Background/Purpose: Ulodesine (BCX4208) is an oral, once-daily, purine nucleoside phosphorylase (PNP) inhibitor in clinical development as add-on therapy for the chronic management of hyperuricemia in patients with gout. Based on the role of PNP in purine catabolism, inhibition of PNP should reduce hypoxanthine (HX), xanthine (X) and uric acid levels.  Ulodesine has demonstrated dose-dependent decreases in serum uric acid (sUA) in multiple clinical trials both as a single agent and in combination with allopurinol¹.  Plasma X and HX concentrations are significantly higher in untreated gout patients compared to hyperuricemic and normal subjects².  Elevated plasma X and HX concentrations are also associated with kidney stones, as seen in xanthine oxidase (XO)-deficient patients and mice^{3, 4}.  Moreover, HX and X are implicated in the production of reactive oxygen species leading to oxidative stress, cell damage and cardiovascular effects⁵.  The objective of the study is to measure plasma X and HX concentrations in gout patients receiving 300 mg/d allopurinol plus either placebo or ulodesine.

Methods:  Two hundred-seventy eight subjects with gout and sUA ≥6.0 mg/dL on allopurinol 300 mg/d for at least 2 weeks were randomized to receive oral  ulodesine 5, 10, 20, or 40 mg/d or placebo for 12 weeks while continuing allopurinol 300 mg/d.  Blood samples were collected at baseline and day 85 into heparin tubes containing BCX34 (PNP inhibitor) to prevent purine metabolism during collection and processing.  Plasma concentrations of X and HX were analyzed by LC/MS/MS.  [¹⁵N₂] xanthine and [D₂] hypoxanthine were used to generate surrogate standard curves for quantification of plasma X and HX concentrations. In normal healthy subjects, the mean (+ SD) concentrations of plasma X and HX were 56 ± 13 ng/mL and < 25 ng/mL, respectively.

Results: Ulodesine combined with allopurinol produced significant reductions in plasma X and HX concentrations from baseline, compared to placebo (Table).  At baseline (subjects on allopurinol 300 mg/d), the mean (+ SD) concentrations of the plasma X and HX were 500 ± 408 ng/mL and 301 ± 293 ng/mL, respectively.  The reduction in mean plasma X and HX concentrations with BCX4208 treatment in gout subjects was dose-dependent.

Conclusion: Using a robust LC/MS/MS method and stabilization of plasma X and HX during blood collection and processing, oral ulodesine administration demonstrated dose-dependent mean reductions in plasma X and HX concentrations in gout patients while under treatment with allopurinol.  These results confirm the mechanism of action of ulodesine.

Table: Mean Change from baseline of Day 85 Plasma Xanthine and Hypoxanthine levels

BCX4208-203 Study 

Metabolite	Change from baseline at day 85 LSM (SEM)
	Placebo(n=40)	5 mg/day(n=39)	10 mg/day(n=38)	20 mg/day(n=41)	40 mg/day(n=36)
Xanthine(ng/mL)	124.9 (76.33)	-66.6 (77.46)**	-114.6(74.25)***	-138.5 (69.03)***	-183.3 (75.19)***
Hypoxanthine(ng/mL)	-22.7 (70.36)	-48.9 (71.25)	-126.8 (68.21)	-165.6 (63.05)*	-201.3 (68.97)**

*p<0.05, **p<0.005, ***p<0.001 vs. placebo

1. Hollister AS, et al.  Ann Rheum Dis 2011; 70 (Suppl 3): 183.
2. Zhao J, et al. Clin Chem 51, No. 9, 2005
3. Gargan T, et al. Saudi J Kidney Dis Transpl 2010; 21(2):328
4. Ohtsubo T, et al. Hypertension 2009, 54;868-876;
5. Xia et al. J Biol Chem 1996, 271; 10096

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ulodesine-bcx4208-add-on-therapy-to-allopurinol-300mg-lowers-hypoxanthine-and-xanthine-plasma-levels-in-a-dose-dependent-fashion-results-from-a-12-week-randomized-controlled-trial-in-patients-with/