Keratase(ISTA Pharmaceuticals, Inc.)

ISTA Pharmaceuticals (formerly Advanced Corneal Systems) has developed an ophthalmic injectable formulation of highly purified hyaluronidase [ovine hyaluronidase, Vitrase] for the initial treatment of vitreous haemorrhage and diabetic retinopathy. Hyaluronidase is a naturally occurring enzyme that digests certain forms of carbohydrate molecules called proteoglycans. The current medical treatment for vitreous haemorrhage is vitrectomy, an invasive surgical procedure that may result in future cataract formation, retinal detachment or other complications. There are currently no approved drug therapies for vitreous haemorrhage. ISTA believes that an injection of Vitrase causes the vitreous to liquefy, thereby promoting the clearance of vision-distorting blood. The elimination of blood helps to restore vision and provides an ophthalmologist with an unobstructed view of the retina, allowing the doctor to diagnose and treat the underlying cause of the hemorrhage. In mid-1997, Advanced Corneal Systems (now ISTA Pharmaceuticals) formed a Singapore subsidiary called Visionex to develop and market the company's technologies in Southeast Asia and China. In March 2000, ISTA completed the acquisition of Visionex. Also in March 2000, subsidiaries of Allergan obtained marketing, sales and distribution agreements from ISTA for Vitrase worldwide, except Mexico (until April 2004) and Japan. ISTA will split Vitrase profits equally with Allergan and receive royalties on sales in non-US countries. ISTA is responsible for all costs of product development, preclinical studies and clinical trials, of Vitrase and may receive up to 35 million US dollars in milestone payments from Allergan upon the achievement of specified regulatory and development objectives. In December 2001, Otsuka gained exclusive rights to develop, market and commercialise Vitrase in Japan. In July 2002, ISTA announced that it has entered into an agreement with Cardinal Health for the manufacture of commercial quantities of Vitrase. The agreement covers the US, Canada, Japan and the European Union. Cardinal Health will also provide manufacturing-related information for the US New Drug Application (NDA). Sophia Laboratories distribute Vitrase in Mexico. The US FDA designated Vitrase as a fast track product in October 1998, which means the FDA will facilitate the development and expedite the review of the product. Vitrase has being investigated in two multinational, randomised, placebo-controlled, phase III trials in patients with severe vitreous haemorrhage. One was conducted in the US, Mexico and Canada (North American trial) with an enrolment of 750 patients. The second trial was conducted in Europe, Brazil, Australia and South Africa and enrolled 556 patients. In March 2002, ISTA began unmasking the data, revealing that although preliminary efficacy results did not show any statistically significant improvement in the primary endpoint, clinically relevant improvements in visual acuity and a decrease in the density of vitreous haemorrhage were observed in patients treated with a 55IU dose of Vitrase, compared with placebo-treated patients. In December 2002, the FDA accepted the NDA for Vitrase for filing. The FDA's Dermatologic and Ophthalmic Drugs Advisory Committee reviewed the Vitrase NDA on 17 March 2003 and voted 8 to 4 that there was insufficient statistical evidence to support the use of Vitrasefor the treatment of vitreous haemorrhage. However, the Committee did recognise that in certain patient subgroups, the benefits of Vitrase therapy outweighed the potential risks. The FDA has recommended that ISTA provide additional analyses from the two pivotal phase III trials conducted. In April 2003, the FDA issued an approvable letter for Vitrase for the treatment of vitreous haemorrhage. ISTA anticipates that the FDA will complete its review of the Vitrase NDA anete its review of the Vitrase NDA and issue the results during the second half of 2003. In addition, ISTA plans to submit a marketing approval application with the European Medical Evaluation Agency (EMEA) in the first half of 2003. A phase II trial in Singapore was being conducted by Visionex. However, in March 2000, ISTA completed the acquisition of Visionex. In its Securities and Exchange Commission (SEC) filing, as at 31 December 2002, ISTA stated that the continued development of Vitrase for diabetic retinopathy will be dependent upon a number of factors including the FDA's evaluation of Vitrase for the treatment of vitreous hemorrhage, the successful completion of any additional clinical trials for the diabetic retinopathy, and the continuing assessment of the market opportunity for this indication compared with other product opportunities that ISTA may be pursuing at the time. ISTA is also developing hyaluronidase products for the treatment of cataracts (Keratase) and keratoconus (Keraform).