Innovation in Retina

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

Anthony P. (Tony) Adamis, MD

A giant in the fight against retinal disease.

JERRY HELZNER, CONTRIBUTING EDITOR

The battle to combat retinal disease has essentially been a story of a series of breakthroughs by individuals or small groups of researchers, with each subsequent achievement building upon an ever-growing body of knowledge. In assessing this chain of milestones, probably no one has been involved in more seminal accomplishments than Anthony P. (Tony) Adamis, MD, currently global head of ophthalmology, immunology, and infectious diseases for Genentech.

His towering stature was further validated in 2014 when Dr. Adamis shared the prestigious one-million euro António Champalimaud Vision Award with six other researchers for their work in the discovery and development of antiangiogenic therapy for retinal disease.

CONNECTING WITH DR. FOLKMAN

Dr. Adamis’ odyssey began when, fresh from his ophthalmology residency at the University of Michigan in 1989 and a fellow at Massachusetts Eye and Ear Infirmary, he attended a lecture given by the late Judah Folkman, MD, whose legendary laboratory at the Harvard Medical School had pioneered the concept that tumor growth was dependent on having a blood supply.

“Dr. Folkman was a compelling speaker,” says Dr. Adamis. “I saw the connection between tumor angiogenesis and the unwanted growth of blood vessels in the eye that characterized certain retinal diseases. Dr. Folkman had already made that connection. He was very interested in the eye and used the eye as a model to prove his theories about angiogenesis. He showed that tumor cells wouldn’t grow in the eye until they were fed by blood vessels. He also had ophthalmologists working in his lab.”

Dr. Tony Adamis

Dr. Adamis says he pressed Dr. Folkman for a position in the lab and was hired after Dr. Folkman warned that the young ophthalmologist would have to totally immerse himself in the mysteries of angiogenesis.

“Once I was working in the Folkman lab, I was allowed to devote all of my efforts to the role of VEGF and its link to retinal disease,” says Dr. Adamis. At the Folkman lab, he worked with Joan Miller, MD, David Shima, PhD, and other vision researchers to attempt to develop therapies that could combat the effects of angiogenesis in the eye.

THE FOLKMAN STYLE

“I was recently reading a book about the Rolling Stones and one of the points it made was that Mick Jagger would always have 10 new ideas for songs,” says Dr. Adamis. “Maybe one of the 10 would work, but he always had this stream of ideas. Dr. Folkman was the same way. He was always at the lab, nights and weekends, and he always came up with new ideas to try. He was truly the driving force, and if you wanted to get his attention, you had to be as committed as he was.”

Though the Folkman lab never directly developed any antiangiogenic drugs, Dr. Adamis said new concepts for treating retinal disease “were never far from our minds.” This goal was to be fulfilled in the next phase of his professional life.

EYETECH AND MACUGEN

While working in the Folkman lab, Dr. Adamis reconnected with David Guyer, MD, who today is chairman of the promising drug development company Ophthotech (New York, NY). The two had been fellows together at Massachusetts Eye and Ear Infirmary. Dr. Guyer had remained in the academic world, eventually becoming chair of the department of ophthalmology at New York University.

Both men were interested in antiangiogenic drug development and the clinical trials process. A first effort that involved the two doctors was backed by Roche and studied the drug interferon-alpha for the treatment of wet AMD. It failed in a clinical trial.

Drs. Guyer and Adamis wanted to continue their work in developing a drug for retinal disease, but no major drug company was willing to back them because ophthalmology was then considered a small market and antiangiogenesis was still an untested approach. Instead, in the mid-1990s Drs. Guyer and Adamis got together with Samir Patel, MD, a brilliant retina specialist who gave up a secure and prestigious position at the University of Chicago to work in the new area of anti-VEGF drug development. The three doctors joined with two former Genentech executives, Marty Glick and John McLaughlin. The goal was to start a company that could successfully develop a drug for wet AMD.

