Background/Purpose: A majority of gout patients treated with 300 mg/d allopurinol do not reach the therapeutic goal range serum uric acid concentration (sUA) of <6.0 mg/dL. Added to allopurinol, ulodesine (BCX4208), a purine nucleoside phosphorylase inhibitor, synergistically reduces sUA and allows a greater proportion of gout patients to reach sUA <6.0 mg/dL. The objectives of this study were (1) to extend the safety assessment of a 12 week efficacy study through 24 weeks of drug administration, (2) to evaluate immune responses to vaccine challenge, and (3) to confirm continued efficacy of ulodesine.

Methods: 278 gout patients (M:F=266:12) with sUA >6.0 mg/dL despite allopurinol 300 mg/d received placebo or  ulodesine at 5, 10, 20, or 40 mg/d for 12 wks. 160 subjects entered the combination treatment extension to 24 wks on their blinded treatment assignment; 27 on placebo, and 39, 32, 33, and 29 on BCX4208 5, 10, 20, and 40 mg/d. All subjects received gout flare prophylaxis with colchicine or naproxen. At 16 or 20 wks, subjects were vaccinated with tetanus toxoid (TT) and/or multivalent pneumococcal polysaccharide vaccine (PPSV), and antibody levels were measured before and 4 wks after vaccination in 84 subjects.

Results: Subject mean (range) age was 49 y (19-69), BMI was 35.9 (22.8-62.2), 45% had mild or moderate renal impairment, and 14% had diabetes in a mostly white population (79%). Total adverse event (AE) rates by 24 weeks were 45.3 per 100 patient-months (pt-mo) for placebo and 33.8, 41.0, 41.3, and 58.2 in the ulodesine 5, 10, 20, and 40 mg/d treatment arms. Infectious AE rates were 8.3 for placebo and 6.3, 6.5, 7.3, and 5.1 per 100 pt-mo, for the respective ulodesine arms. Infection severity, type, location, and causative agent were similar among study arms. There were no opportunistic infections. The ulodesine dose-related reduction of total lymphocyte count and lymphocyte subsets remained at a plateau reached between week 8 and 12. There were 4 and 11 protocol-specified withdrawals for CD4+ cell count <350 cells/mL in the ulodesine 20 and 40 mg/d arms by 24 weeks. The proportion of antibody responses to vaccination with TT (≥4-fold increase in antibody titers) and PPSV (>2-fold increase in antibody titers to >4 of 6 antigens) was similar or greater in ulodesine- than in placebo-treated subjects. The proportion of subjects with sUA levels <6.0 mg/dL among those completing week 24 was 25% (6 of 24) in the placebo group, and 40% (14 of 35), 50% (13 of 26), 46% (12 of 26), and 55% (12 of 22) in the 5, 10, 20, and 40 mg/d ulodesine arms.  

Conclusion: Ulodesine was safe and generally well tolerated when added to allopurinol for up to 24 wks. Patients generated a healthy immune response to vaccination. Adverse event frequency and severity was similar among all groups and no differences were seen in the rate or severity of infections. There were no protocol-driven study drug withdrawals due to low lymphocyte counts in the placebo, 5 mg/d, and 10 mg/d groups.  The efficacy of ulodesine in reducing sUA at 12 wks was sustained at 24 weeks.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ulodesine-bcx4208-long-term-safety-when-added-to-allopurinol-in-the-chronic-management-of-gout-a-phase-2-24-week-blinded-safety-extension-and-vaccine-challenge-study/