木瓜直播

VIENNA -- Improved drugs to force uric acid excretion as a means of treating gout are inching closer to clinical availability in the U.S., with new data reported for two such products.

For one, a product called dotinurad already approved in Japan, a pivotal study conducted in China indicated that the agent was more effective than febuxostat (Uloric). Meanwhile, findings from a 6-month extension of a previously reported phase II trial showed patients maintained reduced uric acid levels for a full year with a drug called AR882.

Both studies were reported at the European Alliance of Associations for Rheumatology (EULAR) annual meeting.

Both agents block a transporter system that acts to keep uric acid in circulation. By inhibiting one element called URAT1 in this pathway, uric acid is instead pushed into the urine stream, thus lowering serum urate. This is not a new idea: drugs including benzbromarone and lesinurad (Zurampic) also block URAT1, but they both have safety issues that effectively put them out of reach. (Lesinurad was marketed in the U.S. for a while, but was because it wasn't selling.) Another URAT1 inhibitor is available in the U.S., probenecid (Probalan), but it requires higher dosing in patients with renal impairment, a common comorbidity in gout.

The new data on AR882, reported by Robert Keenan, MD, MPH, chief medical officer of developer Arthrosi Therapeutics in San Diego, come from one of two randomized phase II studies he presented last November at another meeting. That report summarized results at 6 months for one of the trials and 12 weeks for the other, in both cases the prespecified points for the primary outcomes. The 6-month study included a 6-month extension that Keenan has now reported at EULAR.

Its main focus was on patients' tophi, with serum urate assessed as well. Digital calipers were employed to measure tophi size, and the investigators used dual-energy CT scans to quantify urate crystal deposits.

Patients were randomized into three arms: AR882 monotherapy at 75 mg/day, allopurinol monotherapy, or a combination of both (AR882 dosing was reduced to 50 mg/day in this group). At least one measurable tophus at screening was required. After completing the initial 6-month randomized phase, those assigned to allopurinol monotherapy were invited to have AR882 added at 75 mg/day, while the other arms continued as before in the extension.

The primary analysis at 6 months showed significantly greater reductions in serum urate in the two arms containing AR882 than in the group on allopurinol alone. During the extension phase, the decreases were maintained and patients who had the URAT1 inhibitor added to allopurinol had additional reductions in urate levels, such that each group had essentially the same response by month 12.

Tophus reductions seen at month 6 became more marked with the additional 6 months of treatment, with the biggest improvements seen with AR882 monotherapy, with a volume decrease of 13.3 cm³, although the combination of allopurinol and AR882 at 75 mg/day was a close second (-10.6 cm³). A similar pattern was seen for total crystal volume, with the higher-dose AR882 groups seeing mean decreases of about 26 cm³.

Oddly, though, gout flare rates during months 7-12 were highest for patients receiving allopurinol and AR882 at 75 mg/day, at 0.46 per patient-month. Rates in the other groups were less than 0.3 per patient-month. In general, though, Keenan and colleagues deemed AR882 to be well-tolerated throughout the full 12 months. A phase III trial is expected to start imminently.

Admittedly, the new data on dotinurad won't move the needle very much in terms of getting the drug onto the U.S. market. While they come from a phase III trial with more than 450 patients, it was conducted in China by the Japanese firm Eisai for the purpose of securing approval in China. Development rights in the U.S. are held by a company called Urica Therapeutics, which needs to conduct separate trials in the U.S., and thus far has .

Nevertheless, the Chinese data should make Western clinicians envious. Led by Zhuoli Zhang, MD, PhD, of Peking University First Hospital in Beijing, the trial randomized 451 patients 1:1 to dotinurad or febuxostat, an inhibitor of the xanthine oxidase enzyme required to produce uric acid in vivo. The primary efficacy endpoint was achievement of serum urate of 6 mg/dL or less.

The two drugs seemed about equally effective through 12 weeks of treatment, with about 60% of patients reaching the target urate level. After week 12, the daily dose for both drugs was doubled, from 2 to 4 mg for dotinurad, and from 20 to 40 mg for febuxostat. At that point, response rates for dotinurad shot ahead, hitting 85% at week 12, whereas no further increases in response were seen with febuxostat.

As follow-up approached 24 weeks, responder rates in both arms were decreasing, but remained markedly higher with dotinurad (74% vs 38%). Relative to baseline, mean serum urate levels declined 46% in the dotinurad group by week 24, versus 31% with febuxostat.

Safety findings were similar with the two drugs. Three patients on dotinurad and four assigned to febuxostat had serious adverse events. Eleven febuxostat patients terminated treatment because of adverse events, compared with six receiving dotinurad.

Zhang and colleagues concluded that 2 mg/day of dotinurad was noninferior to febuxostat, and at 4 mg/day it was clearly superior.