Thomas Ciulla, MD, MBA, says his choice of ophthalmology as a career was largely serendipitous, greatly influenced by 2 important mentors he admired while in medical school at the University of California, San Francisco (UCSF).

From there, he was fortunate enough to do his residency in the early 1990s at Harvard University’s Mass Eye and Ear Infirmary, which was affiliated with the legendary Folkman lab. There, a group of young faculty members were doing truly groundbreaking work in angiogenesis that contributed to the eventual development of anti-VEGF therapies for retinal disease.

His time at Mass Eye and Ear led Dr. Ciulla to focus his efforts on the retina subspecialty, while also stoking his interest in in research and clinical trials.

In more than 20 years, initially in an ocular angiogenesis lab and in clinical practice affiliated with Indiana University School of Medicine, Dr. Ciulla conducted research and served as principal investigator in numerous important clinical trials that demonstrated the benefits of anti-VEGF therapy. However, he more recently led research demonstrating that real-world outcomes for anti-VEGF therapy in retinal disease are meaningfully inferior to the results attained in closely monitored clinical trials, demonstrating continued unmet need.

More recently, Dr. Ciulla earned an MBA and made the transition to the world of corporate medicine, where he has held important positions at Ophthotech and now at Spark Therapeutics, where he serves as leader of medical strategy for ophthalmology.

Retinal Physician recently caught up with Dr. Ciulla for a wide-ranging conversation in which he discussed his belief that we are on the precipice of new disruptive advances in retina, which are further enabled by the complementary contributions of academia, practitioners, and industry.

Q. How did you become interested in pursuing your medical career in ophthalmology?

A. The usual answer from residency interviewees is that we choose ophthalmology because it provides opportunities in both complex medical and elegant surgical areas, which is true. But in reality, I think we are subtly influenced by larger-than-life mentors who serendipitously cross our path, as in my case, with curiosity piqued by John Dowling, PhD, FARVO, my undergraduate housemaster at Harvard’s Leverett House. My fate was later sealed at UCSF medical school, when I was exposed to sophisticated eye tumor work by Devron Char, MD, and eloquent mentors like Michael Drake, MD.

Q. You did your residency at Mass Eye and Ear during the early 1990s, when a brilliant group of young faculty members, working under the legendary Dr. Judah Folkman, were doing groundbreaking work in angiogenesis. How did that experience impact you?

A. Mass Eye and Ear and the entire Harvard ophthalmology system was a special place. Here was a group of innovative, hard-working, inspirational people like Joan Miller, MD, Evan S. Gragoudas, MD, Lloyd Aiello, MD, PhD, Tony P. Adamis, MD, and others, who inspired me and others to pursue retina. My time at Mass Eye and Ear also increased my interest in the research aspect of ophthalmology. Later on, working with Ron Danis, MD, and Alon Harris, PhD, MS, FARVO, as a young faculty member at Indiana University and participating in the original Lucentis trials, I witnessed AMD patients improve beyond my expectations. I realized then that my mentors at Mass Eye and Ear had contributed to a very special, exciting, and truly disruptive new therapy, changing people’s lives for the better and initiating a new cycle of innovation.

Q. You are a big believer in disruptive innovation in ophthalmology based on collaboration between academia, practitioners, and industry. You have led large-scale retrospective studies of nearly 50,000 wet AMD and 16,000 DME patients that show real-world outcomes with anti-VEGF therapy are meaningfully inferior to closely monitored clinical trials. What disruptive advances can you envision for the future?

A. Yes, therapeutic innovations are often conceived by academicians, studied by practitioners in clinical trials, and commercialized by industry to provide access. Anti-VEGF therapy has greatly enhanced the standard of care, but there is still much to be done.

