Positive results from Ardea's RDEA594 combination study with febuxostat or allopurinol for gout

Ardea Biosciences, Inc. (Nasdaq: RDEA) announced positive results from two clinical studies of RDEA594 in combination with currently marketed drugs for the treatment of gout patients, febuxostat (Uloric®) and allopurinol.  RDEA594, Ardea's lead product candidate for the chronic management of hyperuricemia and gout, is an orally administered compound that inhibits the URAT1 transporter, a biological mechanism that is different from, but complementary to, that of allopurinol and febuxostat.  While allopurinol and febuxostat account for greater than ninety percent of U.S. prescriptions for the chronic treatment of gout, approximately one half of patients do not adequately respond to standard doses of these drugs, leaving a significant portion of the gout population with limited options.

Combination of RDEA594 and Febuxostat (Study 111)

In this 21-patient, open-label, clinical pharmacology study, 100 percent of patients receiving the combination of RDEA594 and febuxostat achieved serum urate (or "sUA") levels below the clinically important target of 6 mg/dL, compared to 67 percent and 56 percent for 40 mg and 80 mg, respectively, of febuxostat alone.  At the highest combination doses tested (600 mg of RDEA594 and 80 mg of febuxostat), 100 percent of patients also 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 study included 2 cohorts of gout patients with sUA greater than 8 mg/dL on no urate-lowering therapy.  All patients received colchicine beginning one week prior to baseline and continuing for 5 weeks for flare prophylaxis.  The first cohort of patients in the study consisted of 12 gout patients with a median baseline sUA of 9.2 mg/dL who were administered 40 mg febuxostat for the first week, 40 mg febuxostat in combination with 400 mg RDEA594 for the second week, and then 40 mg febuxostat in combination with 600 mg RDEA594 for the third week.  This sequence was repeated with 80 mg febuxostat in a second cohort of 9 patients who had a median baseline sUA of 10.4 mg/dL.

The combination of RDEA594 and febuxostat was synergistic, with the addition of 600 mg RDEA594 producing additional 39 and 51 percent reductions compared to 40 mg and 80 mg febuxostat alone, respectively.  At the highest combination doses in cohorts one and two, patients achieved intraday median sUA levels of 2.4 mg/dL and 2.0 mg/ dL, respectively.  These levels of sUA reduction suggest the combination of RDEA594 and febuxostat may be particularly useful in patients who have accumulated large deposits of uric acid, or tophi.  In these patients, the substantial reduction of sUA, coupled with increased excretion of uric acid associated with RDEA594's URAT1 mechanism, may lead to improved resolution of these tophi.

No clinically relevant drug interactions were observed between RDEA594 and febuxostat.  The combination of RDEA594 and febuxostat was well tolerated, with no serious adverse events or discontinuations due to adverse events.  There were no Grade 2 or higher increases in serum creatinine on RDEA594 alone or the combination with febuxostat, but one Grade 2 serum creatinine increase occurred on colchicine alone.  There was one Grade 3 increase in the liver enzyme, alanine aminotransferase (ALT), on febuxostat 40 mg alone, which normalized during combination treatment with RDEA594.

Combination of RDEA594 and Allopurinol (Study 110)

In this 20-patient, open-label clinical pharmacology study, 100 percent of patients receiving all combinations of RDEA594 and allopurinol achieved sUA reductions to below the 6 mg/dL target.  On 300 mg allopurinol alone, only 20 percent of patients achieved target sUA levels below 6 mg/dL.  On 600 mg RDEA594 alone, 67 percent of patients achieved sUA levels below 6 mg/dL, which was significantly better than allopurinol alone (p < 0.05).  At the highest combination doses tested, 90 percent of patients also reached sUA levels below 5 mg/dL, and 50 percent reached levels below 4 mg/dL.  Study 110's design was similar, but not identical, to Study 111 and included 2 cohorts of gout patients with sUA greater than 8 mg/dL on no urate-lowering therapy who began colchicine dosing one week prior to baseline and continued it for 5 weeks.  In this study, the first cohort of 10 patients with a median baseline sUA of 9.8 mg/dL received 300 mg allopurinol alone for the first week, then 300 mg allopurinol plus 400 mg RDEA594 for the second week, followed by 400 mg RDEA594 alone for the third week.  In the second cohort, 10 patients with a median baseline sUA of 9.1 mg/dL followed the same dosing scheme for the same time period at a dose of 300 mg allopurinol and 600 mg RDEA594.

At the highest combination doses tested, intraday median sUA levels below 3 mg/dL were achieved.  No clinically relevant drug interactions were observed between RDEA594 and allopurinol in this study; however, consistent with prior experience, plasma levels of oxypurinol, an active metabolite of allopurinol, were decreased approximately 25-35 percent.  Despite this small decrease, the combination of 600 mg RDEA594 and allopurinol demonstrated a completely additive response.

The combination of RDEA594 and allopurinol was well tolerated.  There were no serious adverse events or discontinuations that were considered possibly related to RDEA594 or the combination.  There were no clinically relevant increases in serum creatinine or ALT in this study.  Two patients receiving RDEA594 and colchicine had Grade 4 increases in creatine kinase (CK); one of these, although asymptomatic, was considered to be rhabdomyolysis by the investigator.  Both cases were considered possibly related to colchicine and not related to RDEA594.  Elevations in CK and rhabdomyolysis are known side effects of colchicine.  One of these patients was also receiving a statin, which is also known to cause CK elevations, particularly when combined with colchicine.  Clinically significant elevations in CK have not been observed in more than 400 patients exposed to RDEA594 who were not also receiving colchicine.  Furthermore, in a previously reported, randomized, monotherapy, placebo-controlled trial (Study 202), the rate of Grade 4 CK increases was lower in patients receiving RDEA594 plus colchicine (2 percent) than those receiving colchicine alone (4 percent).

"We are very pleased with these results, which demonstrate the ability of RDEA594 in combination with current standard of care to reduce uric acid levels in gout patients to an extent generally only achieved with intravenous therapy," commented Barry D. Quart, PharmD, Ardea's president and chief executive officer.  "Based on these results, we are well-positioned to conduct further studies of these well-tolerated oral combinations in patients with the most severe forms of gout."