FRI0380 Long-term safety of BCX4208 added to allopurinol in the chronic management of GOUT: Results of a phase 2 24-week blinded safety extension and vaccine challenge study
Authors: A.S. Hollister, S. Dobo, A. Maetzel, M.A. Becker, R. Terkeltaub, D. Fitz-Patrick, V. Smith, W. Sheridan
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Most gout patients treated with 300 mg/d allopurinol do not reach the therapeutic goal range serum uric acid concentration (sUA) of &lt;6.0 mg/dL (360 mmol/L).<sup>1</sup> BCX4208, a purine nucleoside phosphorylase inhibitor (PNP), added to allopurinol synergistically reduces sUA and allows a greater proportion of gout patients to reach sUA &lt;6.0 mg/dL<sup>2</sup>. The safety assessment of a 12 week double-blind, placebo controlled efficacy study of combined treatment was extended through 24 weeks (wks) of BCX4208 administration. <h3>Objectives</h3> To assess longer-term rates of adverse events (AEs), total lymphocyte and lymphocyte subset counts, evaluate immune responses to vaccine challenge, and confirm continued efficacy of BCX4208. <h3>Methods</h3> 278 gout patients (M:F=266:12) with sUA ≥6.0 mg/dL despite allopurinol 300 mg/d received placebo or BCX4208 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 measured before and 4 wks after vaccination in 84 subjects. <h3>Results</h3> Subject's mean (range) age was 49 (19-69), BMI 35.9 (22.8-62.2), 45% had mild-moderate renal impairment, and 14% diabetes in the 79% white population. Total AE rates were 45.3 per 100 patient-months (pt-mo) for placebo and 33.8, 41.0, 41.3, and 58.2 in the BCX4208 5, 10, 20, and 40 mg/d treatment arms. Infection AEs were 8.3 for placebo and 6.3, 6.5, 7.3, and 5.1 per 100 pt-mo, for the respective BCX4208 arms. The severity of infections, type, location, and causative agent was similar among study arms. There were no opportunistic infections. The BCX4208 dose-related reduction of total lymphocyte count and lymphocyte subsets CD4+, CD8+, CD20+, and CD56+ remained at a plateau reached between week 8 and 12. There were 4 and 11 protocol-specified withdrawals for CD4+ cell count &lt;350 cells/mL in the BCX4208 20 and 40 mg/d arms. 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 BCX4208- than in placebo-treated subjects. The proportion of subjects with sUA levels &lt;6mg/dL at wk 24 was 25% in the placebo group, and 40%, 50%, 46%, and 55% in the 5, 10, 20, and 40 mg/d BCX4208 arms. <h3>Conclusions</h3> BCX4208 was safe and generally well tolerated when added to allopurinol for up to 24 wks. Patients generated a healthy immune response to vaccination. No differences were seen in the rate or severity of AEs or infections. The efficacy of BCX4208 in reducing sUA at 12 wks was sustained at 24 weeks. <h3>References</h3> Terkeltaub R. Nat Rev Rheumatol 2010; 6: 30. Fitz-Patrick D, et al. Arthritis Rheum 2010; 62 (Suppl 10): 150. <h3>Disclosure of Interest</h3> A. Hollister Employee of: BioCryst Pharmaceuticals, Inc., S. Dobo Employee of: BioCryst Pharmaceuticals, Inc., A. Maetzel Employee of: BioCryst Pharmaceuticals, Inc., M. Becker Consultant for: BioCryst, Takeda, Savient, URL/Pharma, Ardea, Regeneron, Metabolex, Isis, R. Terkeltaub Consultant for: BioCryst, Regeneron, Ardea, Novartis, D. Fitz-Patrick Grant/Research support from: BioCryst, V. Smith Consultant for: BioCryst, W. Sheridan Employee of: BioCryst Pharmaceuticals, Inc.