Gout

Gout Market Overview

In 2008, approximately 5.2 million patients in the U.S., 6.4 million patients in the European Union and 2.9 million patients in Japan were diagnosed with gout¹
Gout is the most common form of inflammatory arthritis in men over 40 and represents a significant medical need with limited treatment options.
In the last 40 years, only one new medication has received FDA approval for the treatment of hyperuricemia associated with gout.

Gout is a painful and debilitating 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, the most widely-prescribed xanthine oxidase inhibitor for the treatment of gout, acts by reducing the production of uric acid in the body. In large clinical trials, approximately 60 percent of patients did not respond adequately to treatment with allopurinol alone. 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. The other 10 percent are believed to produce too much uric acid.

Decision Resources

RDEA594

RDEA594, our most advanced product candidate, is a selective inhibitor of URAT1, a transporter in the kidney that regulates uric acid excretion from the body. RDEA594 has been shown to normalize the amount of uric acid excreted by gout patients previously classified as "under-excretors" of uric acid. Since the majority of gout patients are under-excretors, normalizing uric acid excretion by moderating URAT1 transporter activity with RDEA594 may provide a robust and physiologically appropriate means of reducing blood levels of uric acid, usually referred to as serum urate or sUA, when used alone or in combination with other sUA lowering agents, such as allopurinol or febuxostat (Uloric^®, Takeda Pharmaceutical Company Limited; Adenuric^®, Ipsen and Menarini), the newest xanthine oxidase inhibitor currently available for the treatment of gout. RDEA594 is nearing completion of a comprehensive Phase 2 development program designed to demonstrate its broad clinical utility in a wide spectrum of gout patients. To date, results from this program have shown the following:

When administered as a single agent in a recently completed Phase 2b study, RDEA594 was well tolerated and produced significant sUA reductions. 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 < 6 mg/dL after four weeks of treatment, compared to placebo. The primary endpoint was achieved. Reductions in sUA and increased response rates occurred in a dose-related manner and were highly clinically and statistically significant at the two highest doses tested. At the highest dose, there was a 38 percent median reduction in sUA levels after four weeks compared to a 1 percent increase on placebo (p < 0.0001). This translated into a response rate of 45 percent, compared to 0 percent for placebo (p < 0.0001). The response rate at the highest dose in patients with baseline sUA levels of <10 mg/dL (9.2 mg/dL on average) was 58 percent (p = 0.0012). Industry sources indicate that patients with serum urate levels less than 10 mg/dL represent a large majority of the gout patient population. RDEA594 was also well-tolerated with a profile of possibly drug-related adverse events comparable to placebo and only two patients (2 percent) randomized to RDEA594 discontinuing treatment due to an adverse event.

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. Significant reductions in sUA were also demonstrated when RDEA594 was administered as a single agent in gout patients with mild to moderate renal impairment. The single-agent reductions and response rates observed with RDEA594 were comparable to those achieved with approved doses of allopurinol and febuxostat. The combination of RDEA594 and allopurinol in gout patients was well tolerated and reduced sUA levels an additional 24 percent compared to allopurinol alone.

The combination of RDEA594 and febuxostat in a Phase 1 study in healthy volunteers was well tolerated and resulted in sUA reductions of approximately 70 to 80 percent from baseline.

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, and studies of RDEA594 in subjects with renal impairment.

Next Generation

Our next-generation URAT1 inhibitors have been shown in preclinical studies to demonstrate many of the same positive attributes as RDEA594, but with significantly greater potency against the URAT1 transporter. Preclinical development activities with respect to these next-generation product candidates are ongoing.