It was this group that founded Eyetech, the company that eventually commercialized the first FDA-approved antiangiogenic drug for wet AMD — Macugen.

THE LEGACY OF MACUGEN

Though Macugen (pegaptanib sodium) proved it could halt or slow the progression of wet AMD for most patients and had a brief moment in the sun, it was soon eclipsed by the more effective Lucentis (ranibizumab, Genentech, South San Francisco, CA).

Dr. Adamis notes that Macugen deserves a place in history because it established “many firsts” for the treatment of chronic retinal disease. Macugen was the first medical treatment for wet AMD, the first anti-VEGF in ophthalmology, and it validated the concept of intravitreal injection for a chronic disease. It also achieved reimbursement, which is no small matter when considering the costs of developing drugs for eye diseases.

In another seminal development, while at Eyetech Dr. Adamis teamed with Dr. Shima to implicate anti-PDGF in retinal disease and identify it as a potential target for future drug development.

“Dr. Shima and I read a paper on the role of anti-PDGF in tumor angiogenesis and concluded that it also could play a role in eye diseases, which we validated in animal models,” says Dr. Adamis. “Today, Ophthotech is in phase 3 clinical trials with the anti-PDGF drug Fovista, which entered early development at Eyetech.”

Other major companies are also studying anti-VEGF, anti-PDGF combinations as potential next-generation treatments for retinal disease.

WHAT’S NEXT

Dr. Adamis is keenly interested in making Genentech the leader in developing the next generation of treatments for retinal diseases.

“Anti-VEGF monotherapy is reaching its limits,” he says. “Combination drugs may constitute a new paradigm for treatment. Sustained-release drugs are another concept that have potential, but sustained-release is hard to do because, among other things, the drugs have to be stable to be contained in an implant or device for a long period of time. Fortunately, Lucentis is a very stable drug and we have partnered with ForSight Labs (Menlo Park, CA) to develop a sustained-release format for Lucentis.”

Another area that Dr. Adamis is “watching closely” is gene therapy for serious retinal diseases, which is giving indications of being a viable concept for long-lasting vision improvement that could be measured in years rather than weeks or months.

“More people are doing research in eye disease than ever before,” notes Dr. Adamis. “That is great for patients because competition drives us all to do better.”

With a plethora of fledgling companies backed by venture capital and some with public stock offerings, Dr. Adamis expects to see more collaborations and partnerships in ophthalmic drug development.

“Our collaboration with ForSight is an example of that,” he says.

PERSONALIZED THERAPIES

One area in which Dr. Adamis sees great potential and in which Genentech is a leader is personalized medicine — in which specific drugs will be prescribed only for subsets of patients with certain genetic profiles.

In its MAHALO phase 2 study for the treatment of dry AMD, a subset of patients who were genotyped and had certain complement factor mutations had the best response to Genentech’s lampalizumab.

“These results are very encouraging because these would normally be the most difficult patients to treat and yet they had the best response to this drug,” says Dr. Adamis, who notes that lampalizumab is now moving into two large phase 3 studies.

The results of studies such as MAHALO may open the door for more prognostic and predictive genotyping for eye diseases, as retinal diseases have shown a strong correlation with specific genetic markers.

RISK, COST, AND TIME

Though generally optimistic about the explosion of scientific information now available for the study of eye diseases, Dr. Adamis is concerned about the huge costs, risks, and investment of time required to developed ophthalmic drugs.

“We need more predictive and efficient models for drug development,” he says. “We have an explosion in vision research, but the number of drugs being approved by the FDA each year stays about the same. That is a big concern to me.”

In going back to his roots, Dr. Adamis says that although Genentech is a large company and a subsidiary of Roche, both organizations encourage the creative environment that characterized the Folkman lab.

“Genentech has always had an academic feel, with regular lectures and papers being presented by post-docs,” he says. “We are focused on the patient and focused on the science. You are usually on the right track when all the science points in the same direction.” RP