ASP-634: An Oral Drug Candidate for Diabetic Macular Edema

Abstract

Purpose: : ASP-440, a small-molecule plasma kallikrein inhibitor, was recently shown to be effective, administered systemically, in reducing blood-retinal barrier breakdown in diabetic rats (PMID: 21444925). The goal of this study was to assess the safety and selectivity of ASP-440, and obtain an orally-active prodrug of ASP-440, suitable for oral administration in the clinic for suppressing retinal vascular leakage in diabetic macular edema (DME).

Methods: : In vitro screening against a panel of proteases, receptors and ion-channels, and repeat-dosing studies with ASP-440 in vivo, were used to assess selectivity and safety. A clinically successful prodrug strategy was utilized to generate three distinct prodrugs of ASP-440. Oral dosing in rats and dogs was utilized to select one prodrug that demonstrated sufficient oral bioavailability for once-daily dosing in humans at a pharmacologically acceptable dose.

Results: : Plasma levels of ASP-440 were found to correlate with the extent of inhibition of diabetes-induced retinal vascular leakage (r² = 0.99, p = 0.03), indicating that plasma levels provide a surrogate measure of efficacious exposure. ASP-440 did not exhibit meaningful interaction with any of the 41 off-targets tested. Repeat dosing of ASP-440 (i.v.) at 5 mg/kg for 7 days resulted in daily peak plasma levels >1000x EC₉₀ levels. No adverse effects were noted, including in hematology, clinical chemistry and renal function measures. All prodrugs were found to be orally bioavailable, and were converted to ASP-440 in vivo. Of these, ASP-634 exhibited the highest bioavailability, and oral dosing at 10 mg/kg in rats resulted in peak plasma levels >25x EC₉₀ levels. Oral dosing in dogs at 20 mg/kg resulted in peak plasma levels >150x EC₉₀ levels. All doses were well-tolerated.

Conclusions: : Administered systemically, ASP-440 is a selective, safe and efficacious inhibitor of diabetes-induced blood-retinal barrier breakdown. Oral dosing with the prodrug ASP-634 in rats & dogs resulted in large multiples of efficacious exposure of ASP-440, and these "super"-therapeutic doses were well-tolerated in both species. Based on these data, qd p.o. dosing at 70 mg in the clinic is projected to result in 24 h maintenance of >EC₉₀ levels. ASP-634 is a novel oral clinical candidate for DME.

Keywords: edema • diabetic retinopathy • retina