POS1136\u2005PHARMACOKINETICS OF PEGLOTICASE AND METHOTREXATE POLYGLUTAMATE(S) IN PATIENTS WITH UNCONTROLLED GOUT RECEIVING PEGLOTICASE AND CO-TREATMENT OF METHOTREXATE

Abstract

In an open-label, single-arm trial in adult patients with uncontrolled gout (MIRROR open-label [OL] trial) evaluating pegloticase co-treatment with methotrexate (MTX); 78.6% patients were responders, defined as maintenance of serum uric acid <6\u2009mg/dL for at least 80% of the time during month 6 [weeks 20, 22, and 24]. In comparison, 42% patients achieved a response during month 3 and 6 in historical Phase 3 monotherapy trials of pegloticase (C0405 and C0406)1. MTX co-treatment is shown to improve the pharmacokinetics (PK) of biologics by attenuating the formation of anti-drug antibodies2.To determine the systemic exposures of pegloticase and methotrexate polyglutamate(s) (MTX-PGs) in uncontrolled gout patients receiving pegloticase and MTX; to evaluate the effect of MTX on the PK of pegloticase in comparison to historical pegloticase monotherapy trials (C0405 and C0406)3, 4; and to evaluate the immunogenicity of pegloticase in co-treatment with MTX.In the MIRROR OL trial, MTX (15\u2009mg/week) was given orally 4 weeks prior to the first pegloticase dose and continued weekly, in combination with pegloticase 8\u2009mg given intravenously every 2 weeks, for a treatment duration of up to 52 weeks. Pre-infusion samples were collected to measure MTX-PGs in red blood cells. Pre- and post-infusion blood samples were obtained to measure the peak (Cmax) and trough (Cmin) concentrations of pegloticase at multiple visits. Anti-drug antibody blood samples were collected at multiple visits. The impact of MTX on pegloticase PK was evaluated by comparing pegloticase exposures with MTX from this trial to historical monotherapy data (C0405 and C0406)3, 4. The observed pegloticase concentrations with MTX were also overlaid with the 90% prediction interval based on the population PK model5 from C0405 and C0406.Pegloticase and MTX-PG levels were determined in 14 patients. The 11 responders were generally associated with higher pegloticase exposures than the non-responders, especially Cmin (Figure 1). Concomitant treatment of MTX resulted in fewer patients with Cmin below quantitation limit (BQL) (5/14 [36%] with MTX vs 63/82 [77%] without MTX), and higher overall Cmin (median: 1.03 µg/ml with MTX vs BQL without MTX); Cmax was slightly higher (median [Q1, Q3]: 2.11 [1.65, 2.59] µg/mL with MTX vs 1.51 [BQL, 2.48] µg/mL without MTX). Pegloticase co-treatment with MTX resulted in more concentrations above the predicted median value of pegloticase, compared to monotherapy. ADA data is consistent with pegloticase PK and efficacy. Significant increase in ADA titers were only observed in 2 subjects (both were non-responders) at time corresponding to the loss of pegloticase exposure and increases in sUA levels. Concentrations of MTX-PGs were maintained during the treatment course, suggesting compliance of MTX administration. There was no apparent difference in concentrations of MTX-PGs between responders and non-responders.Pegloticase 8\u2009mg IV every 2 weeks co-treatment with MTX 15\u2009mg weekly resulted in fewer patients with pegloticase Cmin below the quantification limit (BQL) and gave higher overall trough concentrations (Cmin) compared to pegloticase monotherapy in the phase 3 studies.Pegloticase 8\u2009mg IV every 2 weeks co-treatment with MTX 15\u2009mg weekly was associated with an improved response rate for pegloticase in association with improved drug levels in these patients with uncontrolled gout compared to pegloticase monotherapy in the phase 3 studies.[1]Botson J., et al. J Rheumatol. 2020; doi: 10.3899/jrheum.200460[2]Goss S. L., et al. Clin Ther;2018, 40 (2).[3]Lipsky P. E., et al. Arthritis Res Ther;2014, 16 (2).[4]Sundy J. S., et al. JAMA;2011, 306 (7).[5]Yue C. S., et al. ASCPT, Atlanta, 2010.Yang Song Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Yan Xin Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Michael E. Weinblatt Shareholder of: Canfite, Inmedix, Lycera, Vorso, Scipher, Grant/research support from: Crescendo Bioscience, Bristol Myers Squibb, Sanofi, Eli Lilly, Amgen, Jason Chamberlain Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Katie Obermeyer Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Lin Zhao Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Colleen Canavan Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Paul M. Peloso Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Srini Ramanathan Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc.