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INNOVATION IN RETINA: Napoleone Ferrara, MD: Not Resting on His Laurels

Discoverer of VEGF has moved on to academia.

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EDITED BY EMMETT T. CUNNINGHAM JR., MD, PHD, MPH, AND PRAVIN U. DUGEL, MD

Top medical researchers will acknowledge that breakthroughs occur unexpectedly, discoveries often happen by accident, and brilliant scientists can master more than one discipline. When Genentech hired Napoleone Ferrara, MD, in 1988, they thought they were bringing on a reproductive endocrinologist who could be helpful in bringing along relaxin, a pregnancy hormone that the company was developing.

“The drug worked in mice but not in humans,” recalls Dr. Ferrara. Fortunately, the company gave their researchers some latitude and allowed Dr. Ferrara to pursue the research interest that had intrigued him in 2 postdoctoral fellowships at the University of California, San Francisco (UCSF): exploring the basic biology of angiogenesis and the factors that enabled tumors to grow.

During his first fellowship after earlier medical training in his native Italy, Dr. Ferrara was studying pituitary cells and discovered that some of these cells produce factors that can induce endothelial cell growth. He was greatly intrigued by this finding. In his second post-doctoral fellowship at UCSF, he focused on protein biochemistry and did some initial work to isolate vascular endothelial growth factor (VEGF), the angiogenic protein produced by pituitary cells.

“I had also had a clinical fellowship at Oregon Health Sciences University, but I could see that my preference was for research rather than being a practicing physician,” he says. “So I had a good idea of what I wanted to accomplish as a researcher.”

Once at Genentech, with its superb laboratory facilities and technology base, it did not take long for Dr. Ferrara to achieve what proved to be a major breakthrough that would eventually lead to new treatment paradigms for both cancer and retinal diseases. In 1989, he was able to isolate and clone VEGF. Then followed years of painstaking research to identify the key role of VEGF in angiogenesis that would eventually lead to a seminal application in oncology, says Dr. Ferrara. “And by 1993, we had developed a mouse antibody that we believed could be humanized to target VEGF in cancer. That humanized antibody was Avastin [bevacizumab; Genetech], which entered clinical trials in 1997 as a potential therapy for colon cancer. So there were many years of work involved in the development of Avastin, which was approved in 2004.”

Napoleone Ferrara, MD
PHOTO COURTESY DR. FERRARA

FROM AVASTIN TO LUCENTIS

By the mid 1990s, it became apparent that VEGF was a master regulator of physiologic and pathologic angiogenesis, by no means limited to tumorigenesis. So the extensive research that led to the development of Avastin paid off in an unexpected benefit: it also produced a blockbuster drug for retinal diseases, Lucentis (ranibizumab; Genentech).

“Lucentis is a monoclonal antibody derived from an Avastin fragment,” says Dr. Ferrara. “Though it is more potent than Avastin and a little more effective when used in the eye. We found that ranibizumab had the right affinity and properties to potentially be effective in retinal disease. We also had a collaboration with Tony Adamis and Joan Miller at Harvard, which helped in the development of Lucentis by testing the drug in preclinical animal models.”

Lucentis was approved for wet AMD in 2006 and has had a huge impact on the treatment of a range of retinal diseases.

“Genentech was an incredible place for me to work for 25 years. The development of Lucentis was a success in spite of the fact that there was plenty of skepticism at that time. I must say that I would have liked to have seen Lucentis tried at higher doses, in trials other than HARBOR. I think it could have proved to be more effective and durable at higher doses. The recent data with brolucizumab support this idea.”

GETTING A NEW PERSPECTIVE

After his distinguished career at Genentech for which he received numerous honors and awards, in 2013 Dr. Ferrara moved on to an academic setting at the University of California, San Diego, where now at age 61 he serves as distinguished professor in pathology and senior deputy director of basic science at the Moores Cancer Center as well as a distinguished adjunct professor of ophthalmology at the university’s Shiley Eye Institute.

“Working in academia gives you a different perspective,” says Dr. Ferrara. “You have more latitude to choose what you want to work on. But it’s still up to you to make a difference.” Though Dr. Ferrara’s current research focuses on identifying causes of angiogenesis other than VEGF, such as myeloid cells and fibroblasts, he still retains a keen interest in ophthalmic research and potential new therapies for retinal diseases.

“We have the Shiley Eye Institute right here on campus, so I am able to do research in both oncology and ophthalmology,” he notes. “There’s a lot of research in retinal diseases going on now, many good ideas, but only time will tell. The field is crowded and money is pouring in for research. I am optimistic that something novel and important will emerge.”

Dr. Ferrara considers the Novartis anti-VEGF drug brolucizumab “very promising.” He cites the fact that it can be delivered at a high dose with high concentration. He thinks there is considerable potential also in sustained-release delivery and mentions the Genentech LADDER trial for Lucentis as one investigational approach to watch.

When asked about other efforts to combat retinal diseases, he says that generally some are “promising” and others are “redundant.” He also notes that some recent investigational therapies that had compelling phase 2 data failed badly in pivotal phase 3 trials.

Though he is consumed by his research work, Dr. Ferrara finds time to enjoy travel, amateur photography, and riding his motorcycle. He says he has enjoyed working and living in the Bay Area and now in San Diego. RP