Table Info

Table 1.

Uricases approved and in development [23–31]

Uricase	Origin	Approval	Indication	Efficacy with immunomodulation	Anaphylaxis	Half-life	IV administration	PEGylated	Ref.
Rasburicase	Recombinant Aspergillus uricase	FDA, EMA	Tumor lysis syndrome	NA	6.2%	21 h	0.2 mg/kg daily for up to 5–7 days	No	[23, 24]
Pegloticase	Porcine and baboon uricase	FDA	Uncontrolled gout	83%	3% (active treatment groups)	6–14 days	8 mg every 2 weeks	Yes	[25, 26]
SEL-212	Candida utilis	Completed Phase III Submitted to FDA	Uncontrolled gout	High-dose group in 2 Phase III studies 56% and 46%	3.4% (n = 4 anaphylaxis, n = 2 flares)	3 days	0.2 mg/kg monthly	Yes	[27–30]
PRX	Recombinant plant-derived uricase	Phase I	Uncontrolled gout	TBD	TBD	TBD	Dosing TBD	Yes	[31]

NA: not available; TBD: to be determined

Declarations

Author contributions

NS and DK: Writing—original draft, Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

Naomi Schlesinger who is the Associate Editor of Exploration of Musculoskeletal Diseases had no involvement in the decision-making or the review process of this manuscript.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Kippen I, Klinenberg JR, Weinberger A, Wilcox WR. Factors affecting urate solubility in vitro. Ann Rheum Dis. 1974;33:313–7. [DOI] [PubMed] [PMC]

Schlesinger N, Pérez-Ruiz F, Lioté F. Mechanisms and rationale for uricase use in patients with gout. Nat Rev Rheumatol. 2023;19:640–9. [DOI] [PubMed]

Sherman MR, Saifer MGP, Perez-Ruiz F. PEG-uricase in the management of treatment-resistant gout and hyperuricemia. Adv Drug Deliv Rev. 2008;60:59–68. [DOI] [PubMed]

Sundy JS, Baraf HSB, Yood RA, Edwards NL, Gutierrez-Urena SR, Treadwell EL, 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;306:711–20. [DOI] [PubMed]

Johnson RJ, Titte S, Cade JR, Rideout BA, Oliver WJ. Uric acid, evolution and primitive cultures. Semin Nephrol. 2005;25:3–8. [DOI] [PubMed]

Álvarez-Lario B, Macarrón-Vicente J. Uric acid and evolution. Rheumatology (Oxford). 2010;49:2010–5. [DOI] [PubMed]

Kratzer JT, Lanaspa MA, Murphy MN, Cicerchi C, Graves CL, Tipton PA, et al. Evolutionary history and metabolic insights of ancient mammalian uricases. Proc Natl Acad Sci U S A. 2014;111:3763–8. [DOI] [PubMed] [PMC]

Li Z, Hoshino Y, Tran L, Gaucher EA. Phylogenetic Articulation of Uric Acid Evolution in Mammals and How It Informs a Therapeutic Uricase. Mol Biol Evol. 2022;39:msab312. [DOI] [PubMed] [PMC]

Colloc’h N, el Hajji M, Bachet B, L’Hermite G, Schiltz M, Prangé T, et al. Crystal structure of the protein drug urate oxidase-inhibitor complex at 2.05 A resolution. Nat Struct Biol. 1997;4:947–52. [DOI] [PubMed]

10.

Conley TG, Priest DG. Thermodynamics and stoicheiometry of the binding of substrate analogues to uricase. Biochem J. 1980;187:727–32. [DOI] [PubMed] [PMC]

11.

Nyborg AC, Ward C, Zacco A, Chacko B, Grinberg L, Geoghegan JC, et al. A Therapeutic Uricase with Reduced Immunogenicity Risk and Improved Development Properties. PLoS One. 2016;11:e0167935. [DOI] [PubMed] [PMC]

12.

Fishburn CS. The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics. J Pharm Sci. 2008;97:4167–83. [DOI] [PubMed]

13.

Ginn C, Khalili H, Lever R, Brocchini S. PEGylation and its impact on the design of new protein-based medicines. Future Med Chem. 2014;6:1829–46. [DOI] [PubMed]

14.

Isaac AH, Phillips SYR, Ruben E, Estes M, Rajavel V, Baig T, et al. Impact of PEG sensitization on the efficacy of PEG hydrogel-mediated tissue engineering. Nat Commun. 2024;15:3283. [DOI] [PubMed] [PMC]

15.

Garay RP, El-Gewely R, Armstrong JK, Garratty G, Richette P. Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. Expert Opin Drug Deliv. 2012;9:1319–23. [DOI] [PubMed]

16.

Calabrese LH, Kavanaugh A, Yeo AE, Lipsky PE. Frequency, distribution and immunologic nature of infusion reactions in subjects receiving pegloticase for chronic refractory gout. Arthritis Res Ther. 2017;19:191. [DOI] [PubMed] [PMC]

17.

Hershfield MS, Ganson NJ, Kelly SJ, Scarlett EL, Jaggers DA, Sundy JS. 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. Arthritis Res Ther. 2014;16:R63. [DOI] [PubMed] [PMC]

18.

