March 2012
Volume 53, Issue 14
ARVO Annual Meeting Abstract  |   March 2012
ASP-634: An Oral Drug Candidate for Diabetic Macular Edema
Author Affiliations & Notes
  • Tamie J. Chilcote
    ActiveSite Pharmaceuticals Inc, San Francisco, California
  • Sukanto Sinha
    ActiveSite Pharmaceuticals Inc, San Francisco, California
  • Footnotes
    Commercial Relationships  Tamie J. Chilcote, ActiveSite Pharmaceuticals (E), Inventor (P); Sukanto Sinha, ActiveSite Pharmaceuticals (E), Inventor (P)
  • Footnotes
    Support  NIH Grant EY019629
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 2240. doi:
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      Tamie J. Chilcote, Sukanto Sinha; ASP-634: An Oral Drug Candidate for Diabetic Macular Edema. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2240.

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      © ARVO (1962-2015); The Authors (2016-present)

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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 

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