Gene Therapy Could Ease Wet AMD's Injection Burden: Carl Regillo, MD

Missed injections for weeks or months can trigger vision damage that isn't always fully reversible in patients with neovascular age-related macular degeneration (wet AMD), according to Carl Regillo, MD, FASRS, director of the Retina Service at Wills Eye Hospital and professor of ophthalmology at Sidney Kimmel Medical College, Thomas Jefferson University.

In part 1 of his interview with The American Journal of Managed Care^® (AJMC^®), Regillo described how second-generation anti–vascular endothelial growth factor (anti-VEGF) agents like faricimab and high-dose aflibercept have improved durability and disease control compared with earlier drugs. However, real-world outcomes continue to trail clinical trial results mostly because of the logistical, financial, and caregiving burdens that make frequent, indefinite injections difficult for many patients to sustain.

Here, Regillo examines what's at stake when that burden leads to missed visits, how step-edit requirements from payers shape which drugs patients can access and when, and his approach to switching agents for patients who don't respond optimally. He closes by looking ahead to technologies positioned to ease the treatment burden altogether, including the port delivery system, gene therapy, and a pipeline of novel agents that could change how wet AMD is managed over the next several years.

AJMC: When a patient does slip through those logistical cracks and returns after an extended absence, what does the recovery look like? What irreversible damage may already be done by the time they get back in your chair?

Regillo: We’ve witnessed this phenomenon from day 1, because patients do slip through the cracks, and there has been documented variable compliance and non-compliance with the course of therapy. That will lead to vision loss in many patients. Interestingly, we got an even bigger glimpse at the impact of missing visits during the COVID-19 epidemic. When patients are late for their treatments by many weeks or months, the outcomes are highly variable. Some patients seem to do okay while others have really severe disease progression. How much they recover is also very variable, with some not suffering any visual setbacks and others suffering great setbacks.

For patients who do experience setbacks, some losses are reversible to some degree, and some are not. We can’t predict who can tolerate going longer between treatments or missing a visit here and there. Unfortunately, disease recurrence essentially happens, and the choroidal neovascularization [CNV] complex will start to grow again. That in and of itself can be invasive and damaging, producing permanent additional damage and therefore contributing to a lack of complete vision recovery. Chronic exudation can also damage the neurosensory retina, and as the CNV process progresses, fibrosis sets in, which leads to some degree of irreversible neurosensory damage. When patients miss visits or are lost to follow-up for extended periods of time, you see CNV growth, chronic exudation, and fibrosis, with one or all of these contributing to poor or decreased vision.

AJMC: With several approved agents now available, how do you think about first-line selection for a newly diagnosed patient today, and when does that calculus change?

Regillo: I prefer to start with the best, most durable treatments out there. If insurance allows, I'll try to start a second-generation drug, such as faricimab or high-dose aflibercept, for a patient with new wet AMD. However, the reality is that payers will restrict access to these second-generation agents through step edits for most patients. These step-edit mandates make us go through several first-generation agents before we can utilize and justify the use of second-generation agents, which are a bit more expensive. Step edits are typically off-label bevacizumab first for several injections, then typically a first-generation on-label drug next, and then a third step is typically needed to get to a second-generation drug. As a result, it could be 6, 9, or 12 months before we finally get to the drug I wanted to start with.

AJMC: Some patients have persistent fluid even on maximal therapy, and they don't dry regardless of injection frequency or agent. How do you identify and manage those patients, and does switching agents help in that subgroup?

Regillo: In practice, we always start with monthly injections and aim to get the macula dry and get the disease under optimal control. Thereafter, we try to extend the treatment interval through the treat-and-extend approach, which is what most of us do in practice. It’s a trial-and-error process: you start pushing every 2 weeks or so with the treatment interval until there’s disease recurrence, and then you find the interval that works best for that patient. If that interval is relatively infrequent, such as 10 or 12 weeks, that’s usually not only a good response but also a relatively low burden. We’ll tend to stick with the same agent.

If we’re not getting complete drying and therefore have a suboptimal response, or if we have to utilize a first-generation drug very frequently to get optimal disease control, that’s when we start thinking about switching to a second-generation, which almost always gives us some degree of greater durability and, in some cases, also better disease control or better drying.

Sometimes, regardless of all the drugs available to us today, we don’t always achieve a completely dry macula or what we consider optimal control. That’s not necessarily bad; we might have to settle with some exudation, but if it’s just a mild degree of relatively stable subretinal fluid, or maybe subretinal pigment epithelium fluid, that can generally be well tolerated, and patients can still have a good vision outcome.