Chang C, Chen C, Chen B, Su Y, Chen Y, Hershfield MS, et al. A genome-wide association study identifies a novel susceptibility locus for the immunogenicity of polyethylene glycol. Nat Commun. 2017;8:522. [DOI] [PubMed] [PMC]

19.

Mohamed M, Lila ASA, Shimizu T, Alaaeldin E, Hussein A, Sarhan HA, et al. PEGylated liposomes: immunological responses. Sci Technol Adv Mater. 2019;20:710–24. [DOI] [PubMed] [PMC]

20.

Lila ASA, Kiwada H, Ishida T. The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage. J Control Release. 2013;172:38–47. [DOI] [PubMed]

21.

Browning LA, Kruse JA. Hemolysis and methemoglobinemia secondary to rasburicase administration. Ann Pharmacother. 2005;39:1932–5. [DOI] [PubMed]

22.

Garcia AA, Koperniku A, Ferreira JCB, Mochly-Rosen D. Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives. Trends Pharmacol Sci. 2021;42:829–44. [DOI] [PubMed] [PMC]

23.

Fasturtec [Internet]. Amsterdam: European Medicines Agency; c1995–2024 [cited 2024 Jul 16]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/fasturtec

24.

ELITEK™ [Internet]. New York: Sanofi-Synthelabo Inc; c2002, 2004 [cited 2024 Jul 16]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/103946_5017lbl.pdf

25.

KRYSTEXXA™ (pegloticase) [Internet]. East Brunswick: Savient Pharmaceuticals, Inc; c2010 [cited 2024 Jul 16]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125293s0000lbl.pdf

26.

Krystexxa [Internet]. Amsterdam: European Medicines Agency; c1995–2024 [cited 2024 Jul 16]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/krystexxa

27.

Baraf HSB, Khanna PP, Kivitz AJ, Strand V, Choi HK, Terkeltaub R, et al. The COMPARE head-to-head, randomized controlled trial of SEL-212 (pegadricase plus rapamycin-containing nanoparticle, ImmTOR™) versus pegloticase for refractory gout. Rheumatology (Oxford). 2024;63:1058–67. [DOI] [PubMed] [PMC]

28.

Baraf HSB, Kivitz A, Rhodes S, Leung S, Folarin O, Gonzalez-Rivera T, et al. Safety & efficacy of sel-212 in patients with gout refractory to coventional treatment: outcomes from two randomized, double blind, placebo-controlled, multicenter phase III studies. Ann Rheum Dis. 2024;82:200–1. [DOI]

29.

Baraf HSB, Khanna P, Patel A, Singhal A, Sobierska J, Santin-Janin H, et al. Once-Monthly Sel-212 Demonstrates Efficacy And Safety For Up To 6-Months In Gout Refractory To Conventional Therapy: Combined Data From The Dissolve I & II Phase 3, Double-Blind, Placebo-Controlled Clinical Trials. Ann Rheum Dis. 2024;83:408–9. [DOI]

30.

Kivitz A, Singhal A, Patel A, Ayesu K, Sobierska J, Santin-Janin H, et al. Long-Term Improvements In Serum Uric Acid Levels, Gout Symptoms, And Safety Up To 12-Months With Sel-212 In Gout Refractory To Conventional Therapy: Results From The Dissolve I Phase 3, Double-Blind, Placebo-Controlled Clinical Trial. Ann Rheum Dis. 2024;83:405–6. [DOI]

31.

Atsmon J, Brill-Almon E, Nadri-Shay C, Chertkoff R, Alon S, Shaikevich D, et al. Preclinical and first-in-human evaluation of PRX-105, a PEGylated, plant-derived, recombinant human acetylcholinesterase-R. Toxicol Appl Pharmacol. 2015;287:202–9. [DOI] [PubMed]

32.

Allen KC, Champlain AH, Cotliar JA, Belknap SM, West DP, Mehta J, et al. Risk of anaphylaxis with repeated courses of rasburicase: a Research on Adverse Drug Events and Reports (RADAR) project. Drug Saf. 2015;38:183–7. [DOI] [PubMed] [PMC]

33.

Richette P, Briere C, Hoenen-Clavert V, Loeuille D, Bardin T. Rasburicase for tophaceous gout not treatable with allopurinol: an exploratory study. J Rheumatol. 2007;34:2093–8. [PubMed]

34.

Schlesinger N, Yasothan U, Kirkpatrick P. Pegloticase. Nat Rev Drug Discov. 2011;10:17–8. [DOI] [PubMed]

35.

FitzGerald JD, Dalbeth N, Mikuls T, Brignardello-Petersen R, Guyatt G, Abeles AM, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020;72:744–60. [DOI] [PubMed] [PMC]

36.

Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castañeda-Sanabria J, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76:29–42. [DOI] [PubMed]

37.

Lipsky PE, Calabrese LH, Kavanaugh A, Sundy JS, Wright D, Wolfson M, et al. Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic gout. Arthritis Res Ther. 2014;16:R60. [DOI] [PubMed] [PMC]

38.

