Cymabay Therapeutics Inc. said the FDA has agreed to designs for a trio of pivotal phase III studies to test the company's oral, once-daily gout candidate, arhalofenate, with Uloric (febuxostat, Takeda Pharmaceuticals America Inc.), a milestone that gives the company clarity that could help it launch the trials this year and secure a needed partner for the program as well.

Two trials will address chronic gout, while a third will study tophaceous gout, a more advanced form of the disease.

Though arhalofenate significantly trails Astrazeneca plc's recently approved gout drug, Zurampic (lesinurad), in the race to market, Cymabay CEO Harold Van Wart told BioWorld Today that even with that approval, there's a continuing unmet need for a safe and effective uricosuric in light of renal safety concerns that led to an FDA black box warning on Zurampic's label. (See BioWorld Today, Dec. 24, 2015.)

In total, Cymabay said its phase III program for arhalofenate is likely to enroll about 1,300 patients who will be treated for at least 12 months. Each study would consist of three parallel arms to assess serum uric acid (sUA) lowering and gout flares, endpoints that will be assessed after six months of treatment.

Patients in the first of the arms would receive the combination of arhalofenate and the xanthine oxidase inhibitor (XOI) Uloric; those in the second arm would get Uloric alone together with nonsteroidal anti-inflammatory drugs or colchicine for flare prophylaxis; and those in the third arm will get Uloric alone. The dose of arhalofenate would be 800 mg in all three studies. For the two trials in chronic gout, the Uloric dose would be 40 mg, while in the tophaceous gout study, it would be 80 mg. No arhalofenate monotherapy arms will be tested.

The co-primary sUA endpoint would be assessed by comparing the responder rates for the first arm vs. the combined second and third arms in each of the three studies. The co-primary flare rate endpoint would be assessed by comparing the first arm vs. the third arm, while a secondary flare rate endpoint would be a comparison of the first arm vs. the second arm in each study.

A required safety database will track about 650 patients treated with the arhalofenate-febuxostat combination for 12 months together with efficacy data to assess the drug's risk-benefit profile. Though safety signals could emerge during the phase III studies that would lead to a call for a larger safety database, the company is not expecting that to happen, nor is it expecting any postmarket cardiovascular studies should it gain approval, such as the one attached to Zurampic.

The studies could take two to two and a half years to read out, but a partner could influence that timeline, said Van Wart.

During its lengthy development path — a journey that included a name change for the company, once known as Metabolex Inc. — the drug has so far demonstrated sUA lowering and flare reduction to varying dose-dependent degrees across three phase II studies. (See BioWorld Today, Dec. 3, 2013.)

Van Wart said arhalofenate's long pharmacokinetic half-life allows it to accomplish its uricosuric effect very gradually, contributing to the drug's renal safety, which appears to be strong based on the 1,000 patients in which it has been studied so far. It also addresses a need for control of flares, the rates of which increase shortly after the start of uricosuric therapy, because as the treatment lowers uric acid levels, it mobilizes deposits of uric acid crystals. Because of that, many patients stop taking their medicine. By contrast, Van Wart said, arhalofenate suppresses flares due to an anti-inflammatory effect – its ability to block the production of IL-1 beta, the cytokine that triggers flares.

More than 15.8 million people in the major markets have gout, many of whom never meet sUA target levels recommended by the American College of Rheumatology and the European League Against Rheumatism.

Given the size of the trials to come, the size of the gout market and the need for a large primary care sales force required to succeed, Cymabay has long planned to bring on one or more partners to help it move ahead, something it hopes to accomplish by midyear.

"We couldn't be happier with the result of the end-of-phase II discussions," Chief Financial Officer Sujal Shah told BioWorld Today. "We strongly believe it provides us and a potential partner with the most flexibility and the greatest opportunity to capitalize on a very differentiated label for arhalofenate vs. anything else that's in development or on the market for gout in a very reasonably sized program."

Though the talk primarily is for partnerships, Shah said Newark, Calif.-based Cymabay would also consider a full takeout of the asset or some sort of a licensing deal. But "relative to the company itself, we are not looking for a takeout," he said, noting that the company has other candidates in two phase II studies: MBX-8025, which is targeting orphan lipid and liver disorders, and MBX-2982, a potential treatment for type 2 diabetes.

Cymabay shares (NASDAQ:CBAY) rose 2 cents to close at $1 on Wednesday.