FDA advisory committee recommends approval of gout drug lesinurad, with caveats

This article was updated on 10/27/15.

Members of the Food and Drug Administration’s Arthritis Advisory Committee have voted in favor of recommending approval of the investigational uricosuric drug lesinurad at 200 mg daily for the proposed indication of treatment of hyperuricemia associated with gout in combination with a xanthine oxidase inhibitor, such as allopurinol or febuxostat.

The committee’s 10-4 vote on recommending approval came with much discussion over the benefit-to-risk analysis of lesinurad. Members voted 14-0 that the data in the four pivotal phase III trials submitted to the FDA contained enough evidence of a clinically meaningful beneficial effect of lesinurad in combination with a xanthine oxidase inhibitor (XOI) in the treatment of hyperuricemia associated with gout. However, committee members were much less certain of lesinurad’s safety profile, which indicated a narrow therapeutic index, and voted 7-6 in favor of adequate safety data to support approval, with 1 abstention.

Lesinurad 200 mg daily lowered serum uric acid (sUA) levels 1.1-1.3 mg/dL on top of what is already achieved with an XOI in its pivotal phase III trials, but it did not consistently improve patient outcomes, such as reducing gout flares, resolving tophi, and improving Health Assessment Questionnaire-Disability Index scores.

The FDA and the developer of lesinurad, Ardea Biosciences, agreed before the advisory committee meeting not to consider a 400-mg dose of the drug for marketing because it was associated with an increased incidence of renal adverse events (including serious renal AEs, serum creatinine elevations, and kidney stone AEs), compared with placebo. Although, lesinurad 200 mg was not associated with an increased incidence of serious renal or kidney stone AEs, it was associated with a smaller increase in the incidence of overall renal AE and serum creatinine elevations, which suggested dose-dependent toxicity. An imbalance in major adverse cardiovascular event incidence and exposure-adjusted incidence also was observed with lesinurad 400 mg, compared with 200 mg or placebo, although there were a small number of events.

Overall, the average concentration of lesinurad in the studies was higher with 400 mg, compared with 200 mg, but the exposure for the two doses was largely overlapping, raising questions about whether the safety profile of the 200-mg dose will be consistent if used in a larger population with more variability, the FDA said.

Two of the four pivotal phase III clinical trials of lesinurad involved patients who had been taking at least 300 mg/day allopurinol (200 mg/day in patients with estimated creatinine clearance (CrCl) of less than 60 mL/min at baseline) for at least 8 weeks and still had a sUA level of 6.5 mg/dL or greater at the screening visit (and greater than 6.0 mg/dL at the day 7 visit) and also had at least two gout flares in the preceding 12 months. They were randomized to receive placebo, lesinurad 200 mg, or lesinurad 400 mg daily in addition to their background allopurinol for 12 months.

The third study involved the same doses of lesinurad and placebo over a 12-month time frame but instead had lesinurad added on to a background of febuxostat 80 mg and required that sUA had to be at least 8 mg/dL in patients not taking urate lowering therapy (ULT) and at least 6 mg/dL in patients who were on ULT previously. Patients also had to have at least one measurable tophus on the hands/wrists and/or feet/ankles at least 5 mm in width and up to 20 mm in length.

The fourth study was a 6-month study of lesinurad 400 mg monotherapy, compared with placebo, in subjects with gout who had intolerance or contraindication to treatment with an XOI.

Committee members who voted in favor of recommending approval called for postmarketing studies that showed that the drug did indeed improve clinical outcomes such as reducing gout flares and resolution of tophi; long-term safety studies of renal and cardiovascular adverse events, including studies in patients with comorbidities commonly occurring in patients with gout; and structured, specific guidance to providers on who should receive the drug and how prescribers should handle increases in serum creatinine levels during treatment.

Lesinurad inhibits the function of multiple carrier proteins that transport uric acid in the renal proximal tubule epithelium, including uric acid transporter 1 (URAT1) and organic anion transporters 1, 3 and 4.

The FDA is not obligated to follow the recommendations of its advisory committee panels.

