Article Date: 5/1/2007

Untitled Document SUBSPECIALTY NEWS
“Angiogenesis 2007” Meeting Highlights
Avastin Used to Treat ROP.

JACLYN KOVACH, MD, MEDICAL RETINA FELLOW, BASCOMPALMER EYE INSTITUTE

Small studies conducted by researchers in Mexico and Portugal strongly suggest that intravitreal injections of the Genentech drug Avastin can be used effectively to treat retinopathy of prematurity (ROP). A case study based on this research was reported by retina specialists from Bascom Palmer Eye Institute in the January/February 2007 issue of Retinal Physician (“Bevacizumab for salvage therapy in threshold retinopathy of prematurity”). Data from the 2 new studies was among the highlights of the “Angiogenesis 2007” meeting recently conducted by Bascom Palmer. The meeting also highlighted other new research in ocular angiogenesis, drug development for the treatment of numerous debilitating retinal diseases, and the economic impact of new retinal drugs on Medicare. The first Avastin for ROP study involved a series of 18 eyes of 13 patients from Mexico City. Hugo Quiroz-Mercado,MD, reported the efficacy of Avastin in infants with varying degrees of ROP. He reported that 17 of 18 patients improved without further sequelae and 1 patient required vitrectomy. Susan Texeira, MD, of Lisbon, Portugal, reported on a series of 6 eyes injected as salvage therapy, either as monotherapy or in addition to laser therapy. All injected eyes improved, with none requiring additional treatment. No local or systemic adverse events were noted in either study.While both physicians were optimistic about early results, they cautioned that further controlled studies are needed to determine the safety and efficacy of VEGF-inhibiting Avastin in the still-developing eyes of infants. The positive results from the small studies has led to announcement of a trial of Avastin for advanced ROP. This study will be a multicenter, randomized prospective controlled clinical trial of 110 patients. Enrollment is expected to begin this summer. In additional discussion of ROP, Lois Smith,MD, PhD, and Emily Chew,MD, emphasized the importance of omega-3 fatty acids in preventing neovascularization, both in models of ROP and neovascular AMD as reported from AREDS. Michael Trese,MD, emphasized the role of VEGF in ROP and the importance of timing anti-VEGF treatment. Gerald Lutty, PhD, discussed the drug VEGF Trap in a dog model of ROP that showed that inhibition of VEGF blocked preretinal neovascularization. He reported inhibition of normal retinal development at high doses, but lower doses did not appear to be inhibitory. In another presentation, Jayakrishna Ambati,MD, and Cedric Francois,MD, PhD, explored the use of complement inhibition for the treatment or prevention of AMD. Dr. Ambati emphasized inhibition of C3a and C3b receptors. He also discussed a drug from Quark Biotech, a small interfering RNA (siRNA) molecule that inhibits choroidal neovascularization. Other promising treatments discussed included the topical antioxidant OT-551 being developed by Othera Corp. for the treatment of geographic atrophy and an endothelial nicotinic acetylcholine receptor agonist known as mecamlyamine from CoMentis (formerly known as Athenagen) that inhibits angiogenesis. Researchers agree that now is an exciting time for diseases involving ocular angiogenesis, with a number of new therapeutics now available to temper the activity. ROP is a particularly fascinating disease to researchers because modulation of angiogenesis during a crucial time window may provide a definitive cure to those with an entire future before them. Angiogenesis 2007 also featured a number of presentations focusing on the efficacy and safety of Lucentis and Avastin in the treatment of choroidal neovascularization and macular edema. In all of the studies discussed, improvements in visual acuity and macular anatomy were achieved. Finally,William Smiddy,MD, William Rich III,MD, and George Williams,MD, discussed healthcare economics as they relate to the new treatment paradigm for wet AMD. In addition to the role that basic research and clinical trials will play in retinal disease therapy, they asserted that the future of clinical practice in retina will undoubtedly feel the pressure of cost containment.

OSI Plans Eyecare Exit
CEO: Macugen and Patents for Sale.
Calling his company’s 2005 entrance into eyecare “a major misstep,”OSI Pharmaceuticals’ CEO Colin Goddard, PhD, recently updated OSI’s progress in exiting the eyecare business. Sales of Macugen, OSI’s treatment for wet AMD, have declined sharply since the more efficacious Genentech drug Lucentis was approved by the FDA last June. Macugen worldwide sales totaled $10 million for first quarter 2007 after topping out at $50.5 million in the first quarter of last year. This resulted in a loss of approximately $13 million in the quarter for the eyecare business, which OSI now reports as a “discontinued operation.” OSI’s 3-pronged strategy for exiting eyecare calls for:
▪ simplifying OSI’s agreement with its marketing partner Pfizer, thus making it easier for a potential eyecare buyer to structure a deal
▪ reducing Macugen-related staff and expenses to conserve cash until a deal is completed
▪ holding discussions with companies and venture-capital entities that express an interest in ownership of Macugen and/or related patents The first element of the exit strategy has already been achieved. OSI has reached an amended agreement with Pfizer that calls for OSI to have exclusive rights to develop and commercialize Macugen in the United States, while Pfizer has similar rights for the rest of the world. The previous agreement had included a number of provisions for granting licenses, sublicenses, and patents. In regard to conserving cash, Dr.Goddard said the New York headquarters of Eyetech Pharmaceuticals, the original developer of Macugen, had been closed and all remaining Macugenrelated staff moved to an OSI facility in New Jersey. Dr.Goddard said OSI is currently spending about $3 million a month supporting Macugen. Dr. Goddard expressed confidence that Macugen and related eyecare patents would be sold in 2007, with the possibility that there will be a buyer for Macugen and another buyer for the patents. He said that “multiple parties” had expressed interest in the drug and/or the patents. Dr. Goddard said the key phase 4 LEVEL study, which uses Macugen as maintenance therapy after initial treatment with Lucentis, would go forward. He noted that Macugen has an excellent safety record and that safety data could be a factor in increasing the future value of the Macugen franchise. OSI spent approximately $650 million to acquire Eyetech in 2005 but has now written off almost all of its initial investment.

IN BRIEF
Potentia AMD drug. Potentia Pharmaceuticals, Inc., said it is about to begin a phase 1 trial as part of the development for POT-4, its lead drug candidate for the treatment of both the wet and dry forms of AMD. Fifteen to 18 patients with late-stage AMD will receive intravitreal injections of the drug, with treatment starting as early as this summer. Potentia describes POT-4 as a synthetic peptide discovered by John Lambris, PhD, of the University of Pennsylvania. It binds tightly to complement component C3, preventing its participation in the complement activation cascade. “As C3 is the central component of all major complement activation pathways, its inhibition effectively shuts down all downstream complement activation that could otherwise lead to local inflammation, tissue damage, and upregulation of angiogenic factors such as vascular endothelial growth factor,” says Cedric Francois, MD, PhD, Potentia’s president and CEO. Potentia notes that 4 studies have demonstrated a genetic link between the complement system and AMD, providing evidence that complement activation plays a significant role in the cause of the disease. POT-4 will be the first complement inhibitor tested in patients with AMD. “These recent data have sparked hope that AMD can be treated with complement inhibitors, which help treat the early stages of the disease. We are hopeful that POT-4 may represent a new therapeutic option for patients with dry and wet forms of the disease,” says Dr. Francois. Potentia Pharmaceuticals, based in Louisville, Ky, is focused on developing new approaches to the treatment of complement-related inflammatory diseases.


Retinal Physician, Issue: May 2007