ActiveSite Pharmaceuticals’ Small Molecule Protease Inhibitor Blocks Retinal Blood Vessel Damage in Rodent Model of Diabetes

BERKELEY, Calif.--(EON: Enhanced Online News)--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.”

The study’s authors are Allen Clermont, Takeshi Kita, Jia Liu, Priscilla Riva and senior author Edward P. Feener from the Joslin Diabetes Center, and Tamie J. Chilcote and Sukanto Sinha from ActiveSite Pharmaceuticals. It was funded in part by grants from the Juvenile Diabetes Research Foundation and the National Institutes of Health.

About ActiveSite Pharmaceuticals, Inc.

ActiveSite Pharmaceuticals, Inc., is a privately held, preclinical stage pharmaceutical company, located in the San Francisco Bay Area. The company utilizes proprietary lead discovery technology to discover new inhibitors for therapeutic enzyme targets in diseases with unmet medical need. Its lead program, an orally active small molecule plasma kallikrein inhibitor for the treatment of DME, is in preclinical development.