POS1163 PHARMACOKINETICS OF PEGLOTICASE AND METHOTREXATE POLYGLUTAMATE(S) IN PATIENTS WITH UNCONTROLLED GOUT RECEIVING PEGLOTICASE AND CO-TREATMENT WITH METHOTREXATE

Abstract

BackgroundIn a prior open-label, single-arm trial in adults with uncontrolled gout (MIRROR open-label [OL] trial), methotrexate (MTX) co-treatment with pegloticase suggested improved efficacy of pegloticase by reducing its immunogenicity.1,2 The current randomized, controlled trial (MIRROR RCT) confirmed that pegloticase-MTX co-therapy markedly increased pegloticase response rate (response defined as serum uric acid <6 mg/dL during ≥80% of Month 6) compared to pegloticase-placebo (PBO) co-therapy (71.0% vs. 38.5%) with a decreased infusion reaction rate and no new safety signals reported.ObjectivesTo evaluate systemic exposures of pegloticase and its immunogenicity in uncontrolled gout patients receiving pegloticase with and without MTX as part of the MIRROR RCT; and to determine exposure of methotrexate polyglutamate(s) (MTX-PGs) in uncontrolled gout patients through Month 6 of treatment.MethodsIn MIRROR RCT, MTX (15 mg/wk) or matching PBO was given orally 4 weeks prior to the first pegloticase dose and continued weekly, in combination with pegloticase 8 mg given intravenously every 2 weeks, over a 52-week treatment period. Pre-infusion blood samples were collected to measure MTX polyglutamates (MTX-PGs, including MTX-PG1-5) in red blood cells and pre- and post-infusion serum samples were obtained to measure trough (Cmin) and peak (Cmax) concentrations of pegloticase, respectively, at multiple visits. MTX-PG and pegloticase concentrations were summarized by visit and by treatment group. Pre-infusion serum samples for anti-polyethylene glycol (PEG) antibody (Ab) measurement were also collected at multiple pre-defined time points. Anti-PEG Ab incidence and titer were summarized by visit and by treatment group.ResultsOverall, higher Cmax and Cmin of pegloticase were observed in the pegloticase + MTX group than in the pegloticase + PBO group (Figure 1). At Week 14, median (first quartile [Q1], third quartile [Q3]) Cmin was 1.32 (0.73, 1.74) µg/mL and 0.63 (0.30, 1.28) µg/mL for the pegloticase + MTX and pegloticase + PBO groups, respectively. Median (Q1, Q3) Cmax was 3.01 (1.94, 3.94) µg/mL and 2.66 (1.45, 3.20) µg/mL for the pegloticase + MTX and pegloticase + PBO groups, respectively. Improved pegloticase response was associated with higher pegloticase concentrations. At Week 14, Cmin was below the quantitation limit (0.6 µg/mL) for 8 of 10 non-responders and 1.26 (0.72, 1.71) µg/mL for responders. MTX co-administration reduced the incidence of new anti-PEG antibody formation. The proportion of subjects with an increase from baseline in anti-PEG Ab titers or who were negative at baseline and developed an anti-PEG Ab response at ≥1 post-dose time point during pegloticase treatment was 29.5% and 51.0%, for the pegloticase + MTX and pegloticase + PBO groups, respectively. The pegloticase + MTX group had overall lower titer levels than those in the pegloticase + PBO group. Positive anti-PEG Ab status was associated with a lower pegloticase Cmin. Concentrations of MTX-PGs were maintained during the treatment course in the pegloticase + MTX group, suggesting compliance with MTX administration. There was no apparent difference in concentrations of MTX-PGs (including MTX-PG3, the predominant form of MTX-PGs4) between responders and non-responders. MTX-PG concentrations were in the same range as those reported for low-dose oral MTX use in patients with rheumatoid arthritis,3 suggesting no impact of pegloticase on MTX PK.ConclusionPegloticase 8 mg IV every 2 weeks with MTX co-treatment (oral 15 mg weekly) reduced anti-PEG Ab incidence and resulted in higher pegloticase exposures compared to pegloticase administered with PBO, consistent with the increased clinical efficacy observed with pegloticase + MTX co-administration.References[1]Botson J, et al. J Rheumatol 2021;48:767-74[2]Song Y, et al. Arthritis Rheum 2020;72(suppl 10)[3]Dervieux T, et al. Ann Rheum Dis 2013;72:908-10[4]Choi R. J Pharm Biomed Anal 2021;201:114124Disclosure of InterestsYan Xin Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Yang Song Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Michael E. Weinblatt Consultant of: Horizon Therapeutics, Jason Chamberlain Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Jennifer Zarzoso Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Katie Obermeyer Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Stephen Sainati Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Colleen Canavan Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Srini Ramanathan Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics