Background: Gout is a painful inflammatory arthritis caused by persistently elevated serum uric acid (sUA) levels. Pegloticase, an infused recombinant PEGylated uricase, rapidly lowers sUA levels by converting uric acid to allantoin, a water-soluble molecule that is readily excreted by the kidneys. In the phase 3 clinical trials, 42% of patients ¹ dosed with pegloticase every two weeks maintained sUA levels below 6.0 mg/dL during months 3 and 6 of pegloticase treatment. The loss of pegloticase efficacy has been attributed to the development of anti-drug antibodies (ADAs) ^1-3 and these ADAs have been associated with infusion reactions (IRs). ^1,2 Case reports ⁴ and prospective case series ^{5, 6} indicate that methotrexate (MTX) may allow patients to attain more complete therapeutic benefits, presumably through attenuation of pegloticase immunogenicity. The current study prospectively examines the efficacy and safety of MTX-pegloticase co-therapy in patients with uncontrolled gout.

Objectives: To assess efficacy and safety of concomitant pegloticase and MTX therapy in patients with uncontrolled gout.

Methods: Adult patients with uncontrolled gout who were beginning pegloticase therapy were considered for enrollment in this ongoing multicenter, open-label, efficacy and safety study of pegloticase with MTX co-treatment (NCT03635957). Patients were administered oral MTX (15 mg/week) and folate (1 mg/day) 4 weeks prior to the first pegloticase infusion (Day 1) and throughout the pegloticase treatment period. Blood was drawn prior to each infusion to measure sUA level, monitor clinical parameters, and examine for ADA development. All patients followed typical IR prophylaxis protocols (fexofenadine one day before and the morning of each infusion and acetaminophen and IV corticosteroid the morning of each infusion). Patients also received gout flare prophylaxis with either NSAIDs, colchicine or prednisone initiated at least 1 week prior to Day 1. The primary study outcome was the proportion of responders, defined as sUA <6 mg/dL for at least 80% of the time during month 6 (weeks 20, 22, and 24). All analyses were performed on a modified intent-to-treat population, defined as patients who received ≥1 pegloticase infusion.

Results: A total of 17 patients were screened and 14 patients (all men, average age: 49.3 ± 8.7 years) were enrolled. On Day 1, mean sUA was 9.2 ± 2.5 mg/dL and 12 of the 14 patients had visible tophi. At the 6 months timepoint, 11/14 (78.6%, 95%CI 49.2-95.3%) met the responder definition, with 3 patients discontinuing after meeting stopping rules (pre-infusion sUA values greater than 6 mg/dL at 2 consecutive scheduled visits). All patients tolerated MTX. One serious AE of bacterial sepsis occurred (resolved). AEs that occurred in >1 patient during the co-treatment period were: diarrhea and upper respiratory tract infection in 3 patients each, sinusitis, muscle strain, and hypertension in 2 patients each. Gout flares occurred in 12/14 (85.7%) patients. No new safety concerns were identified.

Conclusion: An increased proportion of patients maintained therapeutic response at 6 months when treated concomitantly with MTX and pegloticase (78.6%) when compared to the previously reported 42% using pegloticase alone. ¹ These results support and reflect the improved response rates demonstrated in two prior case series. ^5,6 A definitive randomized double-blinded trial evaluating pegloticase with MTX vs. pegloticase with placebo is ongoing.

REFERENCES:

[1]Sundy JS et al. JAMA 2011;306:711-20.

[2]Baraf HS et al. J Clin Rheumatol 2014;20:427-32.

[3]Lipsky PE et al. Arthritis Res Ther 2014;16:R60.

[4]Bessen SY et al. Semin Arthritis Rheum 2019;49:56-61.

[5]Botson J, Peterson J. Ann Rheum Dis 2019;78:A1289.

[6]Albert JA et al. Arthritis & Rheumatology 2019;71(S10):A1236.

Disclosure of Interests : John Botson Grant/research support from: Horizon Therapeutics (PI and study site), Radius Health (study site), Consultant of: Horizon Therapeutics, Speakers bureau: Celgene, Eli Lilly, Horizon Therapeutics, Mallinckrodt, Novartis, Pfizer, Paul M. Peloso Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Katie Obermeyer Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Michael E. Weinblatt Grant/research support from: BMS, Amgen, Lilly, Crescendo and Sonofi-Regeneron, Consultant of: Horizon Therapeutics, Bristol-Myers Squibb, Amgen, Abbvie, Crescendo, Lilly, Pfizer, Roche, Gilead, Jeff Peterson Grant/research support from: Abbvie, UCB, Smith Klein, Horizon Therapeutics, Consultant of: Lilly, Norvartis, Horizon Therapeutics, Speakers bureau: Lilly, Novartis, Horizon Therapeutics, Abbvie, Genentech