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FRI0372 Pharmacokinetics and immunogenicity of pegloticase (PL) infused every 3 weeks to treat refractory gout (RG), including in organ transplant recipients (TR)
  1. M.S. Hershfield1,
  2. N.J. Ganson2,
  3. S.J. Kelly2,
  4. E.L. Scarlett2,
  5. D.A. Jaggers2,
  6. J.S. Sundy2
  1. 1Medicine and Biochemistry
  2. 2Medicine, Duke University School of Medicine, Durham, United States

Abstract

Background PL is approved for treating RG at 8 mg IV every 2 wks. Phase 1 testing suggested that 8 mg IV every 3 wks might also be effective. We have evaluated this dose in an open-label trial (Duke-3), which included some TR, an important RG subset excluded from previous trials.

Objectives 1) Assess PK of every 3 wk PL, and ability to maintain plasma urate concentration (PUA) <6 mg/dL. 2) Characterize the Ab response to PL, including epitope specificity and relationship to loss of efficacy and AE; 3) Compare immunogenicity and efficacy in TR vs NT RG patients.

Methods Duke-3 was conducted under investigator IND#11274 sponsored by the USFDA in 27 PL-naïve RG patients, including 20 NT and 7 TR (3 NT patients treated in earlier trials and known to be PL Ab+ are excluded from analysis). Prednisone (20 mg) + fexofenadine (60 mg) were given the night before, and fexofenadine + hydrocortisone (200 mg IV) the morning of each infusion. Plasma uricase activity was monitored by radiochemical-HPLC, and PUA by HPLC, before and 2 h after each infusion, then weekly through d21 after the last infusion. Following d2 after infusion #1, loss of efficacy was indicated by return of PUA to ≥6 mg/dL. Screening for IgG Ab to PL was by ELISA; specificity for uricase protein vs PEG was assessed, respectively, by the ability of un-PEGylated recombinant porcine uricase vs 10 kDa PEG to inhibit the screening ELISA. All methods were validated using USFDA guidelines. In patients completing 5 infusions, all PUA values between d2 after infusion #1 through d21 after infusion #5 were averaged; mean PUA <6 mg/dL indicated a sustained response.

Results In 26/27 patients, PUA fell from 10.8±1.3 mg/dL pretreatment, to ≤1 mg/dL by 48 h after infusion #1; one patient experienced an AE and did not complete infusion #1. Including the latter, 10/27 (37%) patients failed to maintain PUA <6 mg/dL, including 9/20 (45%) NT and 1/7 (14%) TR; all 10 developed IgG Ab to PL that was specific for PEG, not uricase protein, and caused rapid clearance of uricase activity from plasma. Titers ranged from ∼1:100 to >1:10,000. Of interest, anti-PEG Ab was detectable in 5 of these 10 patients prior to treatment, and increased after exposure to PL. 21 patients, including 5 TR, completed all 5 infusions; 6 patients including 2 TR did not complete due to AE (details presented in a related abstract) and 5 of these 6 (4 NT, 1 TR) were anti-PEG Ab+. Among the 21 who completed, efficacy was sustained in 16 (including 4 TR), who did not develop significant anti-PEG Ab; their PUA averaged 0.9±0.5 mg/dL over the 15-wk study period. In the other 5 completers, who were anti-PEG Ab+, PUA averaged 6.6±2.1 mg/dL. PK (mean AUC and Cmax for plasma uricase activity) in the 16 completers with sustained efficacy was similar to results obtained for an 8 mg dose of PL in phase 1 testing.

Conclusions This short-term study indicates favorable PK and efficacy with 8 mg PL infused at 3 wk intervals. Detection of anti-PEG Ab prior to treatment predicted increased risk for loss of efficacy and AE. Chronic immunosuppression to prevent graft rejection may protect organ transplant recipients from developing anti-PEG Ab. Testing for anti-PEG Ab may be used to guide trials of immunosuppressive strategies to enhance the therapeutic profile of PL.

Disclosure of Interest M. Hershfield Consultant for: Savient Pharmaceuticals, N. Ganson: None Declared, S. Kelly: None Declared, E. Scarlett: None Declared, D. Jaggers: None Declared, J. Sundy Consultant for: Savient Pharmaceuticals

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