An advisory committee to the US Food and Drug Administration (FDA) voted 10 to 4 to recommend lesinurad (Zurampic, AstraZeneca) 200 mg once daily for the treatment of gout-associated hyperuricemia, in combination with a xanthine oxidase inhibitor (XOI).
The advisory committee voted unanimously that the company presented substantial evidence in favor of the drug's efficacy; the panel voted with narrow margins (7 yes, 6 no, 1 abstention) in favor of the drug's safety.
"The Committee's positive recommendation for lesinurad is an encouraging step for patients suffering from the debilitating effects of gout," Sean Bohen, MD, PhD, Executive vice president of Global Medicines Development and chief medical officer, AstraZeneca, said in a news release. "We look forward to the outcome of the FDA's review and the opportunity to provide a new treatment option that, when combined with a xanthine oxidase inhibitor, addresses both the under-excretion and over-production of uric acid, the underlying causes of gout."
But some committee members have reservations. "I think strict guidelines need to be in place for patients who have baseline renal insufficiency and certainly some of the comorbidities that we see, and I'd really be interested in the long-term safety data as it comes out as these long-term extension trials are ongoing. I still think the…benefits outweigh those risks," said voting committee member Mara L. Becker, MD, from the University of Missouri-Kansas City School of Medicine and Children's Mercy, Kansas City, Missouri.
The long-term management of gout entails controlling hyperuricemia, which addresses the underlying pathology of the disease. Currently available treatments aim to lower uric acid production with XOIs such as allopurinol and febuxostat; increase urinary uric acid excretion with uricosurics such as probenecid; and direct enzymatic breakdown of uric acid with drugs such as pegloticase and rasburicase.
Lesinurad works by decreasing the production of uric acid and increasing its excretion. The proposed dosing regimen is 200 mg orally once daily. If the FDA approves lesinurad, it will be the first selective uric acid reabsorption inhibitor in the United States.
"Among patients treated in clinical trials, less than 50% of patients on allopurinol 300 mg reached [serum uric acid] target levels < 6.0 mg/dL (360 µmol/L)," according to the AstraZeneca news release. "This suggests approximately two million gout patients in the US on urate lowering therapy remain inadequately controlled. For patients who cannot reach target on an XOI alone, the current [American College of Rheumatology] guidelines recommend adding an agent that increases uric acid excretion."
The American College of Rheumatology and the European League Against Rheumatism recommend a target serum uric acid (sUA) level of < 6.0 mg/dL (360 µmol/L).Clinical Trials
The vote follows a discussion of data from three multiregional, randomized, double-blind, placebo-controlled, parallel group trials that enrolled 1537 patients and evaluated lesinurad in combination with an XOI. Patients in the studies had failed to achieve target sUA levels despite treatment with either allopurinol or allopurinol in combination with febuxostat. The trials tested the effect of 200-mg and 400-mg doses of lesinurad given once daily with a concomitant XOI (allopurinol or febuxostat).
Lesinurad significantly improved sUA levels, the primary endpoint, but it did not demonstrate clinical efficacy for the secondary endpoints of flare occurrence, tophus reduction, or improved physical function.
Whereas lesinurad increased the proportion of patients who achieved target sUA levels, the average treatment effect for the 200-mg dose was a decrease in sUA of about 1.1 to 1.3 mg/dL. The panel noted that this may seem like a small treatment effect, but it may help those with less elevated sUA levels reach the normal range and improve symptoms long-term.Increased Adverse Effects at Higher Dose
The 400-mg dose was associated with an increase in the incidence of adverse events, serious adverse events, serious and nonserious renal adverse events, major adverse cardiovascular events (MACE), and death, compared with placebo. Four patients required hemodialysis or renal biopsy, and all serious renal adverse events occurred in patients who received the 400-mg dose.
The 200-mg dose was associated with a smaller increase in the incidence of adverse events, overall renal adverse events, and serum creatinine elevations compared with the larger dose, which suggests that toxicity associated with lesinurad is dose-dependent. The exposure of the two doses is largely overlapping and panel members questioned whether the safety profile of the lower dose will be consistent if the drug is used in the general population.
"The narrow therapeutic index of this drug really does concern me. If we have it out in general use, we're either going to learn that it's safe, or we'll learn that it's not safe and take it off the market later," said temporary voting committee member Peter J. Kaboli, MD, FACPP, FHM, from University of Iowa Carver College of Medicine and Iowa City Veterans Affairs Healthcare System, both in Iowa City, Iowa. Dr Kaboli said that he's concerned that it may help some patients but harm others. For the most part, non-MACE rates did not differ between the treatment groups. There was, however, an imbalance in MACE incidence and exposure-adjusted incidence in the 400-mg groups compared with the 200-mg groups.
There were a total of 17 deaths in all of the phase 1 and phase 3 studies: six deaths in the phase 3 placebo-controlled trials, nine during the phase 3 uncontrolled extension studies, and two in phase 1 studies. In addition, three deaths occurred after the screening period and before receipt of the study medication in the phase 2b and phase 3 trials.
"I…agree with a lot of the sentiments that we need a good phase 4 study to look at comorbidities and look at real-world adverse events. There's been some discussion that's appropriate about having the label include mention of specific creatinine levels, for example," said voting committee member Andreas M. Reimold, MD, from Dallas VA Medical Center, Texas.
The voting panel members have disclosed no relevant financial relationships.
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Cite this: FDA Panel Backs Lesinurad (Zurampic ) for Gout - Medscape - Oct 23, 2015.