AstraZeneca said today it is proceeding with regulatory submissions for its 200 mg dosage of its investigational drug lesinurad after it met all but one its primary endpoints in three Phase III studies assessing its effectiveness in treating symptomatic gout in combination with other compounds.

The company disclosed top-line results from the Combining Lesinurad with Allopurinol in Inadequate Responders (CLEAR)1 and CLEAR2 studies, which studied both the 200 mg and 400 mg once-daily dosages of lesinurad in combination with the xanthine oxidase (XO) inhibitor allopurinol, in symptomatic gout patients not achieving target sUA levels on their current allopurinol dose.

Lesinurad is designed to inhibit the URAT1 transporter, increasing uric acid excretion and thereby lowering sUA. Both lesinurad dosages, combined with allopurinol, saw a statistically significant higher proportion of patients reaching the target goal of <6.0 mg/dL of serum uric acid (sUA) after six months of treatment compared to allopurinol alone. The three most commonly reported adverse events in both trials were upper respiratory tract infection, nasopharyngitis and back pain.

CLEAR1 and CLEAR2 were carried out, respectively, in the U.S. (603 patients) and globally (610 patients). Both were multicenter, randomized, placebo-controlled studies designed to compare the efficacy and safety of lesinurad (200mg and 400mg once daily) when added to the patient’s current stable medically appropriate dose of allopurinol (at least 300mg daily, but at least 200 mg daily for those with moderate renal impairment) compared to placebo plus allopurinol. Patients entering CLEAR1 and CLEAR2 had multiple sUA levels above target and had also reported at least two gout flares in the 12 months prior to randomization.

AstraZeneca also disclosed results from the Combination Treatment Study in Subjects with Tophaceous Gout with Lesinurad and Febuxostat (CRYSTAL) study, which assessed the same dosages of lesinurad in combination with the XO inhibitor febuxostat (80mg once daily) in gout patients with visible nodules of uric acid crystals deposited in joints and skin, known as tophi.

Lesinurad 400mg plus febuxostat met the primary endpoint, with a statistically significant higher proportion of patients reaching the target sUA goal of <5.0 mg/dL after six months of treatment compared to febuxostat alone (p<0.0001). However, lesinurad 200 mg did not achieve statistical significance at month 6—though the dosage combination with febuxostat achieved superior results over placebo plus febuxostat after months 1 to 5, 8, 10 and 12 following treatment.

Also, while incidence of renal-related adverse events (including serious events) and incidence of kidney stones with lesinurad 200 mg plus XO inhibitor was comparable to placebo plus XO inhibitor, such incidences were higher with lesinurad 400 mg plus XO inhibitor.

AstraZeneca did not offer possible reasons for the six-month result and differences in renal-related adverse events, saying instead that results from CRYSTAL as well as CLEAR1 and CLEAR2 will be submitted to an unspecified “scientific meeting” later this year. A full assessment of the safety and tolerability findings of all three studies is ongoing, the company added.

CRYSTAL was a 12-month global multicenter, randomized, placebo-controlled study of 324 patients comparing the efficacy and safety of lesinurad (200 mg and 400 mg once daily) in combination with febuxostat (80 mg) compared to febuxostat (80 mg) plus placebo in gout patients with tophi and sUA levels above target. All patients were started on febuxostat three weeks before initiation of the randomized study medication with either placebo or lesinurad. CRYSTAL’s three most commonly reported adverse events were nasopharyngitis, arthralgia and upper respiratory tract infection.

Patients who completed any of the randomized pivotal Phase III clinical studies had the option to enroll in two ongoing open-label, uncontrolled extension studies to continue to evaluate the safety and efficacy of combination therapy with lesinurad 200 mg and 400 mg with XO inhibitors, AstraZeneca said.

“We are encouraged by our initial review of the top-line results from the CLEAR1, CLEAR2 and CRYSTAL studies which provide important new information on the efficacy and safety of lesinurad in combination with febuxostat and allopurinol. These data indicate that combination therapy with lesinurad may be a potential treatment option for gout patients,” Briggs Morrison, evp, Global Medicines Development and CMO, said in a statement.

All three trials were conducted by Ardea Biosciences, a wholly-owned subsidiary of AstraZeneca following its $1.26 billion acquisition by the pharma giant in 2012. Ardea is developing lesinurad among several molecules for treatment of gout.

Those molecules include RDEA3170, a selective uric acid re-absorption inhibitor (SURI). RDEA3170 offers a different and complimentary method of action—increasing excretion of sUA—to the existing gout standard of care drugs allopurinol, sold as a generic under several brand names; and febuxostat, marketed in the U.S. under the name ULORIC by Takeda Pharmaceuticals under license from Teijin.

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