SBIR-STTR Award

In the 62 million companion dog population in the United States, there has been a three-fold increase in diabetes mellitus (DM) over the last 30 years. In dogs, DM is characterized by the rapid onset of bilateral sugar cataracts which often result in vision loss. Today, nearly one in three 3 dogs with cataracts is diabetic. Sugar cataracts cannot be currently prevented and surgery is the only treatment available. The $2,500 - $5,000 cost for this surgery, however, can be prohibitive because it is not covered by most insurance policies. To address the significant need for an alternate treatment for sugar cataracts, this proposal seeks to develop a topical aldose reductase inhibitor (ARI) formulation, Kinostat, for the veterinary market. Studies have established that aldose reductase initiates sugar cataracts in both diabetic and galactosemic animals and that ARIs prevent sugar cataract formation in both of these animal models. Based on prevention studies in dogs that report that oral administration of ARIs reduce sugar cataract formation in a dose-dependent manner, we have demonstrated in preliminary results that topical Kinostat treatment of galactose-fed beagles with cortical sugar cataracts not only arrests cataract development, but actually partially reverses early sugar cataracts. This indicates that Kinostat not only may serve as a prophylactic treatment against the formation of cataracts but that it can restore functional vision in the dogs with early sugar cataracts, thus reducing the need for surgery in the growing population dogs with DM . Based on these results, the specific aim of Phase I of this proposal is to conduct a 12-month pilot clinical trial with 30 "volunteer" dogs of various breeds with DM to demonstrate that topical Kinostat can inhibit sugar cataract formation and as a result maintain functional vision in diabetic dogs. Lens changes will be documented by retroillumination photography and the extent of opacification in these images will be quantified by computer image analysis. The successful demonstration of Kinostat efficacy in Phase I of this study will be followed in Phase II by a multi-center, masked clinical trial in which Kinostat or placebo will be administered to diabetic dogs with little or no lens changes and no overt cortical or nuclear opacities. Following the demonstration of efficacy in Phase II for successfully inhibiting or significantly delaying the onset and progression of sugar cataracts, Kinostat will be marketed for veterinary use. The availability of a topical inhibitor of sugar cataracts could benefit an estimated 400,000 companion dogs in the United States by reducing the need for cataract surgery. This proposal seeks to develop a topical drug, Kinostat, for the prevention/treatment of sugar cataracts in dogs with diabetes mellitus (DM). Based on preliminary results where Kinostat not only served as a prophylactic treatment against the formation of sugar cataracts but also restored functional vision in galactose-fed dogs with early sugar cataracts, the specific aim of this proposal is to conduct a 12-month pilot trial with 30 "volunteer" dogs of various breeds with DM. The successful demonstration in this Phase I study that topical Kinostat inhibits sugar cataract formation and maintains functional vision in dogs with DM so that the need for cataract surgery is reduced, will be followed in Phase II by a multi-center, masked clinical trial with our ultimate goal being the marketing of Kinostat for veterinary use so that the need for surgery is aleviated in an estimated 400,000 diabetic companion dogs that develop DM in the United States

Diabetes mellitus (DM) in dogs is characterized by a rapid onset of bilateral cataracts that result in vision loss. Over 400,000 dogs annually develop cataracts that results in vision loss and currently the only medical treatment for these dogs is cataract surgery between $3,500-6,000. We have developed an alternative, nonsurgical medical treatment that is composed of an aldose reductase inhibitor in a topical vehicle that has been trademarked as KinostatTM. In our SBIR Phase I study, we established in a masked, multicenter study composed of 40 dogs with naturally occurring DM that topical KinostatTM significantly reduces both cataract formation and the progression of cataracts in diabetic dogs. This Phase II proposal seeks to conduct studies under IAND 11-785 that are required to obtain FDA approval for KinostatTM to become commercially available. Under FDA guidance, the Phase II studies will include a 12-month masked clinical trial conducted at 5 regional clinics with dogs of various breeds with newly diagnosed DM and no cataracts present. Lens changes will be evaluated at the onset, and at 1, 2, 3, 6, and 12 months. The efficacy of topical KinostatTM will be established by comparing the onset and severity of cataract formation in 125 dogs receiving topical KinostatTM compared to 35 dogs receiving placebo. In addition, a 6-month GLP toxicity test in 48 normal dogs of equal gender will be conducted. Both studies will utilize KinostatTM that has been synthesized, formulated and packaged under cGMP and GLP conditions by the future contract manufacturers. Bioequivalence of the manufactured product to the KinostatTM formulation in Phase I will be conducted prior to the start of the clinical trial. In addition, the manufactured formulation will be characterized for consistency of particle size and delivery amounts as mandated by the FDA. The commercial availability of KinostatTM will provide owners of an estimated 1.2 million companion dogs with DM a less costly, nonsurgical alternative medical treatment for cataracts and reduce the incidence of secondary ophthalmic complications. , ,

Public Health Relevance:
This proposal seeks funding to obtain data required by the FDA for approval for marketing KinostatTM, a topical aldose reductase inhibitor formulation, for the prevention of cataracts in the 400,000 diabetic companion and working dogs that annually develop cataracts where vision can only be restored with costly cataract surgery. Once KinostatTM has been successfully established for the prevention of cataracts in diabetic dogs, we will repurpose this drug for humans use as an Orphan Drug for preventing aldose reductase linked cataracts in young children with diabetes. This will alleviate the need for cataract surgery in young children where proper intraocular lens placement and secondary cataracts due to posterior capsule opacification are problematic because their eyes are expected to undergo significant ocular growth after surgery.

Thesaurus Terms:
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