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PROTECTing renal transplant recipients from uncontrolled gout

Dr Brian LaMoreaux, Horizon Therapeutics, Chicago, IL
Kidney Week of the American Society of Nephrology
Phase 4, PROTECT
In the phase 4 open-label PROTECT trial of pegloticase therapy (pegylated recombinant uricase) in treating severe gout in renal transplant recipients, 89% of patients achieved primary endpoint of serum uric acid (sUA) <6 mg/dL for at least 80% of the time during Month 6. Dr Abdul Abdellatif (Baylor College of Medicine, Houston, TX) presented the results from the completed PROTECT trial (NCT04087720) at the Kidney Week of the American Society of Nephrology, which was held virtually 4-7 November, 2021 [1]. Medicom spoke with study author Dr Brian LaMoreaux, MD, MS, Medical Director at Horizon Therapeutics, Chicago, IL, to discuss the results.

Brian Patients with Chronic Kidney Disease (CKD) are at up to 10-fold higher risk for developing severe gout, which can be hard 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 PROTECT [3] 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 ago, 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 2-3 immunosuppressive agents to prevent organ rejection. Of those, 16 patients (88.9%) achieved the primary endpoint, defined as sUA <6 mg/dL for at least 80% of the time during Month 6. No notable eGFR changes were observed. Attenuation results showed that 6 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 in this study, and no anaphylaxis was reported. This study demonstrates that in addition to established improvements in pegloticase efficacy, therapy with pegloticase results in a favourable response rate and safety profile even in patients who have received renal transplants.

Medicom’s correspondent spoke with Dr. LaMoreaux:

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

“Kidney transplant patients 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 non-steroidal anti-inflammatory drugs; 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 flush it out, to prevent gout flares. Being aware of the burden in this population, we launched an open-label 20 patient study of kidney transplant patients with uncontrolled gout.

“At the American Society of Nephrology’s 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 group of patients -to protect their grafted organ- is already on usually a calcineurin inhibitor, sometimes mycophenolate, and then 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 really very, very well, and we are really 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.”

Medicom: Could you also comment of the recent results from the MIRROR RCT trial?

“We are very excited by these results as well from MIRROR RCT (NCT03994731), and they really support the combination of immunosuppression with pegloticase treatment for uncontrolled gout in all patients [4]. We randomised 152 patients, of which 100 were treated with methotrexate with pegloticase. The other 52 received placebo instead of methotrexate in combination with pegloticase. What we saw at 6 months was that the group that received methotrexate with their pegloticase had a 71% response rate, and 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.”

Medicom: 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 uncontrolled gout patients. These 2 randomised control trials strongly support this notion, providing top-level evidence. To us, it means is that these uncontrolled gout patients, the ones who did not do well on oral therapies, who 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 40-42%, now they can go on combining pegloticase with immunomodulating therapy and have a quite high likelihood, 70-80%, of complete response. Consequently, those patients are going to be much more successful in clearing out their urate burden, 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 of those uric crystals that were causing so many problems are not there anymore.

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

  1. Abdelatif A et al. Pegloticase for Uncontrolled Gout in Kidney Transplant Recipients: Provisional Data Report of a Multicenter, Open-Label, Efficacy and Safety Study , American Society of Nephrology Kidney Week, 4-7 Nov 2021, Abstract PO211.

  2. Peterson J, et al. Safety of Pegloticase with Immunomodulation Co-Therapy: Literature Review, American Society of Nephrology Kidney Week, 4-7 Nov 2021, Abstract PUB318.

  3. Keenan RT, et al. Semin Arthritis Rheum. 2021 Apr;51(2):347-352.

  4. Botson JK, et al. J Rheumatol. 2021 May;48(5):767-774.

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