Regarding future advances, I think we have to break it down to near-term, mid-term, and longer-range advances. For the near term, we have to consider sustained-release technology, such as Genentech’s refillable implant for Lucentis. We also have to entertain more durable 3-month therapies such as brolucizumab (Novartis) and abicipar (Allergan). Clearside Biomedical’s suprachoroidal approach is novel and intriguing, because it may deliver greater concentrations of medicine more directly to target choroidal and retinal tissues, with potential safety, efficacy, and durability benefits.

For the mid term, I point to the potential of gene therapy and especially the concept of a biofactory in the eye with a single injection that produces anti-VEGF over a long period of time. Longer range, I think cell therapy has great potential both as a neurotrophic and regenerative therapy, but is currently at a very early stage.

It’s critical that we have more durable therapies for retinal diseases, because current anti-VEGF therapy creates treatment burdens with complex visit logistics right now. As doctors, we might only spend a few minutes with each patient but these are elderly people, many needing caregivers, and keeping an appointment might mean 2 people taking an entire day to travel a distance and keep that appointment.

Q. You didn’t mention topical or oral therapies for retinal disease. Any potential there?

A. We have seen failures in trials of topical anti-VEGF. The challenge is to get the medication to the back of the eye. PanOptica is currently enrolling a phase 2 trial of a topical anti-VEGF for wet AMD, and positive results would be wonderful! Oral therapies would be great as well, but it’s a tall order. Systemic side effects might be an issue with an oral approach. Tyrogenex was to report on its phase 2 trial of an oral agent for wet AMD this year.

Q. You’ve led or been involved in numerous clinical trials. Why is it that some drugs for retinal disease do very well in phase 2 and fail so badly in phase 3?

A. That’s a great question. I was at Ophthotech when we had great hopes for Fovista (anti-PDGF) in combination with anti-VEGF therapy. The phase 2 study was well performed, but a phase 2 may not be as truly representative as much larger phase 3 trials. Also, with increased phase 3 trial size, there is less likelihood of a false positive result, due to a play of chance.

Q. Several years ago, you earned an MBA and made the big transition from academia to the corporate world. What motivated you to make that change?

A. I enjoyed practicing ophthalmology for 20 years, and I still am able to do it on a limited basis in my current role. I think there’s value in continuing to see patients. It keeps me grounded.

I made the change because I feared stagnation and wanted to work on broader issues, such as study design and interpretation, as well as pipeline at the corporate level. I gained a lot of experience at Ophthotech working with David Guyer, MD, and Samir Patel, MD, who commercialized Macugen, the first anti-VEGF. In my current work at Spark Therapeutics, I was involved in the approval and commercialization of Luxturna, the first FDA-approved gene-replacement therapy for a genetic disease. Just as Macugen presented a novel intravitreal anti-VEGF injection paradigm to retina, the first gene therapy has introduced functional vision endpoints, new orphan disease treatment pathways, and precision medicine with unfamiliar genetic testing requirements. But, having a role in these changes makes it fun.

Q. Given your belief in the benefits of collaboration among academia, practitioners, and industry in advancing disruptive innovation, what do you think explains the much-increased funding for novel retina therapies from venture capitalists and startups?

A. First, real-world anti-VEGF outcomes studies have shown us that there is significant unmet need for more durable therapies. Second, the prevalence of AMD and diabetic retinopathy are increasing with the aging of the population and rising prevalence of diabetes respectively. Third, the retina is a prime target for gene therapy, given the large number of monogenic retinal disorders, the retina’s accessibility to target cell delivery, the ability to noninvasively monitor for disease progression or therapeutic response, and the eye’s relative immune-privileged status, which limits inflammatory response.

Also, the high value of vision is being realized throughout society in everyday life with increased visual demands related to constant computer use, smart phones, and platforms like social media. Finally, more clinicians are performing quality research, as academia, clinicians, and industry collaborate more than ever.

Q. Do you have any special interests outside of your work life?

A. My wife Sheryl and I have 3 children, and we spent virtually all of our free time with them, but we are recent empty nesters, with more time to travel. We recently visited Japan. We also have a small place in Sanibel, Florida, which gives us a chance to work on golf and play tennis. RP