Study to Evaluate the Urate-Lowering Activity and Safety of Oral BCX4208 Administered in Subjects With Gout

This study is a Phase 2, randomized, double-blind study to evaluate the efficacy and safety of BCX4208 in approximately 120 subjects with gout. The study will be conducted in 2 parts. Part 1 is a parallel-group design, evaluating doses of BCX4208 previously found to be safe and well-tolerated in healthy subjects and subjects with psoriasis. Part 2 is a dose-escalation study, evaluating higher doses of BCX4208 supported by the nonclinical safety dossier. Part 2 will initiate after review of efficacy and safety data from Part 1, and determination that higher doses of BCX4208 may be necessary to achieve meaningful clinical activity.

In Part 1, approximately 60 subjects will be randomized in a 1:1:1:1 fashion to one of the following 4 treatment groups: 1) Placebo; 2) 40 mg BCX4208; 3) 80 mg BCX4208; or 4) 120 mg BCX4208.

In Part 1, the study will consist of 3 periods: the Screening Period, the Treatment Period, and the Follow-Up Period. The Screening period will begin on Day -30 for subjects receiving urate-lowering therapy; these subjects will discontinue the urate-lowering therapy on Day -30 to allow an appropriate washout period before entering the Treatment Period. For subjects not receiving urate-lowering therapy, the Screening Period may begin on any day from Day -30 to Day -1 (Day -1 being the day immediately prior to dosing), as long as all inclusion and exclusion criteria are satisfied.

Some Screening procedures such as a recording of medical history and some clinical laboratory tests (those that are performed at Screening only) may be performed at any time during the Screening Period (Day -30 to Day -1). Other Screening procedures must be performed within the 6 days prior to the first dose of study drug (i.e., from Day -6 to Day -1); these include: physical examination, height, weight, clinical chemistry (including baseline and qualifying sUA), hematology, and urinalysis evaluations, CD4+, CD8+, CD20+, and CD56+ lymphocyte counts, a serum pregnancy test, 12-lead electrocardiogram (ECG), and vital signs assessments. These assessments will constitute the Baseline assessments for the purpose of comparisons with these same assessments post-dose.

A recording of concomitant medications and adverse events (AEs) will take place from the time of the signing of the Informed Consent Form (ICF) and throughout the duration of the study.

The Treatment Period begins on Day 1. Subjects are to arrive at the study clinic on Day 1 after an overnight fast. After a final review of eligibility criteria, pre-dose vital signs assessments, and pre-dose BCX4208 pharmacokinetic (PK) blood draw have been performed, subjects will be randomized and administered the first dose of study drug. Subjects will remain in the study clinic for Hour 2, Hour 4, and Hour 8 assessments and will return to the study clinic for efficacy and safety evaluations on Days 2, 8, 15, and 22.

Subjects will take study drug daily from Day 1 to Day 21, so that the Day 22 evaluation will occur approximately 24 hours after the last dose of study drug.

After the Day 22 evaluation, subjects will enter the Follow-Up Period and will return to the study clinic on Days 29, 36, 43, and 50 for safety evaluations. Subjects who on Day 50 have unresolved treatment-emergent AEs will be followed beyond Day 50 until either resolution of the AE or until Day 80, whichever occurs sooner. Subjects who on Day 50 have absolute CD4+, CD8+, CD20+, and/or CD56+ lymphocyte counts that are both below the lower limit of normal and < 50% of Baseline will be followed monthly until the sooner of: 1) return of the absolute CD4+, CD8+, CD20+, and/or CD56+ lymphocyte counts to the lower limit of normal range, or 2) 6 months after the Day 50 or Early Termination Visit. All other subjects will conclude their study participation at the Day 50 or Early Termination Visit.

Efficacy will be assessed during the study by means of sUA concentrations. Safety will be assessed during the study by means of physical examination, weight, clinical chemistry, hematology, and urinalysis parameters, absolute CD4+, CD8+, CD20+, and CD56+ lymphocyte counts, 12-lead ECG, vital signs assessments, and AE assessments.

Efficacy, safety, and tolerability data from Part 1 of the study will be reviewed prior to initiation of Part 2.

Part 2 will consist of up to 3 cohorts: 1) 160 mg BCX4208 or placebo; 2) 240 mg BCX4208 or placebo; and 3) 320 mg BCX4208 or placebo. Unlike Part 1, Part 2 is a dose-escalation design whereby each of the cohorts will be enrolled sequentially, following review of the efficacy, safety, and tolerability data of the previous cohort. Enrollment into each cohort during Part 2 will be in a 3:1 ratio of BCX4208 to placebo such that 15 subjects will be randomized into each of the BCX4208 groups (total of 45 subjects) and 15 subjects will be randomized to placebo.

All study procedures for Part 2 of the study, from the Screening through the Follow-Up Period, will be conducted as described for Part 1.