy?
That is exactly right. We are not curing gout. I wish we were, but we are not, the body is still going to accumulate uric acid. Depending a lot on the patient’s genetics, they will eventually raise their serum uric acid again, because they are making more than they can get rid of, quite simply.
I use a cooking metaphor: if you have salt and you are pouring it into the water, eventually the salt is going to sit down on the bottom of the pan. That water will never be “unsalted” unless you get the salt out of the bottom of the pan. Pegloticase can get all that extra deposited salt out of the pan, and by removing the immune response to pegloticase we can help ensure it works even better. At that point we can keep up with the rest of the body processes, and an oral uric acid agent can now adequately keep their serum uric acid at goal. Sometimes it the same oral agent that failed the patient previously, now works better, and we can halve the dose. Patients get their life back.
Going forward, to treat uncontrolled gout, we will be using methotrexate with pegloticase. We may be able to tweak the immunomodulatory agent to improve the response rate incrementally. We also are conducting research to see how the patient experience can be improved. For example, pegloticase is given over 2 hours by IV infusion, every 2 weeks. We are looking to see if we can speed that up, do it 30 minutes, or alternatively reducing the frequency. I think that is going to be the exciting part as we go forward.
