Background Lesinurad (LESUR) is an oral investigational URAT1 inhibitor for the treatment of gout. A Phase 2B study in 208 gout patients with an inadequate response to allopurinol (ALLO) (200-600 mg/day for ≥6 weeks) demonstrated that the combination of LESUR+ALLO resulted in superior reductions in sUA with 79%, 74%, and 63% of patients achieving sUA <6 mg/dL after 28 days of dosing with 600 mg, 400 mg and 200 mg LESUR, respectively, compared to 25% with placebo (PBO)+ALLO (p<0.0001 for all comparisons). Subjects completing the Phase 2B study could enter a 44-week, blinded, PBO-controlled extension, the results of which are presented here. Objectives To assess the ongoing efficacy and safety of LESUR in combination with ALLO vs. PBO+ALLO in patients with an inadequate response to standard doses of ALLO. Methods Subjects completing the double-blind 28-day main study were washed out of LESUR or PBO before entering the blinded extension period, but remained on a stable dose of ALLO. Subjects then restarted their original blinded treatment of LESUR or PBO. All LESUR-treated subjects started on the 200 mg dose and were to have the dose titrated stepwise to 400 or 600 mg if the sUA was not <5 mg/dL. After dose escalation of LESUR or PBO, ALLO dose could be escalated. Results 126 subjects enrolled into the blinded extension study (78 LESUR and 48 PBO); 91 subjects completed 44 weeks at time of this analysis. 78% of LESUR treated subjects maintained sUA <6 mg/dL at 44 weeks, compared to 56% of PBO subjects (LOCF analysis); 59% of subjects receiving LESUR also achieved sUA<5 mg/dL compared to 25% of PBO subjects. ALLO doses were increased in the majority of PBO subjects. 29 subjects (13 PBO/16 LESUR) withdrew from the study for any reason before Week 44. Overall rates of adverse events (AEs) were low and similar between the treatment groups. 4 subjects reported serious AEs (angina pectoris, cerebral artery embolism, tendon rupture, bursitis infective) considered not related to treatment. Transient serum creatinine (sCr) elevations were observed in both groups; on LESUR these generally occurred early or after dose escalations and usually resolved to within the normal range while on LESUR. 4 subjects discontinued due to increased sCr; 1 receiving PBO and 3 on LESUR. Monthly gout flare rates for subjects remaining on the 200 mg dose were generally lower for the LESUR group compared to PBO during Months 7-12. Conclusions In patients who do not respond adequately to ALLO, the addition of LESUR produced consistent, sustained reductions in sUA levels, with the majority of subjects achieving sUA levels of <6 mg/dL and <5 mg/dL. Despite dose increases of ALLO in the majority of PBO subjects, combination therapy was superior. LESUR was well-tolerated with a similar rate of AEs to placebo. The premature discontinuation rate on PBO was higher than on LESUR. LESUR is a promising investigational drug for the treatment of hyperuricemia in gout patients. Disclosure of Interest F. Perez-Ruiz Grant/Research support from: Asociaciόn de Reumatόlogos del Hospital de Cruces y Ministerio de Sanidad, Gobierno de España, Consultant for: Ardea Biosciences, Menarini Pharma, Novartis, Savient, Speakers Bureau: Menarini Pharma, Novartis, J. Sundy Grant/Research support from: Ardea Biosciences, Nuon Therapeutics, Pharmos, Regeneron, Celgene, Savient, Abbot, Jansen, Consultant for: Ardea Biosciences, Nuon Therapeutics, Pharmos, Novartis, Savient, Roche, E. Krishnan Grant/Research support from: Takeda, Consultant for: Takeda, V. Hingorani Consultant for: Ardea Biosciences, J. Welp Employee of: Ardea Biosciences, T. Rodgers Employee of: Ardea Biosciences, K. Manhard Employee of: Ardea Biosciences, M. Cravets Employee of: Ardea Biosciences, D. Hagerty Employee of: Ardea Biosciences, B. Quart Employee of: Ardea Biosciences

Background Lesinurad is a novel URAT1 inhibitor that has been well tolerated in humans, with dose-dependent reductions of serum urate (sUA). In vitro experiments and in vivo human absorption, metabolism, and mass balance (AME) studies indicated that hepatic metabolism, renal excretion, and biliary uptake all contributed to the elimination of lesinurad. Drug-drug interaction (DDI) studies with drugs commonly used by gout patients have been conducted. Projections of DDI potential with drugs in different therapeutic areas have also been generated using established preclinical models. Objectives To evaluate the potential inhibitory effect of lesinurad upon initiation of lesinurad once daily dosing or the potential induction effect of lesinurad following multiple doses of lesinurad on pharmacokinetic (PK) of commonly used drugs such as atorvastatin (OATP1B1 and CYP3A), tolbutamide (CYP2C9 and CYP3A), repaglinide (CYP2C8 and CYP3A), or amlodipine (CYP3A) in healthy subjects, as well as PK and