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Pre-infusion serum urate levels during the methotrexate run-in (4 weeks) and pegloticase + methotrexate treatment (up to 52 weeks) periods. In the 3 non-responders, serum urate (SU) increases above 6 mg/dL were noted at weeks 2 and 4, weeks 4 and 6, and weeks 8 and 10. Data points represent the mean values, and error bars represent standard error (includes patients on treatment, values below the lower limit of detection were set to 0). SU, serum urate
Source publication
Background:
Publications suggest immunomodulation co-therapy improves responder rates in uncontrolled/refractory gout patients undergoing pegloticase treatment. The MIRROR open-label trial showed a 6-month pegloticase + methotrexate co-therapy responder rate of 79%, compared to an established 42% pegloticase monotherapy responder rate. Longer-term...
Citations
... 17 Whether similar benefit from the concomitant treatment of immunomodulating drugs with pegloticase can be achieved during real-world gout management is unknown. [15][16][17][18][19][20][21] Our goal was to ascertain whether conventional concomitant immunomodulatory drugs (eg, methotrexate, mycophenolate, leflunomide, azathioprine) could improve persistence with pegloticase, presumably by reducing immunogenicity, as part of real-world gout management. Our objectives were to compare pegloticase persistence between recipients and nonrecipients of immunomodulatory medications, to evaluate adverse events associated with the concomitant immunomodulatory therapies, and to evaluate potential pegloticase resistance patterns. ...
... Similarly, the MIRROR trial found that additional safety concerns did not develop from administering methotrexate with pegloticase. 17,18 New safety concerns did not arise in the other pegloticase and concomitant immunomodulatory therapy trials described. 19,21 Assessing patients' preinfusion SU levels is part of the recommended routine monitoring procedure for pegloticase and thus presents an opportunity to routinely monitor laboratory tests for concomitant immunomodulatory therapy. ...
... Moreover, previous studies have had limited sample sizes (152 patients or fewer) or have focused on a single immunomodulatory drug. [15][16][17][18]21 This study compares pegloticase persistence with concomitant immunomodulatory treatment for several drugs. However, we do recognize that combining all immunomodulatory drugs into a single group could mask heterogeneity between therapies, if such heterogeneity existed. ...
Objective
The objective of this study was to ascertain pegloticase persistence and adverse events associated with concomitant immunomodulatory drug treatment in patients with gout.
Methods
We conducted a retrospective analysis of patients with gout using the American College of Rheumatology's Rheumatology Informatics System for Effectiveness registry from January 2016 through June 2020. The first pegloticase infusion defined the index date. Based on concomitant immunomodulatory drug treatment, we identified three exposure groups: (1) immunomodulatory drug initiators (patients initiating an immunomodulatory prescription ±60 days from the index date), (2) prevalent immunomodulatory drug recipients (patients receiving their first immunomodulatory drug prescription >60 days before the index date with at least one prescription within ±60 days of the index date), and (3) immunomodulatory nonrecipients (patients receiving pegloticase without concomitant immunomodulatory drugs). We calculated the proportion of patients who achieved serum urate levels ≤6 mg/dL and who had laboratory abnormalities (white blood cell count <3.4 x 10⁹/L, platelet count <135,000, hematocrit level <30%, alanine aminotransferase or aspartate aminotransferase level ≥1.5 times the upper limit normal value) within 180 days after the index date. Cox regression analyzed time to pegloticase discontinuation, controlling for potential confounders.
Results
We identified 700 pegloticase recipients (91 immunomodulatory drug initiators, 33 prevalent immunomodulatory drug recipients, and 576 nonrecipients), with a median follow‐up of 14 months. Immunomodulatory drug recipients were less likely to discontinue pegloticase. The adjusted hazard ratios of pegloticase discontinuation associated with concomitant immunomodulatory drug initiation and prevalent treatment were 0.52 (95% confidence interval [CI] 0.37–0.75) and 0.69 (95% CI 0.42–1.16), respectively. Laboratory abnormalities were uncommon (<5%) and were not higher in concomitant immunomodulatory drug treatment.
Conclusion
Consistent with clinical trials, results from this large observational registry suggest that concomitant immunomodulatory drug treatment improves pegloticase persistence.
