teaser
Pegloticase is a PEGylated uricase enzyme recently approved by the European Medicines Agency, and a new innovation for the treatment of severe debilitating tophaceous gout
Mark Reinders PharmD PhD
Department of Clinical Pharmacy,
Atrium Medisch Centrum Parkstad,
Heerlen, The Netherlands
Email: [email protected]
Gout is one of the most common inflammatory manifestations of arthritis with a prevalence of approximately 2% in Western countries. Gout is the collective name for several clinical disorders that are characterised by dysmetabolism resulting in the formation and deposition of monosodium urate (MSU) crystals. The condition is associated with recurrent episodes of acute joint pain resulting from the deposition of MSU crystals in the synovial fluid. In addition to these effects observed in the joints, skin or subcutaneous tissues and kidneys may also be affected by tophaceous deposits, cellulitis, urate nephropathy, and/or kidney stones. In most cases, no identifiable underlying cause of gout is present, but metabolic factors, such as reduced renal function, obesity, and the use of diuretics or salicylates, are usually present that may contribute to accumulation of urate (uric acid) in the body. Hyperuricaemia may exist for several years to decades before the first symptoms of gout attacks appear, and therefore, it is a disease associated and correlated with ageing.(1)
Pegloticase (Krystexxa®; Savient Pharmaceuticals Inc), has recently been approved by the European Medicines Agency.(2) It is indicated for the treatment of severe debilitating chronic tophaceous gout in adult patients who may also have erosive joint involvement and who have failed to normalise serum uric acid with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these medicines are contraindicated. The decision to treat with pegloticase should be based on an ongoing assessment of the benefits and risks for the individual patient.
A debilitating condition
Debilitating chronic tophaceous gout is a severe outcome of progressive gout resulting from the intolerance to or refractoriness to available urate-lowering therapy (treatment-failure gout; TFG) to prevent further urate crystal deposition. It is characterised clinically by painful arthritis and chronic arthropathy, destructive tophi, impaired quality of life, and chronic disability. Hyperuricaemia and gout are often accompanied by significant medical comorbidities, including cardiovascular disease, hypertension, hyperlipidaemia, diabetes mellitus, chronic kidney disease and obesity. These associated disorders are especially frequent among patients with chronic tophaceous gout.
The combination of severe gout and a high burden of cardiovascular and metabolic comorbidities, often requiring polypharmacy, makes it exceptionally difficult to manage.1 TFG affects approximately 1% of the overall population of patients with gout. However, the prevalence may decrease with the availability of new (oral) antihyperuricaemic drugs such as febuxostat. The severity of TFG is manifested by frequent acute attacks of disabling arthritis, chronic deforming joint disease, destructive masses of urate crystals (tophi), progressive physical disability, and poor health-related quality of life.
Several case reports describe successful (off-label) use of rasburicase in TFG. However, its use in gout is compromised: first, by the risk of immunological reactions; second, by its short half-life (18 hours) that demands an infusion every one-to-two weeks according to serum urate levels for optimal treatment efficacy; and third, by the lack of clinical experience and a dosing scheme consensus for gout. Terkeltaub has proposed to use uricase-based therapy in severe tophaceous gout as bridging therapy for rapid debulking of urate, whereafter a less rigorous regimen might be sufficient, while maintaining a negative urate balance.(3)
Pharmacology
Pegloticase is administered at a dose of 8mg (of uricase protein) (diluted to 250ml) over 120 minutes by intravenous infusion every two weeks. The active substance is a genetically engineered, recombinant, polyethylene glycol (PEG)-conjugated mammalian (porcine-like) uricase enzyme. It metabolises uric acid into soluble allantoin for excretion by the kidney, with hydrogen peroxide and carbon dioxide as oxidative byproducts. It is PEGylated in order to lengthen the circulating half-life of the enzymatically active uricase moiety and to lessen the immunogenicity in long-term use. Because urate, the substrate of this enzyme, is small in size, it is able to diffuse through a web of polymer molecules to reach active sites.(2,4–6)
Data from phase II trials showed that these patients can be categorised into two groups based upon their serum urate (sUr) values after repeated pegloticase treatment: (i) persistent responders (previously referred to as responders), who had a sustained reduction in sUr; and (ii), transient responders (previously referred to as non-responders), who initially had sUr values below 0.36mmol/l but the values increased over time to above 0.36mmol/l. The second group also had a higher risk to develop infusion reactions (IR) due to antibody formation.(1,4–6)
Clinical efficacy
Two phase III, six-month, randomised, double-blind trials were performed in patients with TFG: Gout Outcome and Urate Therapy (GOUT1 and GOUT2).(7) TFG was defined as follows: ≥three flares in previous 18 months; ≥one tophus, or prevalent gouty arthropathy; sUr ≥0.48mmol/l; and contraindication to, or self-reported failure to, control sUr with maximum medically appropriate dose of allopurinol. In total, 212 subjects received (by randomisation 2:2:1) 8mg of pegloticase (of uricase protein) for every two weeks (n = 85) or every four weeks (n = 84) or received placebo (n = 43). Colchicine or non-steroidal anti-inflammatory drugs were used for gout prophylaxis.
