In the phase IV open-label PROTECT trial of pegloticase therapy (pegylated recombinant uricase) in treating severe gout in renal transplant recipients, 89% of patients achieved the primary endpoint of serum uric acid (sUA) less than 6 mg/dL for at least 80% of month 6. Dr. Abdul Abdellatif (Baylor College of Medicine) presented the results from the completed PROTECT trial (NCT04087720) at Kidney Week 2021.1


Patients with Chronic Kidney Disease (CKD) are at up to 10-fold higher risk for developing severe gout, which can be difficult to manage. Pegloticase therapy for uncontrolled gout does not require renal adjustments and is effective across all stages of CKD. Efficacy can be limited by development of anti-drug antibodies, which also increase the risk of infusion reactions, and combination with immunomodulatory drugs can increase pegloticase efficacy.2 However, beyond dialysis, little is known about the effect of pegloticase in controlling gout in renal transplant recipients, who take immunosuppressive medications, and would therefore not require additional immunomodulatory treatment.

The findings from PROTECT3 demonstrated that pegloticase infusion every 2 weeks provided a substantial and sustained decrease in sUA for patients (n=18, mean±SD; age: 53.9±10.9 years, kidney transplant 14.7±6.9 years prior, serum urate 9.4±1.5 mg/dL, gout duration 8.4±11.6 years; all on stable doses of ≥2 immunosuppressive medications) with uncontrolled gout who had received a kidney transplant and who were treated with two to three immunosuppressive agents to prevent organ rejection. Among them, 88.9% achieved the primary endpoint, defined as sUA less than 6 mg/dL for at least 80% of month 6. No notable eGFR changes were observed. Attenuation results showed that six patients discontinued the treatment early, either because their pre-dose sUA was too high (>6 mg/dL at 2 consecutive visits) or based on COVID-19 pandemic concerns.

Among those who completed 24 weeks of treatment, health assessment scores for pain and disability improved by 35.5 (baseline: 42.2) and 0.3 (baseline: 1.0), respectively. Pegloticase administered with immunomodulatory co-therapy had no injection site reactions, and no anaphylaxis was reported. The study demonstrates that in addition to established improvements in pegloticase efficacy, therapy with pegloticase results in a favorable response rate and safety profile even in patients who have received renal transplants.

Physician’s Weekly spoke with study author Dr. Brian LaMoreaux, MD, MS, Medical Director at Horizon Therapeutics in Chicago, to discuss the results.


PW: Could you comment on the prevalence, risk factors, and outcomes of gout in transplant recipients?

BL: Kidney transplant recipients have an extraordinarily high burden of gout, but they also sometimes have limitations of other kinds. It is tough to manage their gout flares, because with a kidney transplant, you should avoid NSAIDs; these individuals simply do not have a lot of options to treat their flares. A better option is to clear out their serum urate altogether to prevent gout flares. Being aware of the burden in this population, we launched an open-label, 20-patient study of kidney transplant recipients with uncontrolled gout.
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At Kidney Week, we presented the final dataset of the PROTECT study, of which there was an 89% response rate to this medicine. We did not have to adjust or add any immunomodulating therapies, because this patient population—to protect their grafted organ—is usually on a calcineurin inhibitor, sometimes mycophenolate, and a low dose prednisone. The study was a huge success with such a high response rate. We did not see any infusion reactions, and the rate of gout flare rate was not as high as in other studies. We could conclude that these patients did very well, and we are thrilled to have a good data set in that particular population of solid organ transplant recipients, which does not get examined with respect to gout very often.


Could you also comment of the recent results from the MRROR RCT trial?

We are excited by the results from MIRROR RCT (NCT03994731) as well; they support the combination of immunosuppression with pegloticase treatment for uncontrolled gout in all patients.4 We randomized 152 patients, of whom 100 were treated with methotrexate with pegloticase. The other 52 received placebo instead of methotrexate in combination with pegloticase. At 6 months, the group that received methotrexate with their pegloticase had a 71% response rate, whereas those who received placebo instead of methotrexate had only a 40% response rate. We saw no new safety concerns, which of course is excellent. We are hoping to take this data set to the FDA early next year to request a label update.


What do these results collectively mean in the broader context of gout therapy development?

PROTECT and MIRROR are the most sophisticated results at the moment showing that immunomodulation combined with pegloticase can provide strong clinical benefit for patients with uncontrolled gout. These two randomized control trials strongly support this notion, providing top-level evidence. To us, it means that patients with uncontrolled gout—who did not do well on oral therapies, were suffering substantially from gout, and sometimes did not have other options—have new options. Instead of the pegloticase monotherapy response rate, which ranges somewhere around 40% to 42%, now they can go on combining pegloticase with immunomodulating therapy and have a quite high likelihood (70%  to 80%) of complete response. Consequently, those patients are going to be much more successful in clearing out their urate burden and resolving their gout symptoms, both short- and long-term. After completing a course of pegloticase, it is often quite simple to go back on an oral therapy for maintenance, and we usually see quite a good response rate. It is easy to get disease control after pegloticase because all the uric crystals that were causing so many problems are not there anymore.

We are always looking to the future. We have a number of early-stage clinical assets with exciting mechanisms, and many are actually oral therapies. We are looking 5-10 years into the future and we very much intend to stay in the gout space and help these patients for years to come.