[email protected]

This article was updated on 10/27/15.

Members of the Food and Drug Administration’s Arthritis Advisory Committee have voted in favor of recommending approval of the investigational uricosuric drug lesinurad at 200 mg daily for the proposed indication of treatment of hyperuricemia associated with gout in combination with a xanthine oxidase inhibitor, such as allopurinol or febuxostat.

The committee’s 10-4 vote on recommending approval came with much discussion over the benefit-to-risk analysis of lesinurad. Members voted 14-0 that the data in the four pivotal phase III trials submitted to the FDA contained enough evidence of a clinically meaningful beneficial effect of lesinurad in combination with a xanthine oxidase inhibitor (XOI) in the treatment of hyperuricemia associated with gout. However, committee members were much less certain of lesinurad’s safety profile, which indicated a narrow therapeutic index, and voted 7-6 in favor of adequate safety data to support approval, with 1 abstention.

Lesinurad 200 mg daily lowered serum uric acid (sUA) levels 1.1-1.3 mg/dL on top of what is already achieved with an XOI in its pivotal phase III trials, but it did not consistently improve patient outcomes, such as reducing gout flares, resolving tophi, and improving Health Assessment Questionnaire-Disability Index scores.

The FDA and the developer of lesinurad, Ardea Biosciences, agreed before the advisory committee meeting not to consider a 400-mg dose of the drug for marketing because it was associated with an increased incidence of renal adverse events (including serious renal AEs, serum creatinine elevations, and kidney stone AEs), compared with placebo. Although, lesinurad 200 mg was not associated with an increased incidence of serious renal or kidney stone AEs, it was associated with a smaller increase in the incidence of overall renal AE and serum creatinine elevations, which suggested dose-dependent toxicity. An imbalance in major adverse cardiovascular event incidence and exposure-adjusted incidence also was observed with lesinurad 400 mg, compared with 200 mg or placebo, although there were a small number of events.

Overall, the average concentration of lesinurad in the studies was higher with 400 mg, compared with 200 mg, but the exposure for the two doses was largely overlapping, raising questions about whether the safety profile of the 200-mg dose will be consistent if used in a larger population with more variability, the FDA said.

Two of the four pivotal phase III clinical trials of lesinurad involved patients who had been taking at least 300 mg/day allopurinol (200 mg/day in patients with estimated creatinine clearance (CrCl) of less than 60 mL/min at baseline) for at least 8 weeks and still had a sUA level of 6.5 mg/dL or greater at the screening visit (and greater than 6.0 mg/dL at the day 7 visit) and also had at least two gout flares in the preceding 12 months. They were randomized to receive placebo, lesinurad 200 mg, or lesinurad 400 mg daily in addition to their background allopurinol for 12 months.

The third study involved the same doses of lesinurad and placebo over a 12-month time frame but instead had lesinurad added on to a background of febuxostat 80 mg and required that sUA had to be at least 8 mg/dL in patients not taking urate lowering therapy (ULT) and at least 6 mg/dL in patients who were on ULT previously. Patients also had to have at least one measurable tophus on the hands/wrists and/or feet/ankles at least 5 mm in width and up to 20 mm in length.

The fourth study was a 6-month study of lesinurad 400 mg monotherapy, compared with placebo, in subjects with gout who had intolerance or contraindication to treatment with an XOI.

Committee members who voted in favor of recommending approval called for postmarketing studies that showed that the drug did indeed improve clinical outcomes such as reducing gout flares and resolution of tophi; long-term safety studies of renal and cardiovascular adverse events, including studies in patients with comorbidities commonly occurring in patients with gout; and structured, specific guidance to providers on who should receive the drug and how prescribers should handle increases in serum creatinine levels during treatment.

Lesinurad inhibits the function of multiple carrier proteins that transport uric acid in the renal proximal tubule epithelium, including uric acid transporter 1 (URAT1) and organic anion transporters 1, 3 and 4.

The FDA is not obligated to follow the recommendations of its advisory committee panels.