IR prophylaxis consisted of oral fexofenadine and paracetamol and hydrocortisone 200mg intravenously before infusion. The primary efficacy endpoint was the percentage of sUr responders, defined as the subjects with sUr <0.36 mmol/l for ≥ 80% of the time in months three and six. Secondary endpoints assessed treatment effect on tophus size, gout flares, number of swollen and tender joints (TJs), quality of life (SF-36, physical component summary score), and disability (health-related quality of life as determined by the Health Assessment Questionnaire Disability Index (HAQ-DI)). Primary endpoint data are reported as replicate analyses; secondary end point data were pooled for GOUT1 and GOUT2.
Subjects, mean age 55 years, were mostly male (82%) and had high cardiovascular comorbidity rates. Plasma urate response was significantly higher in both pegloticase groups versus placebo group in both studies and ranged from 35–42% versus 0% (Table 1). Complete resolution of ≥ one tophus occurred in 40% of patients treated with pegloticase every two weeks (p = 0.002) and in 21% of four weeks patients (not significant versus placebo) versus 7% in placebo subjects; in 22%, tophus resolution occurred within 13 weeks. SF-36, HAQ-DI, and TJs improved significantly in both pegloticase groups versus the placebo group. Incidence and frequency of gout flare were significantly higher during months one-to-three in both pegloticase groups despite prophylaxis, but were significantly lower during months four-to-six in the every-2-weeks group (41%) versus placebo (67%; p = 0.007).
The most common AEs were flares and IRs. AE discontinuations were mostly due to IRs (19/34). Serious AEs, mostly flares and IRs, occurred in 24% of patients treated every two weeks, 23% of patients treated every four weeks, and 12% of placebo subjects.
In conclusion, 42% and 35% of TFG subjects on pegloticase every two weeks and every four weeks, respectively, achieved the primary efficacy endpoint of sUr control. This was accompanied by significant improvement in clinical outcomes. Subjects who completed the GOUT1 or GOUT2 trial were given the option to enter an open-label extension trial under a separate protocol (GOUT3). Efficacy in reduction of sUr concentration and symptomatic endpoints and safety were reported to be maintained with treatment extending up to three years.(8) Complete resolution of tophi was seen in 87% (32/37) of responders and in 31% (11/36) of non-responders.
Safety and tolerability
Three main areas of concern for safety of pegloticase were identified: (i) a higher rate of serious cardiovascular events; (ii) the occurrence of IRs and allergic reactions; and (iii), immunogenicity of pegloticase with an adverse influence on efficacy and safety (Table 2). Deaths were seen in both study arms, in 4% in the pegloticase arm versus 1% in the placebo arm, but there were no significant statistical differences.
The higher rate of serious cardiovascular events was seen in both pegloticase treatment arms and demonstrated no relation to dosage regimen. The cardiovascular events showed no particular pattern and included arrhythmias, ischaemic events, and congestive heart failure.
