ActiveSite's ASP-440 plasma kallikrein inhibitor effective in reducing diabetes-induced blood-retinal barrier breakdown

Mar 28 2011

ActiveSite Pharmaceuticals, Inc., announced today the online publication of a study in the journal Diabetes that describes the effectiveness of its novel plasma kallikrein inhibitor ASP-440 in reducing blood-retinal barrier breakdown in a rodent model of diabetes. Diabetes-induced breakdown of the blood-retinal barrier results in leaky blood vessels in the eye, and the gradual buildup of fluid in the retina from the leakage can result in diabetic macular edema (DME), the primary cause of vision loss in diabetic individuals. DME affects more than 1 million individuals in the U.S. alone, and no FDA-approved medicines are currently available for its treatment.

“Also, because ASP-440 is effective via a systemic route of administration, without need for intraocular delivery, targeting plasma kallikrein opens up the possibility of an orally-administered therapeutic approach to DME.”

In the study, co-authored by scientists from the Joslin Diabetes Center, an affiliate of Harvard Medical School, and ActiveSite Pharmaceuticals, the integrity of the blood-retinal barrier in diabetic rats was measured using a well-established technique that measures the leakage of the plasma protein albumin from the vascular compartment into the retina. Compared to non-diabetic healthy rats, diabetic animals demonstrated a 2.6-fold increase in the rate of albumin leakage into the retina. Treatment of diabetic animals with systemically-administered ASP-440 for four weeks reduced the excess rate of albumin leakage by more than 80%, without affecting blood glucose.

ASP-440 was also effective in preventing blood-retinal barrier breakdown in hypertensive rats, reducing excessive albumin leakage into the retina by 90% following systemic treatment for seven days, without affecting blood pressure. Hypertension is a known risk factor for development of DME.

"The pharmacological activity of ASP-440 in reducing the excessive retinal albumin leakage in diabetic and hypertensive rats suggests that the serine protease plasma kallikrein plays a key role in blood-retinal barrier breakdown caused by hyperglycemia and hypertension, and so inhibition of this enzyme may provide a new therapeutic approach to the treatment of DME", commented Tamie J. Chilcote, Ph.D., chief operating officer of ActiveSite, and a co-author of the study. "Also, because ASP-440 is effective via a systemic route of administration, without need for intraocular delivery, targeting plasma kallikrein opens up the possibility of an orally-administered therapeutic approach to DME."