sUA lowering of febuxostat (FBX; CYP2C9) or oxypurinol (URAT1), the active metabolite of allopurinol (ALLO), following once daily (qd) dosing of lesinurad in gout patients with hyperuricemia. Methods A total of 70 healthy subject volunteers were enrolled across 4 DDI studies with drugs commonly used by gout patients including atorvastatin (N=28), tolbutamide (N=14), repaglinide (N=14), and amlodipine (N=14), given with concurrent administration of first dose or qd doses of lesinurad ranging between 200 and 400 mg. Full PK profiles of these drugs were obtained without coadministration with lesinurad, following first dose, or following at least 10 days of qd doses of lesinurad. A total of 41 gout patients were enrolled across 2 multiple-dose DDI studies with FBX and ALLO. In the ALLO DDI study, patients were administered ALLO 300 mg qd in week 1, a combination of ALLO and lesinurad 400 or 600 mg in week 2, then lesinurad alone in week 3. In the FBX DDI study, patients received FBX 40 or 80 mg qd in week 1, a combination of FBX and lesinurad 400 mg and 600 mg in week 2 and week 3, respectively. Results In healthy subjects, lesinurad showed minimal inhibitory effects (10-30%) on plasma exposure of atorvastatin, tolbutamide and repaglinide upon first dose of 400 mg lesinurad, the highest dose planned for Phase 3 evaluations. Following 400 mg qd doses of lesinurad, plasma exposure of tolbutamide and repaglinide were unaffected, while plasma exposure of atorvastatin, and amlodipine were minimally decreased. In gout patients, although co-administration of lesinurad 400 mg resulted in 26% decrease in oxypurinol plasma exposure, additive reduction in sUA was observed. Coadminstration of lesinurad 400 mg resulted in minimal (<20%) increases in FBX plasma exposure, and synergistic reductions in sUA. Neither allopurinol nor FBX had any effect on the PK of lesinurad. Preclinical DDI modeling of the most commonly used drugs by gout patients identified few potential interactions Conclusions Potential drug-drug interactions are limited to mild reductions in oxypurinol (expected due to URAT1 activity) and mild induction of CYP3A4 at the doses being evaluated in Phase 3. No clinically meaningful drug interactions are anticipated with lesinurad Disclosure of Interest L.-T. Yeh Employee of: Ardea Biosciences, Z. Shen Employee of: Ardea Biosciences, B. Kerr Consultant for: Ardea Biosciences, D. Wilson Employee of: Ardea Biosciences, C. Yang Employee of: Ardea Biosciences, S. Squier Consultant for: Ardea Biosciences, V. Hingorani Consultant for: Ardea Biosciences, D. Hagerty Employee of: Ardea Biosciences, K. Manhard Employee of: Ardea Biosciences, B. Quart Employee of: Ardea Biosciences

The present study was conducted to demonstrate of the immunohistochemical localization of vascular endothelial growth factor (VEGF) and its receptors (flt1/fms, flk1/KDR and flt4) as well as vascular endothelial growth inhibitor (VEGI) and to determine the correlation of VEGF and its receptors and VEGI with serum sex steroids (estrogen and progesterone) in the bovine uterus during the sexual cycle. The stage of the estrous cycle in 30 Holstein cattle was assessed based on the gross and histological appearance of the ovaries and uterus and on blood steroid hormone levels. Tissue samples obtained from the uterus were fixed in 10% formaldehyde for routine histological processing. During both follicular and luteal phases, positive cytoplasmic and membrane staining was achieved for VEGF and its receptors (flt1/fms, flk1/KDR and flt4) as well as VEGI in the luminal and glandular epithelial cells, the connective tissue and smooth muscle cells, and the vascular endothelial cells and smooth muscle cells in the uterus. The intensity, proportional and total scores determined for VEGF and its receptors (flt1/fms and flt4) as well as VEGI were greater in the luminal and glandular epithelial cells compared to the connective tissue and smooth muscle cells (P < 0.05). Furthermore, the number and intensity of the flk1/KDR positive cells were greater among the connective tissue cells compared to the luminal and glandular epithelial cells (P < 0.05). As a result, it was determined that the expression of VEGF and its receptors as well as VEGI in the bovine uterus during the follicular and luteal phases varied with different cell types. This suggests that depending on the stage of the sexual cycle, these factors may mediate the establishment of an appropriate environment for the nutritional supply and implantation of the embryo primarily due to the stimulation of angiogenesis but also through the increase in the secretory activity of the epithelial cells in the uterus. Furthermore, this indicates that ovarian steroid hormones play a significant role in regulating the expression of VEGF and its receptors as well as VEGI.