In the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME), the required frequency of intravitreal injections can represent a substantial burden for many patients. Strategies to reduce this burden include treat and extend (T&E), the development of other targets in addition to VEGFA, and the engineering of more sustained delivery systems.

Retrospective analyses of large databases of US patient populations have shown that nAMD treatment outcomes during the first few years largely depend on treatment frequency. In most anti-VEGF therapy clinical trials that reported improved or maintained vision in nAMD, patients received treatment with a monthly or fixed schedule. In contrast, even in the United States, where we have excellent health insurance coverage, we see the undertreatment of our patients with nAMD. Monthly or fixed treatment is not an option for patients. Thus, most patients are not receiving treatment as frequently as they should and are not getting the visual acuity results that we see in clinical trials. There are multiple reasons for this. Study participants are not always reflective of the average patient; in real life, things come up, and people miss treatments. There are also logistical challenges in health care delivery that might lead to delays in treatment. Results of real-world studies often fall short of those seen in clinical trials, and part of the reason for this may be the ability to control the follow-up schedule more tightly in clinical trials.

We have tried to bridge the gap by implementing different treatment paradigms. One of these paradigms is called treat and extend, and the premise is that you get the patient dry with monthly injections and then, once they are dry, you begin extending the interval between treatments. In T&E, the goal is to identify the interval at which each patient is best treated, because each patient is slightly different. At every treatment visit, the patient is evaluated, they receive a treatment, and the treatment schedule is adjusted accordingly by extending, maintaining, or contracting the interval between treatments. With this approach, over time, the number of injections is dramatically reduced while obtaining similar visual results to what we see in clinical trials. There has been widespread adoption of T&E protocols in clinical practice for these reasons.

Another approach to potentially reduce the anti-VEGF treatment injection frequency is to identify other targets, in addition to VEGFA, that might help improve efficacy and extend durability. There is also interest in optimizing longer-term delivery systems (eg, implantable reservoirs) to achieve more durable results.

Examples of agents that are active at other targets include aflibercept, which antagonizes not only VEGFA but also placental growth factor, a VEGF family member. Faricimab targets VEGFA and angiopoietin 2. And then, there are clinical trials investigating agents that block the activity of VEGFC and VEGFD, as well. Tyrosine kinase inhibitors (TKIs) that target VEGF receptors are conceptually appealing in that they allow all of the VEGF family members to be simultaneously targeted. With TKIs, there is also the potential to target other factors and receptors that mediate vasopermeability. The problem with using TKIs for ophthalmologic applications has always been their delivery, but there is ongoing research to address this issue. The sustained delivery of TKIs is being explored in patients with nAMD. One technology that is being evaluated is to place the TKI axitinib in hydrogel implants.

The goal of creating a delivery system to increase the duration with which the therapeutic agent is present in the vitreous cavity extends to other agents as well, not just TKIs. For example, implantable reservoirs that function as a port delivery system are being studied. One such system that is being evaluated delivers ranibizumab. The port delivery system has demonstrated reliable and continuous drug delivery and typically requires refill exchanges every 6 months.

Gene therapy is yet another approach to increase the length of time between anti-VEGF treatments. With gene therapy, you inject a viral vector that causes the cells to produce anti-VEGF proteins instead of continuously injecting anti-VEGF proteins. We do not yet know if gene therapy leads to a continuous production of anti-VEGF proteins for the rest of a patient’s life, but initial results are promising.

The challenges and potential solutions have been nicely summarized. I agree that one of the real hurdles to treating patients with nAMD or DME is the ability to have regularly scheduled follow-up visits. This can be especially trying for patients with nAMD, who are often older; issues may arise with mobility, transportation, or caregiver availability, for instance. Patients with DME tend to be working age and tend to have additional comorbidities. Whether you consider nAMD or DME, the bottom line is that missed appointments and treatment delays do happen, and they can lead to suboptimal real-world outcomes.

When thinking about those patients who are achieving a suboptimal response, we recognize that many other factors may be involved, in addition to injection frequency. We emphasize the importance of drying up fluid, but there are going to be some patients who can never be dry, despite the fact that we all agree that our goal should be to get rid of their exudation. In some patients, you can reach this goal only by treating them very frequently, which goes to the treatment burden issue that we just discussed.

Some patients may be challenging to treat in part because there could be other mechanisms involved, and this is especially clear in DME, in my view. In DME, we know that there can be other cytokines involved, with inflammatory mechanisms, and other influences aside from VEGF, and, for certain patients, one pathway might be contributing more substantially to their DME. It is important for physicians to be looking for that when making treatment decisions about adding additional or adjunctive therapies both for nAMD and DME. We also need to better understand those subsets of patients who are a bit more advanced in their nAMD or DME, in whom the mechanisms of fluid may be degenerative, and, as a result, unresponsive to all of the currently available therapies.