CymaBay Therapeutics, Inc, a clinical-stage biopharmaceutical company developing therapies to treat metabolic diseases with high unmet medical need, announced that it has successfully concluded its end-of-phase 2 meeting discussions with the U.S. Food and Drug Administration (FDA) on the Phase 3 development program for arhalofenate.
Correspondence with the FDA subsequent to the formal end-of-Phase 2 meeting has resolved the remaining details of the Phase 3 design. Arhalofenate is a novel dual-acting product candidate for the treatment of gout that both lowers serum uric acid (sUA) and reduces gout flares. It is the first compound in a new class of investigational gout therapy that CymaBay refers to as Urate Lowering Anti-Flare Therapy (ULAFT). CymaBay is developing arhalofenate as a combination product with febuxostat.
CymaBay reached agreement with the FDA on all of the key elements of a Phase 3 program that would support registration. The program would include two Phase 3 studies of arhalofenate in combination with febuxostat in patients with chronic gout and a third study in tophaceous gout, a more advanced form of the disease in which patients have deforming nodular deposits of urate crystals in soft tissues and joints referred to as tophi.
Agreement was reached on coprimary efficacy endpoints for the two separate clinical actions of arhalofenate. The sUA lowering would be assessed as responder rates for patients achieving the targets of <6 and <5 mg/dL for chronic and tophaceous gout, respectively. The data could support an indication for the management of hyperuricemia associated with gout in combination with febuxostat in these two patient populations. Flare data will be collected with an electronic diary and assessed using the same flare definition successfully used in the Phase 2 program. These data could support an indication for flare prophylaxis. In addition, agreement was reached on the methodology to be used for assessing the resolution of tophi in patients with tophaceous gout.
In total, the agreed upon Phase 3 program would enroll approximately 1300 patients intended to receive treatment for at least 12 months. Each Phase 3 study would consist of three parallel arms to assess the sUA and flare endpoints after 6 months of treatment. Patients in arm 1 would receive the combination of arhalofenate and febuxostat, those in arm 2 febuxostat alone together with flare prophylaxis (NSAID or colchicine) and those in arm 3 febuxostat alone. The dose of arhalofenate would be 800 mg in all three studies. For the two trials in chronic gout, the febuxostat dose would be 40 mg, while in the tophaceous gout study, it would be 80 mg. No arhalofenate monotherapy arms are required in the Phase 3 program.
The coprimary sUA endpoint would be assessed by comparing the responder rates for arm 1 vs. the combined arms 2 and 3 in each of the three studies. The coprimary flare rate endpoint would be assessed by comparing arm 1 vs. 3, while a secondary flare rate endpoint would be a comparison of arm 1 vs. 2, in each of the three studies. It was agreed that a safety database of approximately 650 patients treated with the arhalofenate-febuxostat combination for 12 months would be sufficient, together with efficacy data, to assess the risk benefit profile.
“If successful in Phase 3, the arhalofenate-febuxostat combination would be the first dual acting treatment for gout providing needed sUA lowering as well as the clinically important benefit of reduction in painful flares,” commented Michael A. Becker, MD, Professor Emeritus of Medicine, The University of Chicago Pritzker School of Medicine.
“If realized, this would be an important distinction from other gout treatment options.”
“We are very pleased with the positive outcome and constructive advice received from the FDA during our end-of-Phase 2 discussions,” commented Harold Van Wart, Chief Executive Officer of CymaBay. “We now have clear direction as to how to conduct a Phase 3 program that could capture the dual benefits of arhalofenate in two separate patient populations with gout. This clarity relating to the Phase 3 program will also help us move forward with our partnering discussions with the goal of starting Phase 3 in 2016.”