A consultation from the FDA Division of Cardiovascular and Renal Drug Products concluded that the distribution of cardiovascular deaths and cardiac severe AEs was not obviously unusual in view of the fact that it occurred in patients predisposed to such events and taking into account the unequal randomisation in the clinical trials.
A higher proportion of patients experienced serious AEs in the pegloticase every-4-week (23%) and pegloticase every-two-week (24%) treatment groups as compared with placebo-treated patients (12%), owing to the high rate of IRs seen in the pegloticase every-four-week (41%) and pegloticase every-two-week (26%) groups. A higher proportion of IRs that were experienced by the patients in the pegloticase every-four-week group (36%) was of moderate-to-severe intensity as compared with the pegloticase every-two-week group (18%). The occurrence of IRs peaked with the administration of dose three or four of pegloticase and declined thereafter.
Pegloticase was shown to be immunogenic, with 88% of patients in the pegloticase every-two-week group and 89% of patients in the pegloticase every-four-week group seroconverting to antibody positivity over the course of these studies. The magnitude of positive antibody titers to pegloticase was associated with a higher rate of IRs and a decrease in urate-lowering effects of therapy. Routine sUr monitoring might be used to prospectively identify patients receiving pegloticase who may no longer benefit from treatment and are at greater risk for IRs.
Because of the formation of hydroxen peroxide by uricase, pegloticase therapy may be complicated in patients with deficiencies of glucose-6-phosphate dehydrogenase or catalase.
In summary, a (better) strategy on prevention of immunologic responses is warranted, for example by prescribing an anti-inflammatory regimen. The same regimen may also be very useful for the prevention of gout flares because of the mobilisation of urate due to the rapid urate metabolism in the circulation by pegloticase.
Conclusions
Pegloticase is a modified enzyme indicated for patients with severe debilitating tophaceous gout, who (apparently) cannot be adequately treated with oral agents. It is an important novel option for this group of patients for dissolution of tophi to prevent further joint complications. Benefits and risks for the individual patient must be assessed. Immunogenic response to pegloticase should be minimised by administration of corticosteroids, and gout flares resulting from urate mobilisation should be prevented by anti-inflammatory therapy.
Key points
- Pegloticase is a polyethylene glycol (PEG)-ylated uricase enzyme, which converts uric acid to allantoin.
- It is approved by the European Medicines Agency for severe debilitating tophaceous gout dosed at 8mg every two weeks.
- Approximately 50% of patients are only transient responders (defined by serum urate <0.36mmol/l) due to antibody formation and they are at higher risk of infusion reactions.
- In complete responders, complete resolution of tophi is seen in 40% after six months and in 87% up to three years’ treatment.
References
- Reinders MK, Jansen T . New advances in the treatment of gout: review of pegloticase. Ther Clin Risk Manag 2010;6:543–50.
- European Medicines Agency. European Public Assessment Report. Krystexxa®. January 2013.
- Terkeltaub R. Learning how and when to employ uricase as bridge therapy in refractory gout. J Rheumatol 2007;34(10):1955–8.
- Sundy JS et al. Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout. Arthritis Rheum 2007;56(3):1021–8. Erratum in: Arthritis Rheum 2007;56(4):1370.
- Sundy JS et al. for Pegloticase Phase 2 Study Investigators. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum 2008;58(9):2882–91.
- Yue CS et al. Population pharmacokinetic and pharmacodynamic analysis of pegloticase in subjects with hyperuricemia and treatment-failure gout. J Clin Pharmacol. 2008;48(6):708–18.
- Sundy JS et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA 2011;306(7):711–20.
- Becker MA et al. Long-term safety of pegloticase in chronic gout refractory to conventional treatment. Ann Rheum Dis 2012; 11 Dec [Epub ahead of print].
- Food and Drug Administration, Center for Drug Evaluation and Research, Division of Anesthesia, Analgesia, and Rheumatology Products. AAC Briefing Document Krystexxa (Pegloticase) 2009. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/UCM165714.pdf (accessed 15 April 2013).
