Session Information
Session Title: Metabolic and Crystal Arthropathies: Basic Science
Session Type: Abstract Submissions (ACR)
Background/Purpose:
In most patients with gout, elevated serum urate is linked to excess uric acid reabsoprtion in the proximal renal tubule by anion transporters/exchangers, including URAT1, OAT4 and OAT10. It is also known that initiation of serum urate lowering therapy (ULT) in gout patients significantly increases the risk of flares, a process that is believed to be mediated by mono sodium urate (MSU) crystal activation of the inflammasome with subsequent release of pro-inflammatory mediators, including IL-1β. Arhalofenate is an investigational drug which has completed phase 2 of development for the treatment of gout patients with hyperuricemia that are at risk for flares. The dual action of arhalofenate was studied for inhibition of uric acid uptake by renal urate transporters and for suppression of MSU crystal stimulated IL-1β production in isolated mouse macrophages and in a murine air pouch model.
Methods:
The activities against the human urate transporters URAT1, OAT4 and OAT10 were determined using the uptake of 14C-uric acid into human HEK293 cells transiently expressing the relevant transporter and compared to uptake into parental HEK293 cells. The anti-inflammatory response was evaluated following acute MSU crystal treatment of (1) mouse macrophages and (2) mouse in an air pouch model, in both cases measuring the elaboration of pro-inflammatory mediators including IL-1β.
Results:
Arhalofenate inhibited uric acid uptake by all three transporters with IC50sof 92 μM for URAT1, 3 μM for OAT4 and 53 μM for OAT10. These results are pharmacologically relevant for inhibition of urate reabsoprtion because arhalofenate acid levels in human urine were found to be 116 ± 23 µM (Mean ± SEM) at a 600 mg dose. In thioglycolate-elicited intraperitoneal macrophages, arhalofenate acid (150 μM) suppressed IL-1β levels by 77% which was indistinguishable from dexamethasone (75%, p<0.05 by one-way ANOVA). In the murine air pouch model, arhalofenate treatment (250 mg/kg) for 3 days prior to MSU crystal induction resulted in 76 % reduction in the elaboration of IL-1β in response to MSU. This response was again similar to that observed for dexamethasone. The anti-inflammatory concentrations of arhalofenate acid are relevant to the human clinical exposures.
Conclusion:
Arhalofenate is a novel anti-inflammatory uricosuric agent with the potential to target both serum uric acid reduction and the painful flares that accompany gout. The data from this study support that arhalofenate acts by mediating inhibition of renal transporters/exchangers of uric acid and by suppression of the production of IL-1β in response to MSU crystals in both in vitro and in vivo models of MSU crystal induced inflammation. These properties strongly support the continued clinical development of arhalofenate for treating elevated serum urate and lowering the risk of flares.
Disclosure:
Y. J. Choi,
Metabolex, Inc.,
3;
V. Larroca,
Metabolex, Inc.,
3;
A. Lucman,
Metabolex, Inc.,
3;
V. Vicena,
Metabolex, Inc.,
3;
N. Abarca,
Metabolex, Inc.,
3;
T. Rantz,
Metaboelx, Inc.,
3;
B. E. Lavan,
Metabolex, Inc.,
3;
C. A. McWherter,
Metabolex, Inc.,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/arhalofenate-is-a-novel-dual-acting-agent-with-uricosuric-and-anti-inflammatory-properties/