Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients
Michael S Hershfield, Nancy J Ganson, Susan J Kelly, Edna L Scarlett, Denise A Jaggers, John S Sundy, Michael S Hershfield, Nancy J Ganson, Susan J Kelly, Edna L Scarlett, Denise A Jaggers, John S Sundy
Abstract
Introduction: Pegloticase, a PEGylated recombinant porcine uricase, is approved for treating refractory gout at a dose of 8 mg intravenous (IV) every 2 weeks. However, during phase 1 testing, pharmacokinetics supported less frequent dosing. Also, single doses of pegloticase unexpectedly induced antibodies (Ab) that bound to polyethylene glycol (PEG). We have conducted a phase 2 trial to evaluate every 3-week dosing, and to further define the Ab response to pegloticase. Organ transplant recipients were included, as they are prone to severe gout that is difficult to manage, and because treatment to prevent graft rejection might influence the immune response to pegloticase.
Methods: Plasma uricase activity (pUox), urate concentration (pUA), and clinical response were monitored during up to 5 infusions in 30 patients, including 7 organ transplant recipients. Depending on whether pUA <6 mg/dL was achieved and maintained, patients were classified as non (NR), persistent (PR), or transient (TR) responders. Ab to pegloticase and 10 kDa mPEG were monitored by enzyme linked immunosorbent assay and specificity was further defined.
Results: We observed 17 PR, 12 TR, and 1 NR; 21 patients (16 PR, 5 TR) received all 5 infusions. Over the 15-week trial, pUA in PR averaged 1.0 ± 0.4 mg/dL; T½ for pUox was approximately 13 days, and area under the curve after dose 5 was approximately 30% higher than after dose 1. PR showed clinical benefit and in some, tophi resolved. In 11 of 12 TR, pUox fell rapidly and hyperuricemia recurred before dose 2. In all TR and NR, loss of response to pegloticase was accompanied by Ab to PEG, which was pre-existing in half of those who had no prior exposure to pegloticase. No PR, and 1 one out of 7 organ transplant recipients, had a sustained Ab response to pegloticase.
Conclusions: Every 3-week dosing is effective and may enhance the utility of pegloticase for treating refractory gout. Ab to PEG, which were pre-existing or induced by treatment, caused rapid loss of efficacy and increased the risk of infusion reactions. Organ transplant recipients can benefit from pegloticase, and may be less prone than non-recipients to developing anti-PEG Ab. Investigation of immunosuppressive strategies to minimize anti-PEG Ab is warranted.
Trial registration: ClincalTrials.gov identifier: NCT00111657.
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References
- Becker MA, Schumacher HR, Benjamin KL, Gorevic P, Greenwald M, Fessel J, Edwards L, Kawata AK, Frank L, Waltrip R, Huang B, Sundy JS. Gout Natural History Study Group. Quality of life and disability in patients with treatment-failure gout. J Rheumatol. 2009;36:1041–1048. doi: 10.3899/jrheum.071229.
- Chao J, Terkeltaub R. A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. Curr Rheumatol Rep. 2009;11:135–140. doi: 10.1007/s11926-009-0019-z.
- Sarawate CA, Brewer KK, Yang W, Patel PA, Schumacher HR, Saag KG, Bakst AW. Gout medication treatment patterns and adherence to standards of care from a managed care perspective. Mayo Clin Proc. 2006;81:925–934. doi: 10.4065/81.7.925.
- Sundy JS, Baraf HS, Yood RA, Edwards NL, Gutierrez-Urena SR, Treadwell EL, Vazquez-Mellado J, White WB, Lipsky PE, Horowitz Z, Huang W, Maroli AN, Waltrip RW 2nd, Hamburger SA, Becker MA. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306:711–720.
- Krystexxa Prescribing Information. NDC#54396-801-01. .
- Sundy JS, Ganson NJ, Kelly SJ, Scarlett E, Rehrig CD, Huang W, Hershfield MS. Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout. Arthritis Rheum. 2007;56:1021–1028. doi: 10.1002/art.22403.
