Gout

• In 2008, approximately 8.3 million patients in the U.S.¹, 6.4 million patients in the European Union and 2.9 million patients in Japan were diagnosed with gout²
• Gout is the most common form of inflammatory arthritis in men over 40 and represents a significant unmet medical need with limited treatment options.
• In the last 40 years, only two new medications have received FDA approval for the treatment of hyperuricemia associated with gout.

Gout is a painful, debilitating and progressive disease caused by abnormally elevated levels of uric acid in the blood stream. This leads to the deposition of painful, needle-like uric acid crystals in and around the connective tissue of the joints and in the kidneys resulting in inflammation, the formation of disfiguring nodules (tophi), intermittent attacks of severe pain (acute flares) and kidney damage (nephropathy). In addition, evidence suggests that the chronic elevation of uric acid associated with gout, known as hyperuricemia, may also have systemic consequences, including an increased risk for kidney dysfunction and cardiovascular disease.

While gout is a treatable condition, there are limited treatment options, and a number of adverse effects are associated with most current therapies. Allopurinol and febuxostat (Uloric^®, Takeda Pharmaceutical Company Limited; Adenuric^®, Ipsen and Menarini) are the two most widely-prescribed xanthine oxidase inhibitors for the treatment of gout. Xanthine oxidase inhibitors act by reducing the production of uric acid in the body. However, since only about 10 percent of gout patients are believed to produce too much uric acid, xanthine oxidase inhibitors have been associated with limited efficacy. For example, in large clinical trials, approximately 60 percent of patients did not respond adequately to treatment with allopurinol alone or febuxostat alone at its approved starting dose of 40 mg per day. In large clinical trials to date, the tolerability profile of febuxostat has been shown to be very similar to allopurinol with liver function abnormalities and nausea the most commonly reported adverse events. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel and as of May 12, 2010, the FDA had received 11 reports of hypersensitivity reactions to febuxostat.

While only about 10 percent of gout patients are believed to produce too much uric acid, approximately 90 percent of gout patients are considered to have a defect in their ability to excrete sufficient amounts of uric acid and are classified as "under-excretors" of uric acid.

1. NHANES
2. Decision Resources

• When administered as a single agent in a Phase 2b study (Study 202), RDEA594 was well tolerated and produced significant reductions in uric acid in the blood. In this randomized, double-blind, placebo-controlled, dose-escalation study of 123 gout patients with hyperuricemia (sUA levels greater than or equal to 8 mg/dL) the primary endpoint was a significant increase in the proportion of patients who achieved a response, defined as a reduction of sUA to below 6 mg/dL after four weeks of treatment, compared to placebo. The primary endpoint was achieved. The response rates on placebo, 200 mg RDEA594, 400 mg RDEA594 and 600 mg RDEA594 were 0 percent, 13 percent, 42 percent and 60 percent, respectively. The response rates in both the 400 mg and 600 mg dose groups were highly clinically and statistically significant. For patients with baseline uric acid levels less than 10 mg/dL, who represent the majority of gout patients in clinical practice, response rates were 57 percent and 75 percent in the 400 mg and 600 mg dose groups, respectively.

• In a 21-patient, open-label, Phase 1b clinical pharmacology study of RDEA594 in combination with febuxostat (Study 111) in gout patients, 100 percent of patients receiving the combination achieved sUA levels below the clinically important target level of 6 mg/dL, compared to 67 percent and 56 percent for patients receiving 40 mg and 80 mg, respectively, of febuxostat alone. At the highest combination doses tested (600 mg RDEA594 combined with 80 mg febuxostat), 100 percent of patients reached sUA levels below 4 mg/dL, with 58 percent achieving levels below 3 mg/dL. No patient achieved these reduced sUA levels on either dose of febuxostat alone. The combination of RDEA594 and febuxostat was well tolerated with no serious adverse events or discontinuations due to adverse events and no clinically relevant drug interactions were observed between RDEA594 and febuxostat.

• In a 20-patient Phase 1b clinical pharmacology study evaluating the use of RDEA594 in combination with 300 mg allopurinol, administered once daily in gout patients (Study 110), 100 percent of patients at all combination doses evaluated achieved sUA levels below the target of 6 mg/dL, compared to 20 percent of patients on allopurinol alone. Of patients receiving RDEA594 600 mg alone, 67 percent achieved sUA levels below 6 mg/dL, which was significantly higher than the percent reaching target on allopurinol alone (p < 0.05). At the highest combination doses tested (600 mg RDEA594 combined with 300 mg allopurinol), 90 percent of patients reached sUA levels below 5 mg/dL, and 50 percent reached levels below 4 mg/dL. The combination of RDEA594 and allopurinol was well tolerated, with no serious adverse events or discontinuations that were considered possibly related to RDEA594 or the combination.

• In a Phase 2a study, RDEA594 was well tolerated and produced significant reductions in sUA levels when administered as a single agent and when combined with allopurinol in gout patients with hyperuricemia.

• Results from multiple studies have indicated that the activity of RDEA594 is not diminished in patients with varying degrees of renal impairment.

Additional data from our Phase 2 development program will include results from a Phase 2b study evaluating 200 mg, 400 mg and 600 mg of RDEA594 as an add-on to allopurinol in patients that do not respond adequately to allopurinol alone.