... Moreover, Pegloticase, a PEGylated porcine-like uricase produced by E. coli [15], has a longer half-life and higher bioavailability than Rasburicase [34]. However, its prolonged use may lead to poor therapeutic efficacy due to the production of high titers of Pegloticase antibodies [35][36][37][38]. In fact, side effects related to hypersensitivity reactions are still reported more frequently for both drugs, constraining their application scope. ...
The growing prevalence of hyperuricemia necessitates the urgent development of more potent treatments. This study aimed to develop, optimize, and evaluate the safety and efficacy of porcine–human recombinant uricase (PHRU) both in vitro and in vivo . The study employed gene editing of PHRU through site-directed mutagenesis, with recombinant proteins expressed in vitro utilizing Escherichia coli . The polyethylene glycol (PEG) approach was employed to augment uricase stability and diminish immunogenicity. The pharmacokinetics and pharmacodynamics of PHRU were tested in vitro and in Sprague Dawley rats. Successful expression of the fusion protein in E. coli and the development of the PEGylated drug were achieved. In vitro experiments confirmed the efficacy of PEG-PHRU in degrading uric acid, with PEGylation not markedly affecting the biological activity of PHRU. Animal studies revealed that PEG-PHRU significantly lowered plasma uric acid levels and mitigated hyperuricemia-induced renal damage in rats. Both drug metabolism and pharmacokinetics exhibited favorable characteristics without observable adverse effects in experimental animals. This novel fusion protein shows the potential for ameliorating hyperuricemia and related renal complications, highlighting it as a promising drug candidate with substantial market applications.
... Infusion reactions, including anaphylaxis, are attributed to the development of anti-drug antibodies (ADA) and are the most common side effect of pegloticase use, which render pegloticase ineffective [52,79,80]. Because of the presence of ADA, the concomitant use of pegloticase with methotrexate (MTX) was studied, and an improved pegloticase response rate was observed in the case series [81,82]. In the recent EULAR 2022 congress, the MIRROR (Pegloticase in Combination With Methotrexate in Patients With Uncontrolled Gout) trial showed a marked pegloticase response rate at month 6 when pegloticase was used with MTX compared to pegloticase monotherapy [83]. ...
Gout is the most common type of inflammatory arthritis, and its impact on cardiovascular health and quality of life is often underestimated. The prevalence and incidence of gout are increasing globally. Further, ischemic heart disease (IHD) and chronic kidney disease (CKD) are prevalent in gout patients. Some unmet needs for gout management include physicians' low initiation rate of urate-lowering therapy (ULT) and poor treatment adherence in patients with gout. There is also a lack of randomized controlled trials that establish safe doses of acute and long-term treatment for gout, particularly in patients with IHD and stage 4 CKD and above (including end-stage renal failure). Furthermore, there is also a lack of studies showing optimal serum uric acid (SUA) target and validated clinical outcome measures, including disease activity and remission criteria for gout tailored to treat-to-target approaches and the high cost of newer gout medications. The causal relationship between asymptomatic hyperuricemia or gout with comorbidities such as IHD and CKD has yet to be fully elucidated. There is a pressing need for collaborative international efforts to address the overall suboptimal management of gout.
... The 6-month results from the MIRROR open-label trial suggest that methotrexate (MTX) administered in conjunction with pegloticase nearly doubles the responder rate (79% during month 6 [11 of 14 patients], 95% confidence interval: 49-95%) with lower IR occurrence and otherwise similar safety profile as pegloticase monotherapy [21]. Furthermore, 12-month MIRROR open-label safety and efficacy findings indicate that urate-lowering is sustained over the long-term in patients remaining on therapy with both pegloticase and methotrexate [22]. Here, longer-term (12-month) exploratory endpoints of the MIRROR open-label trial are reported, including joint involvement, Health Assessment Questionnaire, and Global Assessments of Gout. ...
... Study medications have been previously described [21,22]. Briefly, this study included screening, a 4-week MTX run-in period (week − 4 through day 1), and a pegloticase + MTX co-therapy treatment period. ...
