Novel Gout Drug Aces Mid-Stage Tests

Derick Alison
Derick Alison
6 Min Read

SAN DIEGO — An investigational once-daily oral agent that inhibits urate transporter-1 (URAT1) as a means of forcing uric acid excretion showed good efficacy and safety in a pair of phase II trials reported here.

In one of these studies, the new product, called AR882 for the time being, reduced serum urate by 40% to 60% in dose-dependent fashion over a 12-week treatment period, whereas a placebo group showed essentially no change in this key biomarker, according to Robert Keenan, MD, MPH, chief medical officer of AR882’s developer, Arthrosi Therapeutics in San Diego.

The second trial focused on gout patients with significant tophi, perhaps the most important patient-centered symptom of gout after pain. It confirmed the urate-lowering effect, Keenan told attendees at the American College of Rheumatology annual meeting, and also demonstrated that AR882 effectively diminished the size and, in almost one-third of patients, the number of tophi.

URAT1 isn’t a new target in gout. This molecule mediates the reabsorption of uric acid; inhibiting then causes the kidneys to dump more uric acid into the urine. Medications such as benzbromarone and lesinurad (Zurampic) also block URAT1, but the former is somewhat hepatotoxic and is not sold in most countries, including the U.S.; lesinurad also had significant adverse effects and its manufacturer pulled it from the market in 2019 because of poor sales.

Another URAT1 inhibitor is probenecid (Probalan), for which safety is less of an issue, but it requires higher doses in patients with renal impairment. Patients with glomerular filtration rates (GFRs) below 30 mL/min may not respond to probenecid at all.

Arthrosi developed AR882 with the belief that it will be safer and more effective in patients with kidney disease, a common comorbidity in gout.

The study to demonstrate urate-lowering ability enrolled 140 patients in the U.S., Taiwan, and Australia, randomized to placebo or either 50 or 75 mg/day of AR882. Serum urate at baseline averaged about 8.5 mg/dL.

After the first week of treatment, mean serum urate declined to 5 mg/dL in the low-dose group and to 3.5 mg/dL with the 75-mg dose; the placebo group showed no change. Urate levels then remained constant through the rest of the 12-week treatment period.

About half of patients on 75-mg AR882 achieved serum urate levels below 4 mg/dL by week 12; this degree of response was achieved in only a handful of participants in the low-dose group and none assigned to placebo.

Notably, the study found the same degree of urate lowering in the subgroup with renal impairment — estimated GFR in the range of 45-60 mL/min — as in those with more normal kidney function.

The second study enrolled 40 people with tophaceous gout. Patients needed to have at least one tophus; the mean among all participants was about 440 mm2 in tophus area. Serum urate was measured regularly as well.

Patients were randomized to three treatment groups: allopurinol monotherapy at 300 mg/day, allopurinol at this dosage plus 50 mg/day of AR882, or 75 mg/day of AR882 with no allopurinol. Blinded treatment lasted 6 months, followed by a voluntary extension; those initially assigned to allopurinol then had 50 mg/day of AR882 added.

Effects on serum urate were similar to those seen in the other trial. Patients on allopurinol monotherapy showed smaller reductions than either of the two AR882 groups.

Some 29% of the higher-dose AR882 group (four of 14) showed complete resolution of at least one tophus. Keenan said it was “almost unheard of” to see total disappearance of a tophus with just 6 months of an oral drug. Mean change in tophus volume was -8.3 cm3. In the other two groups, just one patient each had a tophus resolve completely.

Keenan also reported “exploratory” outcomes for which the trial wasn’t really powered. Rates of gout flare were numerically lower in the two AR882 groups (43%-46% vs 77%) over the first 3 months, a difference that was maintained out to month 6.

Safety findings were encouraging as well, with “no cardiovascular, renal, or hepatic signals,” Keenan said.

A phase III trial is now in the works, according to Arthrosi.

  • author['full_name']

    John Gever was Managing Editor from 2014 to 2021; he is now a regular contributor.

Disclosures

The studies were sponsored by Arthrosi Therapeutics.

Keenan and most other authors were company employees.

Primary Source

American College of Rheumatology

Source Reference: Keenan R, et al “AR882, an efficacious and selective URAT1 inhibitor for patients with chronic gouty arthritis and subcutaneous tophi: results from a global, prospective, proof-of-concept trial using dual energy computed tomography” ACR 2023; Abstract L15.

Secondary Source

American College of Rheumatology

Source Reference: Wei J, et al “Efficacy and safety of AR882, a selective uric acid transporter 1 (URAT1) inhibitor, in gout patients with various baseline characteristics following 12-week treatment in patients” ACR 2023; Abstract 0244.

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