Dismiss the Dogma

What drew you to age-related macular degeneration (AMD)?

It was my background interest in molecular biology and genetics. At Johns Hopkins, I got both my MD and PhD degrees at the same time – my research focused on genetics and I had a particular interest in the evolution of disease in the back of the eye, and specifically, retinal degenerations. I started with a post-doctoral research fellowship at the Massachusetts Eye and Ear Infirmary (MEEI) working with Ted Dryja – who was the first to clone the retinoblastoma gene – and Eliot Berson. I fully intended to pursue a career in retinal degeneration and other vitreoretinal diseases, but I was drawn to AMD, as Johanna Seddon clued me in that it was a genetic disease. I became fascinated with both her clinic and her studies that looked at twins with AMD, and this started me on the path of AMD; the genetic and the clinical aspects, and the realization that there was a huge unmet need for treatments.

What do you find the most rewarding aspect of working on clinical trials?

To this day, what I enjoy doing the most is designing clinical trials with appropriate endpoints and necessary controls, so that at the end of the trial we will get a definitive answer. I like asking questions that no-one else is asking, and I had always seen myself running a laboratory and being involved with both medical and surgical retinal diseases. Starting at the Bascom Palmer Institute, I quickly learned there was nothing better than running your laboratory in the clinic – it is an excellent way to blend my research and clinical interests and compliments both aspects of my career.

Any challenges throughout your career?

With every study that I have participated in, or designed, I have come away with a better appreciation of what needs to get done. In the photodynamic therapy trials in the 1990s, I learned a tremendous amount, and that set the groundwork for my ability to design clinical trials with anti-VEGF therapy. At the time, coming up with a treatment for wet AMD seemed like a herculean effort. Now, focusing on dry AMD makes focusing on wet AMD “low-hanging fruit.” We have a huge unmet need in dry AMD, but I think that everything is positioning so that hopefully in the next few years we are going to be able to demonstrate unequivocally that there is a treatment that can slow down disease progression. It is a big area. If we can stop dry AMD at an earlier stage, then all the downstream vision loss that occurs from both advanced late dry macular degeneration and wet AMD can be avoided.

What is exciting you at the moment?

Right now, I am currently working with collaborators to develop the next generation of OCT, swept source OCT, and we really hope to move the field forwards with this cutting edge technology. As for treatments, I still believe in the “holy grail” of genetics research, that is, if you identify the genetic locus involved in the disease and manipulate the gene product from that locus, then you should alter disease progression and improve outcomes. But when we talk about complex genetic diseases, like AMD, the question is how we can manipulate pathways to improve patient outcomes? AMD clearly looks like a complement-mediated disease, and I feel that complement inhibition, or some form of complement regulation, is going to be very, very important in controlling macular degeneration at some stage.

You were the first to inject off-label Avastin into someone’s eye. How did you feel?

It was nerve-wracking! That is why I had to choose the right patient, where there was really no other option as all the approved therapies had failed. She was a nurse, she understood the risks – she was going blind. So we gave it a shot, and to this day I see her, and she is just so grateful because we were able to preserve her vision.

Ophthalmology is a very special profession. The more I work with companies working in other fields of medicine, I am reminded that ophthalmology, and in particular the field of retina, is very special because of the way they think scientifically and are research-driven. And, I have to credit my colleagues. I started the process with both intravenous and intravitreal Avastin for wet AMD, but without everyone coming on board, picking up the ball, and moving it forwards, we wouldn’t be where we are today.

What are your thoughts on the Moorfields-Google Deepmind collaboration that’s using artificial intelligence on retinal photographs and OCT images to identify those with early stages of disease?

I think this is fantastic: this is the next wave of innovation and discovery. There is so much information out there, and pulling it together is going to be crucial. Big data has its own set of problems, but if you have good people who understand the limitations and analyze the data appropriately, this is going to be wonderful –not only when it comes to exploring early stage diseases and the features indicative of disease progression, but also in looking at treatment outcomes across the board. The National Health Service system in England is set up perfectly for it; I don’t think it could be implemented here in the US because of the way that our fractured health care system is set up.

What anti-VEGF dosing strategy do you prefer – treat and extend, or as needed (PRN)?

I consider myself to be the father of PRN dosing, and that all came about from the PrONTO study, which was designed when we began to appreciate the power of OCT as a technology for following disease progression and the need for re-treatment. But I have evolved. What I have learned over the years is that patients don’t really mind injections, and they much prefer a treatment regimen where they can avoid coming in as frequently. So most of the time I use the treat and extend strategy, but I do still use PRN in some patients who really don’t want the injection.

If you could go back to the beginning of your career, what would you tell yourself?

The best advice I would give myself is to focus on the unmet needs of your patients and be willing to pivot with your research objectives to follow where the data points. And this pivoting strategy pertains to one of my favorite sayings of “sacred cows make the best hamburger” – always question what someone thinks as dogma, and never be satisfied unless the answers make sense. After all, everyone knew antibodies directed against VEGF wouldn’t be effective if injected into the eye. Not!