... The study's primary endpoint (6-month pegloticase response) has been fully described elsewhere [21], as has efficacy, safety, pharmacokinetic, and pegloticase immunogenicity findings through 12 months [22]. The full study schedule of events is included in those publications. ...
Background
Uncontrolled/refractory gout patients are recalcitrant/intolerant to oral urate-lowering therapies (ULTs), experiencing frequent gout flares, functionally limiting tophi, and low quality of life. Pegloticase lowers urate, but anti-pegloticase antibodies limit urate-lowering efficacy and increase infusion reaction (IR) risk. Immunomodulator + pegloticase co-administration may improve treatment response rates, with 79% of MIRROR open-label trial (MIRROR-OL, pegloticase + oral methotrexate) participants meeting 6-month response criteria. Exploratory outcomes from MIRROR-OL are described here.
Methods
Adults with uncontrolled gout (serum urate [SU] ≥ 6 mg/dL and ULT-intolerance/recalcitrance or functionally limiting tophi) were included. Oral methotrexate (15 mg/week) was administered 4 weeks before and during pegloticase treatment (biweekly 8 mg infusion, ≤ 52 weeks). Exploratory outcomes included change from baseline (CFB) in number of affected joints, Health Assessment Questionnaires (HAQs), and Gout Global Assessments.
Results
Fourteen patients received ≥ 1 pegloticase infusion, with 13 included in 52-week analyses (1 enrolled before treatment-extension amendment, exited at 24 weeks). Three patients prematurely exited due to SU rise; 10 completed 52-week evaluations (8 completed 52 weeks of co-therapy, 2 completed 24 weeks [met treatment goals]). At 52 weeks, SU averaged 1.1 ± 2.5 mg/dL, with improvements in HAQ pain and health (CFB: − 33.6 and − 0.7, respectively), Patient and Physician Global Assessments (CFB: − 4.6 and − 5.7, respectively), and joint involvement (CFB: − 5.6, − 8.4, − 6.0 tender, swollen, tophi-affected joints, respectively). Two patients underwent dual-energy computed tomography, showing concomitant monosodium urate volume reductions. All patients had ≥ 1 AE, with 92.9% experiencing acute flare. One mild IR (“cough”) occurred and no new safety signals were identified.
Conclusion
Pegloticase + methotrexate co-therapy resulted in sustained SU-lowering with meaningful improvements in clinical measures, urate burden, and patient-reported outcomes.
Trial registration
ClinicalTrials.gov (NCT03635957)
Introduction:
Kidney transplant (KT) recipients have a high prevalence and severity of gout. Pegloticase (pegylated recombinant uricase) rapidly metabolizes serum uric acid (sUA), and its efficacy is not impacted by kidney function.
Methods:
This open-label, Phase 4 trial (PROTECT NCT04087720) examined safety and efficacy of pegloticase in 20 participants with KT > 1 year prior to enrollment and with uncontrolled gout (sUA ≥7 mg/dL, intolerance/inefficacy to urate lowering therapy, and ≥1 of the following: tophi, chronic gouty arthritis, ≥2 flares in past year) and functioning KT (estimated glomerular filtration rate [eGFR] ≥15 mL/min/1.73 m2 ) on stable immunosuppression therapy.
Results:
The primary endpoint was sUA response during month 6 (sUA < 6 mg/dL for ≥80% of time). The study enrolled 20 participants (mean ± SD); age: 53.9 ± 10.9 years, time since KT: 14.7 ± 6.9 years, sUA: 9.4 ± 1.5 mg/dL, gout duration: 8.4 ± 11.6 years; all on ≥2 stable doses of immunosuppression agents. Pegloticase (8 mg intravenous every 2 weeks) in KT recipients with uncontrolled gout showed a high response rate of 89% (16/18 responders). Two participants discontinued treatment solely due to COVID-19 concerns prior to month 6 were not included in the primary analysis. Pegloticase exposures were higher than those historically observed with pegloticase monotherapy, and no anaphylaxis or infusion reaction events occurred during the study.
Conclusions:
This improved response rate to pegloticase in the KT population reflects observations from other trials and reports on immunomodulation with pegloticase. As the KT population has a high prevalence of gout and limitations with oral urate lowering medication options, these findings suggest a potential option for uncontrolled gout therapy in KT participants.
