Many young physicians devote a great deal of time and study to choosing their specialty. Not so Nancy Holekamp, MD. While still a medical student at Johns Hopkins University, she connected with an inspirational mentor, retina specialist Stuart Fine, MD. She then involved herself in his research projects, became a valued member of his team, and, despite a case of sweaty palms, delivered a well-received presentation on bilateral drusen in AMD before thousands of ophthalmologists in the main hall of the American Academy of Ophthalmology annual meeting.

“That was it,” recalls Dr. Holekamp. “From then on, I was committed to retina and research.”

Following her internship and residency at Washington University of St. Louis, Dr. Holekamp completed a fellowship in vitreoretinal surgery at Retina Consultants of St. Louis and, in collaboration with the Barnes Retina Institute, performed a decade of groundbreaking work as the retina specialist on a team studying the cause of nuclear sclerotic cataracts.

Since joining Pepose Vision Institute in St. Louis in 2010, Dr. Holekamp has established herself as one of the nation’s leading researchers in medical retina, taking part in numerous clinical trials in studies ranging from Genentech’s Port Delivery System (PDS) for sustained-release delivery of ranibizumab for wet AMD to treatment of diabetic retinopathy. In this conversation, Dr. Holekamp assesses the landscape for potential advances in retinal disease therapies that could emerge over the next 3 to 5 years.

Q. You have an interesting way to characterize the coming emergence of new therapies and concepts for treating retinal diseases.

A. Yes. The last 15 years I call “anti-VEGF 1.0” because it has been the era of regular intravitreal injections of ranibizumab, aflibercept, and bevacizumab. What we are about to see is “anti-VEGF 2.0,” with more durable therapies and new concepts for delivering anti-VEGF.

Q. You delivered the main presentation on the PDS at the recent American Academy of Ophthalmology meeting. Do you see the PDS as the therapy that is closest to approval?

A. The PDS, a refillable reservoir implanted in the OR that provides continuous ranibizumab for 6 months, has efficacy equivalent to monthly ranibizumab. This represents a fivefold decrease in treatment burden. The PDS has completed its phase 3 ARCHWAY trial for wet AMD, and I could see it being approved for that indication within a year or so. It is also now in a phase 3 trial for diabetic macular edema and a phase 3 trial for diabetic retinopathy.

Q. The PDS might also eliminate compliance and undertreatment issues. You also reported that more than 93% of patients preferred the PDS over the intravitreal injections they had previously been receiving.

A. Yes, the strong preference is overwhelming. I see it in my own practice.

Q. What do you see as the next advance in durability via intravitreal injection?

A. You have to look at what has already made it to phase 3 as possibly next in line for approval. That would be Genentech’s bispecific faricimab that targets both VEGF and Ang2. Faricimab would represent an advance in durability, ideally about 16 weeks between injections. Then, we have the highly promising Kodiak ABC (antibody biopolymer conjugate) platform KSI-301 that has shown great durability in early-stage phase 1b trials in wet AMD, DME, and RVO. KSI-301 is now moving into pivotal trials and might be 3 years away.

Q. Talking longer term, what do you think of gene-derived anti-VEGF that would require little or no retreatment over a period of years.

A. That’s a very advanced concept that greatly interests me. Adverum Biotechnologies and Regenxbio are getting some positive data on long-term efficacy in wet AMD in early-stage trials. Of course, there’s a long way to go, but the possibility of “one and done” is definitely intriguing.

Q. Geographic atrophy (GA) therapy is still a great unmet need. In fact, developing effective therapies for GA is more urgent than ever, because GA progression is actually more rapid and relentless than previously thought, as you reported in the Proxima A study and confirmed by large numbers recently compiled by the IRIS Registry. We see a number of interesting approaches to combating GA being tried. Where do you see progress?

A. I look at GA as similar to glaucoma in that you cannot really cure it. For now, the best aprroach would be reducing lesion growth and limiting vision loss. We have seen some promising data in that regard from Apellis (APL-2) and Iveric bio (Zimura), whose targets are complement inhibition. APL-2 is directed at the C3 complement cascade, while Zimura targets the C5 complement.

At an earlier stage of clinical development, but with promising early data, are Gemini Therapeutics, which enhances normal complement factor H, and Gyroscope Therapeutics, whose gene therapy is aimed at increasing production of the complement factor I protein.

Q. We also have a couple of non-complement-factor approaches to GA at very early stages.

A. Yes, very early. Lineage Cell Technologies has a cell transplantation approach with positive, but extremely limited data, and Stealth Biotherapeutics is studying the drug elamipretide using subcutaneous injections. Its initial phase 1 ReClaim trial had positive results.

Q. Do you think oral and topical therapies can be effective against retinal diseases?

A. Ohr did get to phase 3 with an eye drop for wet AMD, but the phase 3 trial failed. I remain doubtful that oral or topical therapies are an answer.

Q. Some of the new concepts you have been studying, such as the PDS and suprachoroidal drug delivery, will require retina specialists to do things differently than they have in the past. Do you think they will adjust to these new concepts?

A. There are early adopters and there are doctors who are more conservative. We know that. The PDS does introduce a surgical element that is new to anti-VEGF delivery, but I believe all retina specialists have the skillset to master these new approaches successfully.

Q. The retina community has a well-deserved reputation as a very diverse and cooperative group that emphasizes mentoring, mutual support, and sharing best practices. You yourself are involved in Women in Retina, whose mission is mentoring. Why do you think the retina community is such a collegial group?

A. First of all, we are relatively small and pretty much all know each other. We also have a number of organizations and publications within the community that allow us to stay informed and share our latest research. This was all brought home for me in a personal way when my 15-year-old daughter, Katie, suddenly developed a rare and sight-threatening retinal tumor. The outpouring of support and advice from colleagues was overwhelming and she was able to have surgery with a good outcome.

Q. In the little free time that you do have, do you have any sports or hobbies that you enjoy pursuing?

A. All the racquet sports from tennis to ping pong, golf, cycling, and traveling for pleasure. RP