Thursday, January 7, 2016
The Food and Drug Administration has approved lesinurad (Zurampic, AstraZeneca) 200 mg tablets in combination with an xanthine oxidase inhibitor (XOI) to treat gout-related hyperuricemia in patients who have not achieved target serum uric acid (sUA) levels with an XOI alone.
Lesinurad works by inhibiting the urate transporter, URAT1, which is responsible for the majority of the renal reabsorption of uric acid. In combination with the current standard of care, allopurinol or febuxostat, lesinurad increases uric acid excretion and lowers sUA levels offering relief for gout patients who have not responded to current treatments.
David Belton, a patient advocate with CreakyJoints, has struggled with gout for 20 years, but he received some relief from symptoms after participating in a trial for lesinurad. “It has been over a year now since my last major flare,” he told CreakyJoints in an online interview.
In a news release issued by AstraZeneca, Lawrence Edwards, M.D., chairman and chief executive officer of the Gout and Uric Acid Education Society, said this combination therapy is long overdue. “A new approach to treating gout is long overdue given there has been limited therapy innovation over the last 50 years,” he said.
About Hyperuricemia and Gout
The underlying cause of gout is hyperuricemia (elevated sUA), which leads to the deposition of crystals primarily in the joints and in other tissues. This can result in recurrent attacks of inflammatory arthritis and, if left uncontrolled, could lead to chronic, progressive arthritis, and tophus (visible deposits of urate crystals) formation.
The goal of hyperuricemia-lowering treatment is to reduce hyperuricemia levels to the target level of <6.0mg/dL (360 µmol/L) as recommended by the American College of Rheumatology and the European League Against Rheumatism. In those with greater disease severity and urate burden, such as those with tophi, guidelines recommend lowering sUA to <5.0mg/dL (300 µmol/L) to achieve better disease control.
Among patients treated in clinical trials, less than 50% of patients on allopurinol 300mg reached sUA target levels <6.0mg/dL (360 µmol/L). For patients who cannot reach target on an XOI alone, the current ACR and EULAR guidelines recommend adding an agent that increases uric acid excretion.
The FDA approval is based on data from three phase III studies, CLEAR1, CLEAR2 and CRYSTAL, which represent the largest clinical trial data set of gout patients (n=1,537 total) treated with combination urate lowering therapy.
CLEAR1 and CLEAR2 were phase III studies that evaluated the efficacy and safety of a once daily dose of lesinurad in combination with allopurinol compared to allopurinol alone. Lesinurad met the primary endpoint in both studies with approximately twice as many patients achieving the serum uric acid (sUA) goal of <6.0mg/dL (360 µmol/L) by month 6, compared to those treated with allopurinol alone.
CRYSTAL was a phase III study that evaluated the efficacy and safety of a once daily dose of lesinurad in combination with febuxostat 80 mg compared to febuxostat 80 mg alone in gout patients with tophi. Patients were administered febuxostat 80 mg orally once daily for 3 weeks before randomization. Lesinurad 200 mg, in combination with febuxostat, demonstrated greater (nominal p<0.05) sUA lowering to the target for tophaceous gout of <5.0mg/dL (300 µmol/L) compared to febuxostat alone at all months except at the time of the primary endpoint, month 6 (56.6% vs. 46.8%, non significant). In the subgroup of patients with baseline sUA ≥5.0mg/dL (300 µmol/L) (i.e. those above recommended sUA treatment target for tophaceous gout on febuxostat alone), lesinurad 200mg in combination with febuxostat resulted in more subjects reaching target sUA of <5.0mg/dL (300 µmol/L) compared to febuxostat alone at month 6.
In a pooled analysis of the three clinical trials (CLEAR1, CLEAR2 and CRYSTAL), the safety profile was similar for lesinurad 200mg in combination with an XOI to that of an XOI alone, with the exception of an increased incidence of predominantly reversible serum creatinine (sCr) elevations.
The most common adverse reactions in the clinical trials were headache, influenza, increased blood creatinine, and gastroesophageal reflux disease.
Zurampic has a boxed warning that provides important safety information for health care professionals, including the risk for acute kidney (renal) failure, which is more common when used without an XOI and with higher than approved doses of Zurampic.
The FDA is also requiring a postmarketing study to further evaluate the renal and cardiovascular safety of Zurampic.
Gout is common in most countries in North America and Western Europe, with prevalence in the 1–4% range. In the United States, 3.9% of the adult population (age ≥20 years) self-reported gout between 2007–2008, according to one study cited in the review.
"The prevalence of gout in more affluent countries seems to be increasing in recent decades. However, only a few studies give reliable data on secular trends in gout prevalence. The US NHANES study found a significantly higher age-adjusted prevalence (3.9%) in 2007–2008 than the estimate in 1988–1994 (2.9%). This trend paralleled an observed increase in hyperuricaemia,” according to the authors of a review of literature published in the November issue of Nature Reviews Rheumatology.