One of the priorities in optimizing the treatment paradigm has been to reduce the burden of treatment by finding ways to decrease the frequencies of intraocular anti-VEGF injections and office visits. An early approach that was developed in the treatment of DME or nAMD was an as-needed (PRN) regimen. With a PRN injection strategy, a patient with DME may be given their initial loading doses of anti-VEGF therapy and then return to the office after 4 weeks for a follow-up visit to determine if there is fluid in the macula, which would trigger an injection. If there is no fluid in the macula, the patient would not receive an injection and would then return, perhaps 1 month later, and receive an injection if there is recurrent edema. 

There are 2 problems with this approach. The first issue pertains to the recurrent macular edema that develops prior to each injection, which may be present for several weeks. Over time, the many recurrences may cause a permanent reduction in vision. The second issue is that the frequency of clinic visits is high, so the treatment burden for the patients and their families is not reduced.  

Anatomical changes are the basis for monitoring in both DME and nAMD. With regard to the presence of fluid and what that means in terms of visual loss, DME can be a little more forgiving than nAMD, but each reoccurrence of edema in DME can take a toll. Frequent reoccurrences with a collection of fluid in the macula cause damage to the photoreceptor cells and can lead to a gradual decline in vision. Therefore, PRN anti-VEGF treatment is not ideal, as it can often lead to a reduction in vision over time. 

Another approach is called treat and extend (T&E). With this approach, every time a patient comes in, they receive an anti-VEGF injection, regardless of whether or not they have edema. The goal of this approach is to lengthen the period of time between visits to find the optimal time between injections for which there are no reoccurrences. There is some capacity for adaptation and course correction built into the T&E approach in that the time between visits is lengthened until there is a mild recurrence of macular fluid, and then the time between injections is shortened a bit. When the patient has been fluid free for several visits, the length of time between visits can be extended. With these incremental adjustments, the time between visits can be modified over time to accommodate changes in disease activity.  

For most patients, the optimal injection interval for anti-VEGF therapy is fairly predictable; however, a problem with both PRN and T&E strategies in nAMD and DME is that, in some patients, disease activity may increase unpredictably in between visits. For example, a patient might have excellent control of exudation with injections every 6 weeks for a year and then return 6 weeks after an anti-VEGF injection with a severe recurrence. We are seeking ways to reduce or eliminate the need for course correction and to make treatment more predictable.

Dual targeting of VEGF and Ang2 is one of the strategies that is being explored to achieve more consistency when utilizing a T&E protocol. By blocking Ang2, endothelial cells become less responsive to VEGF, and this may lengthen the period of time between recurrences, because, as VEGF levels begin to rise, the endothelial cells are less prone to leakage for a longer period of time. Faricimab targets both Ang2 and VEGFA and is approved by the US Food and Drug Administration for the treatment of nAMD and DME with the option for extending the treatment interval in the first year following 4 loading doses. Clinical trial data with faricimab have shown that many patients with DME were well maintained with injections every 12 or 16 weeks for the duration of the trial. We do not know whether that treatment interval can be maintained long-term, but it is encouraging that these data show the potential to lengthen the period between treatments and reduce the burden for patients with DME.

Another strategy is to develop a sustained delivery of anti-VEGF agents that provides continuous treatment for many months. An example is the port delivery system, an implantable reservoir that continuously releases ranibizumab into the vitreous cavity and can be refilled every 6 months. An additional example is ocular gene therapy to provide constant expression of an anti-VEGF protein in the retina. So, in addition to finding new targets to improve on the efficacy and durability of anti-VEGF therapy, gene therapies and sustained delivery systems may also be a part of the solution.