AJMC: The port delivery system takes a fundamentally different approach from longer-acting molecules with continuous drug delivery rather than a longer half-life. You led the Archway and Portal trials, and 5-year data presented at the American Society of Retina Specialists ASRS 2025 meeting showed about 95% of patients going 6 months between refills.¹ What does continuous delivery change for patients that a longer-interval injection doesn’t?

Regillo: One of the reasons I’ve been a big fan of the port delivery system [PDS] is the proof of concept here that sustained delivery with adequate drug levels can give us excellent long-term vision outcomes, much better than what we see in the real world. PDS gives us continuous, adequate therapeutic drug levels, and that really translates into better overall long-term disease control. When we do bolus injections in practice, they’re done intermittently, and there’s going to be some degree of disease fluctuation and exudation over time, which is probably damaging. There are also lapses of treatments, as we talked about, with disease recurrences that tend to decrease acuity, but none of that is really at play when you have sustained delivery providing adequate therapeutic levels for 95% of patients for no less than 6 months. That’s why the results have been so good with 5-year outcomes, even 7-year outcomes now.²

AJMC: Gene therapy for wet AMD has moved from concept to late-stage development, and early data shows durable effects lasting more than a year from a single injection. How close are these for patients, and what would eliminating the need for chronic injections mean for the people most burdened by the current treatment model?

Regillo: I think gene therapy for wet AMD holds great promise. This is the concept of the ultimate sustained delivery: indefinite disease control with 1 injection. Studies are showing that with a single administration of gene therapy—whether subretinal, suprachoroidal, or intravitreal—we’re seeing very good disease control with little or no additional treatment needed for many patients. Not all patients. Some patients still need supplements here and there, but most will have a decrease in need for anti-VEGF injections in the office. At the very least, it’s decreased treatment burden, and I think it also holds the promise of better long-term vision outcomes.

We're also seeing, with gene therapy, some unique safety issues, such as some inflammation, especially with intravitreal approaches.³ But the long-term safety at currently tested doses, especially at phase 3 and with the various routes of administration, seems adequately safe given the existing data. I think the concerns there have definitely been addressed.

AJMC: Given everything in the pipeline—sustained-release platforms, gene therapy, and multi-targeted agents—what does meaningful progress for patients with wet AMD realistically look like in the next 3 to 5 years?

Regillo: I think we're going to make ongoing progress with effective, safe, long-term disease control with less injection and fewer office visits in the future. That's where we've been heading, and that's where I think we'll make some great progress in just the coming years.

We mentioned the port delivery system as one currently available option because it’s FDA-approved.⁴ But coming up there are the tyrosine kinase inhibitor products, which are small molecules packaged in biodegradable intravitreal implants. They show great promise for sustained delivery over 6 or more months.⁵ And we mentioned gene therapy, which is likely to be in our hands soon thereafter.

We’re also going to see a whole host of novel injectable biologics with either new or different mechanisms of action. In addition to blocking VEGF, there are other targets, blocking Ang-2, and there are higher-affinity agents in testing such as IL-6 inhibition and Wnt agonism. All these different mechanisms of action are not directly related to the VEGF pathway being explored. There are also novel ways to extend delivery, such as biologics that not only block VEGF-A but bind the heparin within the vitreous, which could potentially allow for a depot-like effect and some sustained delivery. A lot of really fascinating, interesting, new approaches are going to come our way in just the next few years.

References

1. Roche’s Susvimo maintains vision over five years with two refills per year in people with neovascular age-related macular degeneration (nAMD). News release. Roche. July 31, 2025. Accessed July 7, 2026. https://www.roche.com/media/releases/med-cor-2025-08-01

2. Regillo CD, Stevenson S. Retina World Congress 2026: Port Delivery System shows durable outcomes at 7 years in neovascular AMD. Modern Retina. May 30, 2026. Accessed July 7, 2026. https://www.modernretina.com/view/retina-world-congress-2026-port-delivery-system-shows-durable-outcomes-at-7-years-in-neovascular-amd

3. Barthelemy N, Sridhar J, Sengillo JD. Gene therapy for wet age-related macular degeneration. Bioengineering (Basel). 2025;12(10):1072. doi:10.3390/bioengineering12101072

4. FDA approves Roche’s Susvimo, a first-of-its-kind therapeutic approach for neovascular or “wet” age-related macular degeneration (nAMD). News release. Roche. October 21, 2021. Accessed July 7, 2026. https://www.roche.com/media/releases/med-cor-2021-10-22b

5. Amin R, Kaiser PK. Tyrosine kinase inhibitors for wet age-related macular degeneration: The current developmental landscape. J Pharmacol Exp Ther. 2026;393(3):103803. doi:10.1016/j.jpet.2026.103803