This new column features innovators in the field of vitreoretinal disease. Successful translation of scientific ideas into useful medical treatments and technologies requires many elements. Each of the innovators featured here has a story to tell that often combines an exceptional understanding of disease, foresight, perseverance, and an ability to obtain funding for an unrecognized technology. The stories featured will provide a snapshot of what it has taken to bring these breakthroughs to our patients. The authors will range from scientists to clinicians to bankers to venture capitalists, and some will do a little of all.

The inaugural piece features Samir Patel, MD. Dr. Patel, along with David Guyer, MD, and Tony Adamis, MD, started Eyetech Pharmaceuticals. Although this company was not started in the proverbial garage, it began as a virtual company that resulted in the first FDA-approved anti-VEGF agent for choroidal neovascularization. Dr. Patel served as a founder, chief medical officer, and board member of Eyetech. Currently he is co-founder and president and CEO of Ophthotech, an early-stage company that is identifying and studying new drugs for the treatment of dry and wet forms of age-related macular degeneration.

This month's issue will feature the founding of Eyetech. In the next issue, Dr. Patel will continue by describing his new venture, Ophthotech, which was created to address novel therapeutics in the anti-VEGF era.

—Elias Reichel, MD

In the late 1980s and early 1990s, progress in the field of age-related macular degeneration (AMD) primarily centered upon imaging technologies and led to further understanding of wet AMD phenotypes. On the therapeutic front, advances in laser technology resulted in the development of tunable photocoagulators, transpupillary thermotherapy (TTT), and photodynamic therapy (PDT). Other therapeutic options were also investigated to address wet AMD, such as radiation therapy, retinal pigment epithelium transplantation, and surgical extraction of choroidal neovascular tissue. Although emerging imaging technologies made some important differences in understanding the nature of the disease and permitting earlier diagnosis, the treatment options focused on destruction or closure of the abnormal choroidal neovascularization (CNV). The visual outcome for the vast majority of patients with these modalities was marginal at best.

In the 1990s, pharmacotherapy for wet AMD was studied in a standardized manner for the first time. Interferon alpha-2 was investigated by the Pharmacological Therapy for Macular Degeneration Study Group, led by David Guyer, MD, and colleagues1 (sponsored by Hoffmann-LaRoche, Basel, Switzerland). Although this international collaborative effort led to a new standard for trials for wet AMD and stimulated the field of posterior segment pharmacotherapy, the results were unfortunately negative. Interferon alpha-2 was an "antivasogenic" drug and did not address the underlying biology of the disease.

Simultaneously, the drug discovery field was developing rapidly, fueled by the progress in genomics and biotechnology. Advances in technologies such as recombinant DNA, DNA microarray, x-ray crystallography, and bioinformatics shifted the focus of drug discovery to the cellular and molecular levels, targeting and attacking the underlying biology of the disease. This quantum leap generated widespread interest in academia, the pharmaceutical industry, and the wider public arena.

Since its description in 1989,2 targeting vascular endothelial growth factor (VEGF) has received considerable attention in oncology. Historically, oncology has attracted major investment for novel therapeutics and research. Recently, a large amount of this funding has been directed toward research in angiogenesis inhibitors. This generated a potential for application of these antagonists in the ophthalmic space, where similar destructive effects of angiogenesis are responsible in AMD.

In 1994, Drs. Anthony Adamis3 and Lloyd Paul Aiello,4 along with their co-investigators, independently demonstrated the role of VEGF in ocular disease. Considerable research into the expression, regulation, and signaling of VEGF and its receptors supported the role of VEGF in the pathogenesis of AMD. This offered an exciting chance to develop new targeted therapeutics for the treatment of AMD. The area of ophthalmology had not received the same level of funding as oncology because the ophthalmic market was incorrectly perceived to be small. Furthermore, to date, there had not been a successful launch of a purely pharmacological product for posterior segment diseases. This meant that major pharmaceutical companies were not committed to investing in this area. On the other hand, smaller biotech companies with potential targets applicable to ophthalmology were focused on oncology and not interested in the AMD space due to limited resources and/or lack of ophthalmic expertise.

SCIENTIFIC RATIONALE
Although the scientific rationale for targeting VEGF for AMD and other angiogenic posterior segment diseases was very strong, it was quite evident to Drs. Guyer, Adamis, and me that this market was completely neglected and misunderstood by the industry. It was a large market with an unmet medical need and breakthrough science. Given the financial hurdle for drug development, academia could not be expected to support this process. The best chance for bringing this much-needed potential therapy for our patients to the market was for us to enter the drug development field. As a result, we cofounded Eyetech Pharmaceuticals (New York, New York) led by Dr. Guyer, as the chief executive officer of the company and also a member of the board of directors (BOD). I served as the chief medical officer and a member of the BOD, and Dr. Adamis served as the chief scientific officer. In addition, joining us as cofounders and members of the BOD were two ex-Genentech (South San Francisco, California) executives, John McLaughlin and Marty Glick.

Eyetech was a virtual company with no cash or products. We searched and identified compelling assets but were initially unsuccessful in attempting to in-license them. We encountered the "chicken-or-the-egg story" at every turn. Without a product or capital and given the high degree of risk, it was difficult to attract a management team with a successful track record. Conversely, without a proven management team or funding, in-licensing a late-stage product (ready to start phase 1 studies) was an uphill struggle.

In early 2001, a window of opportunity presented itself when Gilead Pharmaceuticals (Foster City, California) announced its intention to out-license its anti-VEGF aptamer (Macugen). In order to optimize our chance of in-licensing this asset, we recognized the importance of swiftly recruiting a management team and securing funding. We generated a clearly written business plan with a sound model demonstrating the attractive opportunity. With persistence, a genuine belief in our purpose, and the strong leadership of Dr. Guyer, we were able to establish an outstanding management team with a successful track record. With this team in place, we highlighted our core strengths to the Gilead Pharmaceuticals business development team: in-depth knowledge of the scientific and clinical aspects of their asset, an ability to develop the product in an accelerated manner, and insight into the regulatory pathway to bring this product to market. Each member of the management, consulting, and BOD team brought a unique skill set and perspective to the table. After long and thorough negotiations, we were successful in our bid for Macugen.

FUNDING COSTS
To fund the in-licensing cost and the initial product development, the licensing agreement was contingent upon obtaining capital of approximately $15 to $20 million. We successfully raised $34 million via pre-seed, seed, and venture capital sources. This initial financing round was led by SV Life Sciences (Foster City, California). The subsequent success of Eyetech has been well chronicled and includes the first US Food and Drug Administration-approved anti-VEGF agent for wet AMD, a landmark partnership deal with Pfizer (New York, New York) and a successful initial public offering with a subsequent sale of the company to OSI Pharmaceuticals (Melville, New York).

The new era of pharmacotherapy for posterior segment disease is currently in its infancy and the compelling science holds great promise for patients with AMD.

Elias Reichel, MD, is Vice Chair for Research and Education, Department of Ophthalmology, at the New England Eye Center, Tufts University School of Medicine, in Boston. He is a member of the Retina Today Editorial Board and may be reached at EReichel@tufts-nemc.org.

Samir Patel, MD, is President & CEO of Ophthotech Corp., located in Princeton, New Jersey. He may be reached at info@ophthotech.com