- Hershfield MS, Roberts LJ 2nd, Ganson NJ, Kelly SJ, Santisteban I, Scarlett E, Jaggers D, Sundy JS. Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo. Proc Natl Acad Sci U S A. 2010;107:14351–14356. doi: 10.1073/pnas.1001072107.
- Ganson NJ, Kelly SJ, Scarlett E, Sundy JS, Hershfield MS. Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. Arthritis Res Ther. 2006;8:R12. doi: 10.1186/ar1861.
- Harris JM, Chess RB. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov. 2003;2:214–221. doi: 10.1038/nrd1033.
- McDonnell T, Ioannou Y, Rahman A. PEGylated drugs in rheumatology – why develop them and do they work? Rheumatology (Oxford) 2014;53:391–396. doi: 10.1093/rheumatology/ket278.
- Schellekens H, Hennink WE, Brinks V. The immunogenicity of polyethylene glycol: facts and fiction. Pharm Res. 2013;30:1729–1734. doi: 10.1007/s11095-013-1067-7.
- Stamp L, Searle M, O'Donnell J, Chapman P. Gout in solid organ transplantation: a challenging clinical problem. Drugs. 2005;65:2593–2611. doi: 10.2165/00003495-200565180-00004.
- Sundy JS, Becker MA, Baraf HS, Barkuizen A, Moreland LW, Huang W, Waltrip RW 2nd, Maroli AN, Horowitz Z. 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. Arthritis Rheum. 2008;58:2882–2891. doi: 10.1002/art.23810.
- Yue CS, Huang W, Alton M, Maroli AN, Waltrip RW, Wright D, Marco MD. Population pharmacokinetic and pharmacodynamic analysis of pegloticase in subjects with hyperuricemia and treatment-failure gout. J Clin Pharmacol. 2008;48:708–718. doi: 10.1177/0091270008317589.
- Becker MA, Baraf HS, Yood RA, Dillon A, Vazquez-Mellado J, Ottery FD, Khanna D, Sundy JS. Long-term safety of pegloticase in chronic gout refractory to conventional treatment. Ann Rheum Dis. 2013;72:1469–1474. doi: 10.1136/annrheumdis-2012-201795.
- Sherman MR, Williams LD, Sobczyk MA, Michaels SJ, Saifer MG. Role of the methoxy group in immune responses to mPEG-protein conjugates. Bioconjug Chem. 2012;23:485–499. doi: 10.1021/bc200551b.
- Choi HK, Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation. 2007;116:894–900. doi: 10.1161/CIRCULATIONAHA.107.703389.
- Krishnan E, Svendsen K, Neaton JD, Grandits G, Kuller LH. Long-term cardiovascular mortality among middle-aged men with gout. Arch Intern Med. 2008;168:1104–1110. doi: 10.1001/archinte.168.10.1104.
- Stack AG, Hanley A, Casserly LF, Cronin CJ, Abdalla AA, Kiernan TJ, Murthy BV, Hegarty A, Hannigan A, Nguyen HT. Independent and conjoint associations of gout and hyperuricaemia with total and cardiovascular mortality. QJM. 2013;106:647–658. doi: 10.1093/qjmed/hct083.
- Strasak A, Ruttmann E, Brant L, Kelleher C, Klenk J, Concin H, Diem G, Pfeiffer K, Ulmer H. Serum uric acid and risk of cardiovascular mortality: a prospective long-term study of 83,683 Austrian men. Clin Chem. 2008;54:273–284. doi: 10.1373/clinchem.2007.094425.
- Strasak AM, Kelleher CC, Brant LJ, Rapp K, Ruttmann E, Concin H, Diem G, Pfeiffer KP, Ulmer H. Serum uric acid is an independent predictor for all major forms of cardiovascular death in 28,613 elderly women: a prospective 21-year follow-up study. Int J Cardiol. 2008;125:232–239. doi: 10.1016/j.ijcard.2007.11.094.
- Perez-Ruiz F, Martínez-Indart L, Carmona L, Herrero-Beites AM, Pijoan JI, Krishnan E. Tophaceous gout and high level of hyperuricaemia are both associated with increased risk of mortality in patients with gout. Ann Rheum Dis. 2013;73:177–182.
Source: PubMed