Botson JK, Baraf HSB, Keenan RT, Albert J, Masri KR, Peterson J, et al. Expert Opinion on Pegloticase with Concomitant Immunomodulatory Therapy in the Treatment of Uncontrolled Gout to Improve Efficacy, Safety, and Durability of Response. Curr Rheumatol Rep. 2022;24:12–9. [DOI] [PubMed] [PMC]

39.

Botson JK, Tesser JRP, Bennett R, Kenney HM, Peloso PM, Obermeyer K, et al. Pegloticase in Combination With Methotrexate in Patients With Uncontrolled Gout: A Multicenter, Open-label Study (MIRROR). J Rheumatol. 2021;48:767–74. [DOI] [PubMed]

40.

Keenan RT, Botson JK, Masri KR, Padnick-Silver L, LaMoreaux B, Albert JA, et al. The effect of immunomodulators on the efficacy and tolerability of pegloticase: a systematic review. Semin Arthritis Rheum. 2021;51:347–52. [DOI] [PubMed]

41.

Khanna PP, Khanna D, Cutter G, Foster J, Melnick J, Jaafar S, et al. Reducing Immunogenicity of Pegloticase With Concomitant Use of Mycophenolate Mofetil in Patients With Refractory Gout: A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol. 2021;73:1523–32. [DOI] [PubMed] [PMC]

42.

Lamoreaux B, Francis-Sedlak M, Svensson K, Holt R. Immunomodulation co-therapy with peglticase: database trends 2014–2019. Ann Rheum Dis. 2020;79:108. [DOI]

43.

Masri KR, Padnick-Silver L, Winterling K, LaMoreaux B. Effect of Leflunomide on Pegloticase Response Rate in Patients with Uncontrolled Gout: A Retrospective Study. Rheumatol Ther. 2022;9:555–63. [DOI] [PubMed] [PMC]

44.

Rainey H, Baraf HSB, Yeo A, Lipsky P. Companion immunosuppression with azathioprine increases the frequency of persistent responsiveness to pegloticase in patients with chronic refractory gout. Ann Rheum Dis. 2020;79:442–3. [DOI]

45.

KRYSTEXXA® (pegloticase) is now approved to be given with methotrexate [Internet]. Chicago: Horizon Therapeutics plc. c2022 [cited 2024 Sep 18]. Available from: https://www.krystexxa.com/krystexxa-methotrexate/

46.

Kishimoto TK. Development of ImmTOR Tolerogenic Nanoparticles for the Mitigation of Anti-drug Antibodies. Front Immunol. 2020;11:969. [DOI] [PubMed] [PMC]

47.

Kivitz A, DeHaan W, Azeem R, Park J, Rhodes S, Inshaw J, et al. Phase 2 Dose-Finding Study in Patients with Gout Using SEL-212, a Novel PEGylated Uricase (SEL-037) Combined with Tolerogenic Nanoparticles (SEL-110). Rheumatol Ther. 2023;10:825–47. [DOI] [PubMed] [PMC]

48.

Botson JK, Saag K, Peterson J, Obermeyer K, Xin Y, LaMoreaux B, et al. A Randomized, Double-Blind, Placebo-Controlled Multicenter Efficacy and Safety Study of Methotrexate to Increase Response Rates in Patients With Uncontrolled Gout Receiving Pegloticase: 12-Month Findings. ACR Open Rheumatol. 2023;5:407–18. [DOI] [PubMed] [PMC]

49.

Hanania U, Ariel T, Tekoah Y, Fux L, Sheva M, Gubbay Y, et al. Establishment of a tobacco BY2 cell line devoid of plant-specific xylose and fucose as a platform for the production of biotherapeutic proteins. Plant Biotechnol J. 2017;15:1120–9. [DOI] [PubMed] [PMC]

50.

Schlesinger N, Lipsky PE. Pegloticase treatment of chronic refractory gout: Update on efficacy and safety. Semin Arthritis Rheum. 2020;50:S31–8. [DOI] [PubMed]

51.

Becker MA, Baraf HSB, Yood RA, Dillon A, Vázquez-Mellado J, Ottery FD, et al. Long-term safety of pegloticase in chronic gout refractory to conventional treatment. Ann Rheum Dis. 2013;72:1469–74. [DOI] [PubMed] [PMC]

52.

Schlesinger N. Treatment of chronic gouty arthritis: it is not just about urate-lowering therapy. Semin Arthritis Rheum. 2012;42:155–65. [DOI] [PubMed]

53.

Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41. [DOI] [PubMed]

54.

Schlesinger N, Mysler E, Lin H, Meulemeester MD, Rovensky J, Arulmani U, et al. Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study. Ann Rheum Dis. 2011;70:1264–71. [DOI] [PubMed] [PMC]

55.

Botson J, Peterson J. POS0277 Canakinumab Prophylaxis Without Corticosteroids, Prevented Flares In Patients Initiating Pegloticase With Methotrexate For Uncontrolled Gout: A Prospective, Multicenter, Open Label, Proof-Of-Concept, Phase IV, Clinical Trial. Ann Rheum Dis. 2024;83:410–1. [DOI]