Arthrosi therapeutics San Diego, CA, United States
Disclosure information not submitted.
Roy Fleischmann1, James Cheng-Chung Wei2, Zancong Shen3, sarah Morris4, Elizabeth Polvent5, Andrea Clouser-Roche4, Vijay Hingorani6, Rongzi Yan7, Shunqi Yan8, Robert Keenan9 and Li-Tain Yeh10, 1Division of Rheumatology, University of Texas Southwestern Medical Center, Metroplex Clinical Research Center, Dallas, TX, 2Chung Shan Medical University Hospital, Department of Rheumatology, Taichung, Taiwan, 3Arthrosi Therapeutics, San Diego, CA, 4Arthrosi Therapeutics Inc, San Diego, CA, 5Arthrosi Therapeutics, Inc., Roseville, CA, 6Vanguard Healthsciences, Inc., San Diego, CA, 7Arthrosi Therapeutics, Inc, Irvine, CA, 8Arthrosi Therapeutics, Inc., Laguna Hills, CA, 9Arthrosi Therapeutics, Chapel Hill, NC, 10Arthrosi Therapeutics, Inc., Irvine, CA
Background/Purpose: In early phase studies AR882 exhibited good dose proportionality, long half-life and dose-dependent serum urate (sUA) lowering effect in a broad range of doses in healthy subjects and gout patients. In a phase 2b study, following once-daily dosing up to 3 months, the pharmacokinetics (PK) and pharmacodynamics (PD), including sUA lowering effect of AR882, were evaluated in all patients; in a subset of these patients more frequent laboratory monitoring was done.
Methods: In the phase 2b, 12-week study, 140 subjects were enrolled into three treatment groups: placebo (n=47), AR882 50 mg (n=46) and AR882 75 mg (n=47) at approximately 1:1:1 ratio. A single blood sample was collected for PK/PD assessment at each clinical visit (every 2 weeks) through Week 12. In addition, a total of 25 gout patients participated in an optional sub-study with more frequent sampling occurring on baseline, Week 2, and Week 8 visits.Serial blood samples were collected up to 24 hours post-dose for AR882 and sUA measurements.
Results: Following long-term treatment, AR882 showed stable exposure across the entire treatment period. At steady-state, AR882 was readily absorbed with median Tmax of 1.50 to 3.50 hours post-dose. AR882 demonstrated dose-dependent increase in plasma exposure. Average half-life of AR882 ranged between approximately 14 and 22 hours. Its active metabolite AR896 was formed with median Tmax between 5- and 8-hours post-dose. Consistent with observations in the early phase studies, AR896 constituted of approximately 9% of Cmax and 10-12% of AUC exposures with longer half-life (29-36 hours) than the parent drug. In the sub-study group with more frequent sampling, sUA lowering effect in both AR882 treatment groups showed a smooth, consistent and flat profile across 24 hours with the lowest mean sUA reduced from baseline 8.6 mg/dL to 4.1 mg/dL (-53%) in the 50 mg group and to 3.2 mg/dL (-62%) in the 75 mg group (Figure 1). sUA lowering effects and the response rates in these patients were similar to those observed in an earlier, well-controlled, 3-week, cross-over design phase 2a study (Table 1). Mild or moderate adverse events including gout flares, diarrhea, headache, and upper respiratory infection were observed. None of the AEs led to discontinuation of investigational product.
Conclusion: In a subset of patients with full PK/PD collection, AR882 showed potent sUA lowering effect with similar exposures to those observed in closely monitored early-phase studies. AR882 50 mg and 75 mg doses were well tolerated during the entire study with an unremarkable safety profile.
Figure 1. Mean (SE) sUA levels following 8-week dosing of AR882
Table 1. Similar response in sUA lowering between gout patients in phase 2b PKPD subset and phase 2a studies.
