Background: In 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.

Objectives: To 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.

Methods: In 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-PG _1-5 ) 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.

Results: Overall, 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-PG ₃ , the predominant form of MTX-PGs ⁴ ) 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.

Conclusion: Pegloticase 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;201:114124

Disclosure of Interests: Yan 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