Early findings from the PROTECT trial,1 presented at the 2022 American Society of Nephrology’s Kidney Week, demonstrate substantial and sustained serum urate reduction in renal transplant recipients with uncontrolled gout. These findings are consistent with other reports on the effect of immunomodulation use with pegloticase.

Advanced disease develops in approximately 15% of patients with gout2 and is characterized by subcutaneous nodules composed of monosodium urate (tophi), unremitting articular inflammation, and potential joint erosion and deformity.

Kidney transplant (KT) recipients have a high prevalence and severity of gout. Pegloticase (pegylated recombinant uricase) rapidly metabolizes urate and efficacy is not impacted by CKD stage. Immunomodulator co-therapy with pegloticase has improved treatment response rates over phase 3 monotherapy trials by attenuating anti-drug antibodies. The ongoing Phase 4 PROTECT trial examined safety and efficacy of pegloticase in KT recipients with uncontrolled gout (UCG). Data were presented by Abdul Abdellatif, MD, FASN, a nephrologist at Baylor College of Medicine and CLS Health.

The primary endpoint was the number of patients reaching serum urate levels less than 6 mg/dL for at least 80% of time at month 6, with an additional 3 months of follow-up. secondary endpoints included the Health Assessment Questionnaire (HAQ) pain (most severe: 100) and Disability Index (HAQ-DI) scores. In total, 20 patients were enrolled (mean age, 53.9 ± 10.9; time since renal transplant, 14.7 ± 6.9 years; serum urate, 9.4 ± 1.5 mg/dL; gout duration, 8.4 ± 11.6 years; all on ≥2 immunomodulation agents).

At the time of analysis, 10 patients completed treatment, three discontinued the study, two met serum urate monitoring rules (pre-dose SU >6 mg/dL at 2 consecutive visits) and discontinued pegloticase, and fiver were ongoing. All patients experienced initial substantial reductions in serum urate, which was maintained in the majority; two patients met monitoring rules. At week 24, no notable eGFR changes were observed. In patients who completed treatment, HAQ-pain and HAQ-DI scores improved by 26.7 ± 30.3 (baseline, 35.9 ± 30.2) and 0.2 ± 0.5 (baseline, 1.0 ± 1.0), respectively, at week 24 (N=10). Safety analyses revealed seven serious adverse events (2 cellulitis, 1 duodenal ulcer, 1 sepsis, 1 atrial fibrillation, 1 diverticulitis, 1 localized infection), none of which were deemed to be related to pegloticase, in five patients. No anaphylaxis events occurred.

Dr. Abdellatif and colleagues concluded that future studies will look at long-term benefits of controlling gout; several meta-analyses have shown that patients who develop gout after transplant have increased risk for transplant complications and rapid progression to end-stage renal disease, compared with those who do not develop gout. During the PROTECT trial, the investigators saw a reduction in systolic, diastolic, and mean arterial blood pressure during treatment, which was sustained in the follow-up period. Treatment did not have any negative effect on kidney function during the clinical trial compared with baseline. There is additional research needed.

Physician’s Weekly spoke with study co-author Bradley Marder, MD.

PW: What Is the Current Unmet Need in Patients With Gout?

Dr. Marder: The biggest unmet that requires addressing for treating uncontrolled gout is the fact that once a patient has gout for long enough to accumulate a sizeable burden of monosodium urate crystals in the body, really the oral urate-lowering medications, like allopurinol and febuxostat, are often no longer effective. Those medications can prevent the production of uric acid, but they cannot really do anything about the uric acid that has already accumulated. That is where pegloticase, which is really the only option for these patients who failed other urate-lowering therapies, can be dramatically effective at reducing the monosodium urate burden.

The mechanism of pegloticase is just simply fantastic. It can metabolize uric acid, turning it into soluble products which are then, in turn, much more easily excreted by the kidneys. Nevertheless, it is an IV biologic; and as a biologic, it does have the capacity to cause immunogenicity or cause the production of anti-drug antibodies that both limit the effectiveness of the drug and also make patients who take it at risk for infusion reactions during the administration of the medication.

Thus, the big unmet need for these patients is not just the fact that they have uncontrolled gout that is not responding to oral urate-lowering medications, but that they can get this really dramatically effective medication that, unfortunately, is not effective because they may develop anti-drug antibodies.

With regard to safety, there can be infusion reactions to pegloticase. Twelve years now after pegloticase was approved by the FDA, there is still research being done to try and make this medication more effective for patients who really need it. And that is exactly what the PROTECT randomized control trial sought to do, using pegloticase in combination with other immunomodulatory medications to prevent the production of anti-drug antibodies.

PW: How Did the PROTECT Study Attempt to Solve Those Problems? 

Dr. Marder: PROTECT is a trial using pegloticase for patients with uncontrolled gout who also have kidney transplants. That population was studied because patients with kidney transplants have a high prevalence of gout. They have reduced kidney function and also they are taking medications often that increase serum uric acid levels and make them predisposed to getting gout. For example, some medications they take to prevent rejection of their kidney transplant—notably the calcineurin inhibitors and some of the diuretics that are very commonly given to patients with a kidney transplant—also increase their uric acid levels. So, these patients have a high risk for gout. There are isolated reports of pegloticase efficacy in transplant recipients,3 but this question is largely unanswered.

At the same time, these patients are on medications to prevent rejection of their kidney transplants. So, the theory was that these medications would also reduce their immunogenicity, or reduce their tendency to develop anti-drug antibodies. The PIVOTAL trial for pegloticase in 2010 showed that 42% of patients had a complete response, meaning 58% developed anti-drug antibodies to the point that the drug was not effective for the 6-month endpoint. We all agree that only 42% is just not good enough for these patients who really have no other options. For the PROTECT trial, all patients were on immunosuppression medications to protect their kidney transplant from rejection. And instead of a 42% response rate, the PROTECT trial found that those patients had an 89% response rate. Also, in the PIVOTAL trial, 25% of patients had infusion reactions, but in the PROTECT trial, none who were on immunosuppression had infusion reactions. Not only did we find that the drug was more than twice as effective, there was also just a fraction of the risk involved.

The data presented at Kidney Week was actual anti-drug antibody and pharmacokinetic data for patients enrolled in that trial. We had already reported the clinical response rate and safety profile for these patients with transplants taking pegloticase. But we really wanted to show a confirmation that patients with kidney transplants had higher drug exposures than patients who were not on any kind of immunomodulating therapy and had no production of anti-drug antibodies except for the two patients who lost response. The 89% efficacy rate in this context is very promising.