Cyclosporine History

Renee Kaswan, DVM, MS, DACVO (Diplomate, American College of Veterinary Ophthalmology) was both a resident in veterinary ophthalmology and a master's student in veterinary immunology at the University of Georgia College of Veterinary Medicine in 1983. The subject of her master's dissertation was to research the cause of keratoconjunctivitis sicca (KCS) in dogs, with the hypothesis that most cases of canine KCS, as well as human KCS, were autoimmune.

In September 1983 Nussenblatt et al published their findings using cyclosporine, administered orally to human patients with severe uveitis. Although effective in suppressing the uveitis, the side effects of systemic cyclosporine were severe, even life threatening. Following this publication, Kaswan conceived the idea to administer cyclosporine locally, as an eyedrop to avoid the adverse systemic side effects, and she proceeded to test ophthalmic cyclosporine in animals with various types of uveitis, keratitis, and KCS.

As a newcomer, and outsider, Kaswan's hypotheses met skepticism in the human medical research community. At that time, human ophthalmologists refused to believe that topical application of cyclosporine would suppress an immune response in the eye, and some even accused Kaswan of contriving her results. Also at that time, Sandoz held the patents for the molecule cyclosporine and developed the drug, Sandimmune®, which quickly grew to over a billion dollar per year product used as an anti-rejection drug for organ transplantation. For this and other reasons, Sandoz had no interest in developing cyclosporine for ophthalmic application.

During the search for research dollars to support her work, Kaswan found that ophthalmic pharmaceutical companies would only invest in a new drug if it were patentable. Consequently she applied for patent protection for ophthalmic cyclosporine. The first patent application was submitted March, 1985. As of this time, she was a member of the faculty of the College of Veterinary Medicine, University of Georgia, where she taught ophthalmology to veterinary students from 1984-2001. As a faculty member, she was required to assign her patents to the University of Georgia Research Foundation, who would assume the responsibility to commercialize her inventions and make them available to the public.

Cyclosporine did not become available as a generic compound until 2002, so development of an ophthalmic product required cooperation with Sandoz Phamaceuticals. Sandoz would later merge with Ciba Geigy to become Novartis, but in the 1980's, Sandoz neither had nor were interested in ophthalmic products. In 1987 Kaswan discovered that topical cyclosporine actually increased tearing in KCS dogs, a major breakthrough discovery in ophthalmology. In order to bring this discovery to market, Kaswan started KB Visions Inc., and licensed her own patents from the University of Georgia Research Foundation (UGARF) for the field of veterinary use. Shortly thereafter, Sandoz decided to license the human field of use for ophthalmic cyclosporine from the University of Georgia Research Foundation (UGARF). In 1989 KB Visions licensed the veterinary use of ophthalmic cyclosporine exclusively to Schering-Plough Animal Health, and they developed a 0.2% ointment, Optimmune® which was FDA approved to treat canine KCS in 1995.

From 1987 to 1995 for compassionate care reasons, Kaswan allowed, and even encouraged veterinary ophthalmologists and a couple of compounding pharamacists to make cyclosporine eyedrops to treat dogs with KCS. When Optimmune® was approved, persuading veterinarians to use only the FDA approved product became a problem for Kaswan, UGARF and Schering-Plough. The drop formulation was easier to administer for some clients, but Schering-Plough chose not to seek appoval for a new formulation.

Enforcement of the patents was primarily the duty of the UGARF, however, UGARF also felt a duty to the unmet patient needs for ophthalmic cyclosporine drops, both for human and veterinary use. Schering-Plough wanted KB Visions and UGARF to protect its product, Optimmune®, from unfair competition from compounding pharmacies. Compounding pharmacies did not have the expenses for research & development and FDA approval that Schering-Plough had encountered. In Sept. 2001 the FDA cited Schering-Plough Corporation for manufacturing infractions, unrelated to Optimmune®, at its New Jersey and Puerto Rico facilities. The production of Optimmune® was subsequently suspended.

In 1993 Sandoz decided to sublicense the development of ophthalmic cyclosporine to Allergan Pharmaceuticals. Allergan developed an aqueous emulsion formula and proceeded to develop Restasis® for the treatment of moderate to severe KCS in humans. In August, 1999 the FDA issued an approvable letter for Restasis® but required additional clinical trials. On December 23, 2002, the FDA approved Restasis® for the treatment of chronic dry eye in human patients. Allergan anticipates Restasis® will be available early April 2003. Please see www.restasis.com for updates and details.

Research and Publications on KCS and Cyclosporine
by RL Kaswan DVM, MS DACVO

KB Visions, Inc.
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