Krystexxa (Pegloticase) Efficacy and Clinical Use
Efficacy Profile
Pegloticase demonstrates profound urate-lowering efficacy, achieving serum uric acid levels below 6 mg/dL in 42% of patients treated with 8 mg every 2 weeks for at least 80% of the time during months 3-6, compared to 0% with placebo. 1
Urate-Lowering Effects
- Pegloticase rapidly reduces serum uric acid to below 6 mg/dL within 6 hours of infusion by enzymatically degrading uric acid into allantoin 2, 1
- The 8 mg every 2 weeks regimen achieved response rates of 47% (Trial 1) and 38% (Trial 2) for the primary endpoint of sustained urate lowering 1
- The every 4 weeks regimen showed lower efficacy (20% in Trial 1,49% in Trial 2) and was associated with increased frequency of anaphylaxis and infusion reactions 1
Disease-Modifying Benefits
- Complete resolution of one or more tophi occurred in 45% of patients receiving pegloticase 8 mg every 2 weeks versus 8% with placebo 3, 2
- Significant improvements in chronic arthropathy, tender and swollen joint counts, pain reduction, and health-related quality of life were demonstrated 3, 4
- Pegloticase significantly decreases blood pressure in patients with chronic refractory gout but has no significant effect on renal function 4
Indications and Patient Selection
Pegloticase is reserved exclusively for patients with crystal-proven severe debilitating chronic tophaceous gout and poor quality of life in whom the serum uric acid target cannot be reached with any other available drug at maximal dosage, including combinations. 3, 5, 2
Specific Criteria
- Patients must have failed or be intolerant to appropriately dosed oral urate-lowering therapy (allopurinol, febuxostat, uricosurics, or combinations) 3
- Pegloticase is NOT recommended as first-line urate-lowering therapy for any gout scenario 3, 5
- Patients should have documented crystal-proven gout with severe disease burden (tophi, chronic arthropathy, frequent attacks) 3, 2
Dosing Schedule
The recommended dose is 8 mg administered as an intravenous infusion every 2 weeks. 1
Administration Protocol
- Infuse over no less than 120 minutes via gravity feed, syringe-type pump, or infusion pump 1
- Do NOT administer as an intravenous push or bolus 1
- Discontinue all oral urate-lowering agents (allopurinol, febuxostat, probenecid) before starting pegloticase to avoid masking loss of efficacy 5, 6, 1
Pre-medication Requirements
- All patients must be pre-medicated with antihistamines and corticosteroids before each infusion 1
- Acetaminophen should also be administered 1
- Gout flare prophylaxis with NSAIDs or colchicine should be initiated at least one week before treatment and continued for at least 6 months unless contraindicated 1
Monitoring Recommendations
Measure serum uric acid levels prior to EVERY infusion and consider discontinuing treatment if levels increase above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. 1
Critical Monitoring Strategy
- Rising serum uric acid above 6 mg/dL indicates loss of therapeutic response and dramatically increases the risk of infusion reactions 2, 1, 7
- 91% of all infusion reactions occurred in patients with pre-infusion serum uric acid greater than 6 mg/dL 7
- For patients maintaining pre-infusion serum uric acid below 6 mg/dL, infusion reactions occurred in fewer than 1 per 100 infusions 7
- Post-hoc analysis showed that stopping pegloticase after 2 consecutive uric acid levels greater than 6 mg/dL would reduce infusion reactions by 50% with minimal impact on efficacy 1
Additional Monitoring
- Screen patients at higher risk for G6PD deficiency (African and Mediterranean ancestry) before starting treatment due to risk of hemolysis and methemoglobinemia 1
- Monitor patients closely for an appropriate period after each infusion for signs of anaphylaxis or infusion reactions 1
- Administer only in healthcare settings with providers prepared to manage anaphylaxis 1
Safety Profile and Major Limitations
The major limitation of pegloticase is immunogenicity, with anti-drug antibodies resulting in increased drug clearance, loss of efficacy, and infusion reactions occurring in approximately 25-30% of patients. 6, 4
Infusion Reactions and Anaphylaxis
- Infusion reactions occurred in 45% of patients, with chest discomfort (15%), flushing (12%), and dyspnea (11%) being most common 7
- Most reactions were mild to moderate; 7% were severe 7
- Anaphylaxis can occur with any infusion, including the first, and generally manifests within 2 hours 1
- All reactions resolved with slowing, interrupting, or stopping the infusion; no patient required blood pressure or ventilatory support 7
Other Important Safety Considerations
- Gout flares occur frequently upon initiation (88% of patients in trials) but treatment need not be discontinued 1, 8
- Exercise caution in patients with congestive heart failure; exacerbation occurred in 2% of patients receiving 8 mg every 2 weeks 1, 9
- Pegloticase has not been formally studied in patients with congestive heart failure 1
Treatment Duration
There is no firm consensus on the appropriate duration of pegloticase therapy once symptoms and signs of gout have decreased, including reduction in size or resolution of tophi. 3, 5
- Some experts suggest considering a switch to oral urate-lowering therapy once all tophi have disappeared, if feasible 5
- Patients who completed randomized trials were eligible for a 2-year open-label extension study 1
- Preliminary data suggest long-term treatment may maintain plasma uric acid normalization in sustained responders 9