“Here’s to the crazy ones. The misfits. The rebels. The troublemakers. The round pegs in the square holes. The ones who see things differently.”

— Apple advertisement, “Think Different.”

The history of anti-VEGF therapy is an interesting one. A young retina specialist from a very prestigious practice in New York City wanted to start a company to develop anti-VEGF therapy for AMD. He asked the CEO of Regeneron to license an anti-VEGF therapy they had on the shelf called aflibercept (now Eylea). Thinking he could not possibly raise the capital required, the CEO passed. Undaunted, he continued searching and found a small company in Colorado called NeXstar Pharmaceuticals that had an aptamer against VEGF-165 that he could license. At the time, the idea of giving an intravitreal injection every 6 weeks was blasphemy. But Dr. David Guyer and his early partners, including Dr. Samir Patel, dared to “think different,” and a few years later, pegaptanib (now Macugen; Bausch + Lomb) was born.

The only treatments available were verteporfin photodynamic therapy (vPDT) (Visudyne; Bausch + Lomb) and laser photocoagulation, so this was a big jump forward. And it came with a very high price tag — I said they thought differently.

Fast forward a few years: The ranibizumab studies, MARINA and ANCHOR, showed even better results than pegaptanib and vPDT. However, it would take the US FDA a while to approve the product and with monthly injections instead of every 6 weeks. To make matters worse, the price was even higher.

Another young doctor from a prestigious practice in Miami started a study using intravenous injection of off-label bevacizumab (now Avastin; Genentech) in AMD patients. The study worked, but hypertension was a significant side effect. This may have stopped some people. But with the blessing and support of his equally forward-thinking chairman, Dr. Carmen Puliafito, Dr. Philip Rosenfeld injected a man with a CRVO with intravitreal bevacizumab, and the rest is history. These two thought so differently that no animal or toxicity studies were done before the first patient was treated. With a price tag around $50 and numerous studies illustrating its safety and efficacy, bevacizumab truly has changed our field.

Anti-VEGF revolutionized management of retinal diseases as well as the business of retina. We needed entire offices with full-time employees to manage inventory, insurance issues, accounts receivable, and payments. We hired physicians simply to handle the volume of injections. In this issue, we will look at how the business of anti-VEGF has changed our practices as well as the cost effectiveness of anti-VEGF.

If Dr. Guyer had successfully licensed aflibercept, there would be no off-label use of bevacizumab, and maybe no ranibizumab (Lucentis; Genentech). Thinking different is how our field moves forward. The Apple advertisement quoted above continues, “And while some may see them as the crazy ones, we see genius. Because the people who are crazy enough to think they can change the world are the ones who do.” Thanks to all the pioneers in anti-VEGF therapy for not respecting the status quo. RP