Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Pegloticase is a recombinant modified mammalian uricase conjugated to mPEG which was approved in the US in 2010 for treating hyperuricemia in patients with refractory chronic gout. The pegloticase development program comprised 2 randomized, placebo-controlled trials (6 months; N=212) followed by an open-label extension study for a total treatment duration of up to 3 years. Trial entry was preceded by a 1 week washout period for urate-lowering therapies. Patients were considered “responders” if they met the primary efficacy endpoint of uric acid (UA) <6 mg/dL for 80% of time during months 3 and 6. 42% of patients met this definition (vs. 0% with placebo; p<0.001) in the randomized trials1.
Post-hoc analyses revealed a significant relationship between a loss of urate-lowering response to therapy and the presence of high titer anti-pegloticase antibodies. Loss of response was also associated with increased risk of infusion reactions (IRs). Further analyses confirmed that the great majority of IRs occurred in patients who had already lost their urate-lowering response to therapy (20/22 or 91% for patients receiving pegloticase 8 mg q2wks and 24/34 or 71% for patients treated q4wks). These two findings led to clear guidance that patients treated with pegloticase should discontinue treatment if UA levels rose above 6 mg/dL (particularly with 2 consecutive levels >6 mg/dL). New information provided by post-marketing pharmacovigilance suggests a relationship between serum UA levels <6 mg/dL, IRs and concomitant use of xanthine oxidase inhibitors (XOIs).
Methods: Post-marketing AE data were collected as standard, unsolicited reporting and summarized from September 14, 2010 to November 30, 2011 to evaluate concomitant XOI use.
Results: During approximately one year of commercial pegloticase use in the US, IRs were reported in 20 patients and anaphylaxis in 8 patients. Among the reports of IRs, 8 patients had UA >6, 7 had UA <6 and UA was unknown at the time of the IR in 5. Among the reports of anaphylaxis, 4 patients had UA levels >6, 2 had UA levels <6 and 2 had unknown UA. Importantly, AE reporting revealed that 40% of patients (8/20 IRs and 3/8 cases recorded as anaphylaxis) were receiving one or both XOIs in addition to pegloticase. Details of these 11 patients are provided in the table.
Conclusion: Post-marketing adverse event reporting provided valuable information regarding pegloticase administration in the real world setting. Importantly, the use of concomitant urate-lowering therapies has the potential to mask the rise of UA levels in patients treated with pegloticase and confound the use of UA as a biomarker of response. XOIs should be discontinued prior to initiation of pegloticase and not restarted while on treatment. Further, UA monitoring and discontinuation of pegloticase upon loss of efficacy are critical to safe and effective care.
1. Sundy et al. JAMA 2011;306:711-20.
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Patients with infusion reactions receiving concomitant XOIs
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ID
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SUA on XOI
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Infusion #
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Previous SUA
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Demographic
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Patient A |
8.2 mg/dL on febuxostat |
3rd |
Previous infusion 5-6 mg/dL range |
Caucasian male, unspecified age |
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Patient B |
3.4 mg/dL on febuxostat |
2nd |
4.1 mg/dL at baseline on febuxostat |
87 year old (yo) white male |
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Patient C |
9.5 mg/dL on febuxostat |
3rd |
Previous 4.5 mg/dL prior to 2nd infusion |
49 yo Caucasian male |
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Patient D |
undetectable on febuxostat |
3rd |
Previous very low (unspecified) |
57 yo Caucasian male |
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Patient E |
8.6 mg/dL on allopurinol |
4th |
Previous 5.2 mg/dL prior to 3rd infusion |
55 yo Caucasian male |
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Patient F |
6.8 mg/dL on allopurinol |
3rd |
Previous 1.3 prior to 2nd infusion |
31 yo male, of unknown origin |
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Patient G |
5.5 mg/dL on both XOIs |
3rd or 4th
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Previous 5.3 mg/dL |
38 yo Caucasian male |
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Patient H |
7.4 mg/dL on both XOIs |
3rd |
Previous 4.6 mg/dL prior to 2nd infusion |
42 yo African-American male |
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Patients with anaphylaxis receiving concomitant XOIs
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ID
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SUA on XOI
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Infusion #
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Previous SUA
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Demographic
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Patient I
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6.7 mg/dL on allopurinol |
3rd |
Previous 7.6 mg/dL but had missed appt |
58 yo white male |
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Patient J |
4.3 mg/dL on allopurinol |
2nd |
Previous 4.3 mg/dL prior to 2nd |
60 yo white male |
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Patient K |
7.1 mg/dL on febuxostat |
3rd |
Previous <0.5 prior to ?2nd infusion |
47 yo white male |
Disclosure:
K. M. Bahrt,
Savient Pharmaceuticals, Inc.,
1,
Savient Pharmaceuticals, Inc.,
3;
A. E. Yeo,
Savient Pharmaceuticals, Inc.,
1,
Savient Pharmaceuticals, Inc.,
3;
T. L. Howson,
Savient Pharmaceuticals, Inc.,
1,
Savient Pharmaceuticals, Inc.,
3;
F. D. Ottery,
Savient Pharmaceuticals, Inc.,
3,
Savient Pharmaceuticals, Inc.,
1.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/post-marketing-safety-surveillance-data-reveals-patterns-of-use-for-pegloticase-in-refractory-chronic-gout/