In the original 12-week study, 279 patients were randomized and 160 patients entered the extension phase. Patients continued their blinded, randomized therapy of BCX4208 at doses of 5 mg, 10 mg, 20 mg, 40 mg and placebo once-daily. Allopurinol 300 mg once-daily was administered in all study arms.
This longer-term safety profile of BCX4208 is consistent with the 12-week
primary analysis results originally reported in
The previously observed lymphocyte plateau reached by 12 weeks of treatment remained unchanged in the 5 mg, 10 mg and 20 mg BCX4208 arms through 24 weeks. The 40 mg study arm met a protocol-defined cohort stopping rule based on the number of withdrawals for CD4+ cell counts, and this arm was discontinued after week 24. No patients from the placebo, 5 mg or 10 mg cohorts discontinued study drug for confirmed reductions of lymphocyte or CD4+ cell counts below certain protocol-specified thresholds; through 24 weeks, a total of four patients were discontinued from the 20 mg group and eleven patients from the 40 mg group for reductions in CD4+ cell counts.
A healthy immune response was seen in all study arms in a vaccine challenge sub-study conducted in 84 patients. The vaccines were administrated at either 16 or 20 weeks of treatment, and responses were assessed by measuring changes in antibody titers 4 weeks later. The response rates to tetanus toxoid (50%-100%) and polyvalent pneumococcal vaccine (64%-67%) in patients treated with BCX4208 were similar to placebo-treated patients who received tetanus toxoid (50%) and pneumococcal vaccine (64%). The response rates for placebo-treated patients are consistent with responses in normal individuals reported in literature.
The approximate doubling of sUA response rates with BCX4208 seen at 12 weeks was sustained through 24 weeks of treatment. After 24 weeks of treatment, BCX4208 doses of 5 mg, 10 mg, 20 mg and 40 mg/day showed response rates of 40%, 50%, 46% and 55% respectively, compared to 25% for placebo. These results are consistent with the previously reported positive findings at the 12-week primary efficacy time point.
There was a low incidence of gout flares in this study. Gout flares over 24 weeks occurred in 5% of placebo-treated patients compared to 7-16% of patients treated with BCX4208.
"We are very pleased to confirm the continued favorable safety profile
and sustained efficacy for BCX4208 as an add-on therapy for gout. The
sustained efficacy, healthy immune responses to vaccines, and clean
safety profile from 900 patient-months of drug exposure in this study
provides a robust basis for Phase 3 trials," said Dr.
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BCX4208 is a novel enzyme inhibitor with the potential for once-a-day oral dosing suitable for chronic administration to treat gout. It acts upstream of xanthine oxidase in the purine metabolism pathway to reduce sUA in patients with gout and has a mechanism of action that complements xanthine oxidase inhibitors, such as allopurinol and febuxostat, in reducing uric acid production. With its unique mechanism of action, clinical activity and safety in clinical studies to date, BCX4208 is nearing the end of Phase 2 development as an add-on therapy to xanthine oxidase inhibitors to address unmet medical needs in patients with gout. To date, BCX4208 has been studied in over 500 patients in clinical trials.
Gout is a chronic inflammatory arthritis caused by monosodium urate crystal deposits in joints and the kidneys resulting from elevated sUA levels in the blood, a condition known as hyperuricemia. The consequences of gout may include intense, painful flares affecting one or more joints, impaired kidney function and joint destruction. Gout continues to grow in prevalence and severity, affecting over 17 million people in major markets, including 8.3 million in the U.S. A majority of gout patients are also treated to manage other chronic conditions, including hypertension, diabetes and/or high cholesterol. Decreasing sUA to the recommended level (less than 6 mg/dL) can reduce the risk of gout attacks over the long-term. A minority of patients treated with the current standard of care, allopurinol, achieve this therapeutic goal. There is a need for new therapies that effectively and safely get a larger portion of gout suffers to goal without the risk of drug-drug interactions. More information regarding gout and hyperuricemia is available on the CDC website at www.cdc.gov/arthritis/basics/gout.htm.
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