[email protected]

This article was updated on 10/27/15.

Members of the Food and Drug Administration’s Arthritis Advisory Committee have voted in favor of recommending approval of the investigational uricosuric drug lesinurad at 200 mg daily for the proposed indication of treatment of hyperuricemia associated with gout in combination with a xanthine oxidase inhibitor, such as allopurinol or febuxostat.

The committee’s 10-4 vote on recommending approval came with much discussion over the benefit-to-risk analysis of lesinurad. Members voted 14-0 that the data in the four pivotal phase III trials submitted to the FDA contained enough evidence of a clinically meaningful beneficial effect of lesinurad in combination with a xanthine oxidase inhibitor (XOI) in the treatment of hyperuricemia associated with gout. However, committee members were much less certain of lesinurad’s safety profile, which indicated a narrow therapeutic index, and voted 7-6 in favor of adequate safety data to support approval, with 1 abstention.

Lesinurad 200 mg daily lowered serum uric acid (sUA) levels 1.1-1.3 mg/dL on top of what is already achieved with an XOI in its pivotal phase III trials, but it did not consistently improve patient outcomes, such as reducing gout flares, resolving tophi, and improving Health Assessment Questionnaire-Disability Index scores.

The FDA and the developer of lesinurad, Ardea Biosciences, agreed before the advisory committee meeting not to consider a 400-mg dose of the drug for marketing because it was associated with an increased incidence of renal adverse events (including serious renal AEs, serum creatinine elevations, and kidney stone AEs), compared with placebo. Although, lesinurad 200 mg was not associated with an increased incidence of serious renal or kidney stone AEs, it was associated with a smaller increase in the incidence of overall renal AE and serum creatinine elevations, which suggested dose-dependent toxicity. An imbalance in major adverse cardiovascular event incidence and exposure-adjusted incidence also was observed with lesinurad 400 mg, compared with 200 mg or placebo, although there were a small number of events.

Overall, the average concentration of lesinurad in the studies was higher with 400 mg, compared with 200 mg, but the exposure for the two doses was largely overlapping, raising questions about whether the safety profile of the 200-mg dose will be consistent if used in a larger population with more variability, the FDA said.

Two of the four pivotal phase III clinical trials of lesinurad involved patients who had been taking at least 300 mg/day allopurinol (200 mg/day in patients with estimated creatinine clearance (CrCl) of less than 60 mL/min at baseline) for at least 8 weeks and still had a sUA level of 6.5 mg/dL or greater at the screening visit (and greater than 6.0 mg/dL at the day 7 visit) and also had at least two gout flares in the preceding 12 months. They were randomized to receive placebo, lesinurad 200 mg, or lesinurad 400 mg daily in addition to their background allopurinol for 12 months.

The third study involved the same doses of lesinurad and placebo over a 12-month time frame but instead had lesinurad added on to a background of febuxostat 80 mg and required that sUA had to be at least 8 mg/dL in patients not taking urate lowering therapy (ULT) and at least 6 mg/dL in patients who were on ULT previously. Patients also had to have at least one measurable tophus on the hands/wrists and/or feet/ankles at least 5 mm in width and up to 20 mm in length.

The fourth study was a 6-month study of lesinurad 400 mg monotherapy, compared with placebo, in subjects with gout who had intolerance or contraindication to treatment with an XOI.

Committee members who voted in favor of recommending approval called for postmarketing studies that showed that the drug did indeed improve clinical outcomes such as reducing gout flares and resolution of tophi; long-term safety studies of renal and cardiovascular adverse events, including studies in patients with comorbidities commonly occurring in patients with gout; and structured, specific guidance to providers on who should receive the drug and how prescribers should handle increases in serum creatinine levels during treatment.

Lesinurad inhibits the function of multiple carrier proteins that transport uric acid in the renal proximal tubule epithelium, including uric acid transporter 1 (URAT1) and organic anion transporters 1, 3 and 4.

The FDA is not obligated to follow the recommendations of its advisory committee panels.

[email protected]