Session Type: Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: AR882 is a potent and selective uric acid transporter 1 (URAT1) inhibitor under development for the treatment of hyperuricemia or gout. Phase 1 single ascending dose and multiple ascending dose clinical studies in healthy adult male subjects demonstrated linear pharmacokinetics and dose-dependent serum uric acid (sUA) lowering effect. A phase 2a study in patients with gout is ongoing to evaluate efficacy following a three-week treatment regimen comparing AR882 with 40 mg febuxostat.
Methods: In a phase 2a, single-center, two-sequence, cross-over study, adults with gout (sUA > 7 mg/dL) were randomized to receive a once-daily, three-week treatment with AR882 50 mg alone or in combination with febuxostat 40 mg. Eleven patients have been enrolled in this ongoing study. Serial blood samples were collected for measurement of sUA, AR882 or febuxostat pharmacokinetics and pharmacodynamics at the end of each treatment week (Day 7, Day 14 and Day 21). Urine samples were collected for assessment of uric acid excretion. Laboratory safety tests, vital signs, and electrocardiograms were collected throughout the study.
Results: Following treatment of AR882, 100% of patients had sUA levels below 6 mg/dL, with 63% of patients below 5 mg/dL. AR882 reduced sUA from baseline (9.0 ± 1.3 mg/dL) to 4.7 ± 0.7 mg/dL at 24 hours postdose following multiple doses, corresponding to 47.1 ± 9.4% reduction. In comparison, febuxostat 40 mg reduced sUA levels to 6.1 ± 1.3 mg/dL (33.7 ± 6.7% reduction), with 50% and 13% patients below 6 and 5 mg/dL, respectively. The combination of AR882 and febuxostat further reduced sUA levels to 3.5 ± 1.1 mg/dL (61.0 ± 10.0% reduction) at 24 hours postdose with percentage of patients < 6, 5, 4 mg/dL at 100%, 78%, 67%, respectively. Fractional excretion of uric acid following AR882 treatment was higher than baseline. Exposure of AR882 in gout patients was slightly lower than in healthy subjects presumably due to higher BMI and body weight. AR882 showed similar exposure between patients with normal renal function and mild renal impairment. In mildly renal impaired patients, AR882 reduced sUA from 8.6 ± 1.1 mg/dL mg/dL to 4.5 ± 0.8 mg/dL. AR882 was well tolerated. There were no clinically significant laboratory or ECG abnormalities noted. All adverse events were mild or moderate in severity. One subject with viral bronchitis was discontinued due to concern of COVID-19.
Conclusion: AR882 produced marked reductions in sUA, with all patients achieving and maintaining levels below 6 mg/dL following multiple dosing of AR882. These data provide clear guidance for dose selection in future large phase 2 studies and support continued development of AR882 alone or in combination with XO inhibitors for treatment of gout.
To cite this abstract in AMA style:Yeh L, Polvent E, Shen Z, Hingorani V, Clouser-Roche A, Mikelatis C, Yan S, Yan R. AR882, a Potent and Selective Uricosuric Agent, Significantly Reduced Serum Urate in Patients with Gout in a Phase 2a Study [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/ar882-a-potent-and-selective-uricosuric-agent-significantly-reduced-serum-urate-in-patients-with-gout-in-a-phase-2a-study/. Accessed November 28, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ar882-a-potent-and-selective-uricosuric-agent-significantly-reduced-serum-urate-in-patients-with-gout-in-a-phase-2a-study/