J. S. Sundy*1, H. S. B. Baraf2, M. A. Becker3, N. L. Edwards4, S. R. Gutierrez-Urena5, E. L. Treadwell6, J. Vázquez-Mellado7, R. A. Yood8, Z. Horowitz9, W. Huang9, A. N. Maroli9, R. W. Waltrip9
1, Duke University Medical Center, Durham, 2, Center for Rheumatology & Bone Research, Wheaton, 3, University of Chicago, Chicago, 4, University of Florida, Gainesville, United States, 5, Hospital Civil de Guadalajara, Guadalajara, Mexico, 6, East Carolina University, Greenville, United States, 7, Hospital General de México, Mexico City, Mexico, 8, Fallon Clinic, Worcester, 9Clinical Development, Savient Pharmaceuticals, Inc., East Brunswick, United States

Background: TFG occurs in patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom those drugs are contraindicated.
Objectives: To assess the efficacy and safety of PGL (PEGylated recombinant mammalian uricase) vs placebo (PBO) in TFG.
Methods: Subjects (212) were randomized to PGL 8 mg q2w (85) or q4w (84) or PBO (43) in replicate, Phase 3, 6-month, randomized, double-blind (DB) trials, Gout Outcome and Urate Therapy 1 (GOUT1) and GOUT2. TFG was defined as: ≥3 flares in previous 18 months, or ≥1 tophus, or prevalent gouty arthropathy; serum urate (sUA) ≥8.0 mg/dL; and contraindication to or self-reported failure to control sUA with maximum medically appropriate dose of allopurinol. Primary efficacy endpoint was the percentage of plasma urate (pUA) responders, defined as subjects with pUA <6.0 mg/dL ≥80% of the time in Months 3 and 6. Secondary endpoints assessed treatment effect on tophus size, gout flares, number of swollen and tender joints (TJs), quality of life (SF-36), and disability (HAQ-DI). Primary endpoint data are reported as replicate analyses; secondary endpoint data were pooled for GOUT1 and GOUT2. Subjects who completed the DB trials were given the option to enter an open label extension trial under a separate protocol (GOUT3).
Results: Subjects, mean age 55 yrs, were mostly male (82%) and had high comorbidity rates: 100% cardiovascular disease including 72% hypertension, 17% atherosclerotic disease, 17% conduction disorders and arrhythmia, and 13% congestive heart failure and cardiomyopathy; 49% hyperlipidemia; 30% chronic kidney disease; and 23% diabetes. pUA response was significantly higher in both PGL groups vs PBO in both studies (Table). Complete resolution of ≥1 tophus occurred in 40% q2w (P=0.002) and 21% q4w (not significant vs PBO) vs 7% PBO subjects. SF-36 physical component summary score, HAQ-DI, and TJs improved significantly in both PGL groups vs PBO. Gout flare incidence and frequency were significantly higher during Months 1-3 in PGL groups; but, were significantly lower during Months 4-6 in q2w group, vs PBO. Most common adverse events (AEs) were flares (77% q2w, 83% q4w, 81% PBO) and infusion reactions (IRs; 26% q2w, 41% q4w, 5% PBO). AE discontinuations were mostly due to IRs (19/34). Serious AEs, mostly flares and IRs, occurred in 24% q2w, 23% q4w, and 12% PBO subjects.
pUA Responders in GOUT1 and GOUT2 (ITT)

GOUT120/43 (46.5%) (P<0.001)* 8/41 (19.5%) (P=0.044)* 0/20 (0%)
GOUT216/42 (38.1%) (P<0.001)* 21/43 (48.8%) (P<0.001)* 0/23 (0%)
GOUT1 and GOUT236/85 (42.4%) (P<0.001)* 29/84 (34.5%) (P<0.001)* 0/43 (0%)


Conclusion: 42% and 35% of treatment failure gout subjects on pegloticase q2w and q4w, respectively, achieved the primary efficacy endpoint of plasma urate control. This was paralleled by significant improvement in clinical outcomes. Most frequent adverse events were gout flares and infusion reactions.

Disclosure of Interest: J.Sundy, H.Baraf, M.Becker, NL.Edwards, S.Gutierrez-Urena, E.Treadwell, J.Vázquez-Mellado, R.Yood, Savient Pharmaceuticals, Research Support
Z.Horowitz, W.Huang, A.Maroli, R.Waltrip, Savient Pharmaceuticals, Employee