The Challenges of Drug Delivery for Retinal Diseases - Episode 9
Types of delivery methods currently being explored to improve treatment for patients with retinal disorders.
Albert J. Augustin, MD: Let us focus a bit on the delivery methods that are being explored. Currently, we only have biodegradable and nonbiodegradable implants such as Ozurdex [dexamethasone] and Iluvien [fluocinolone acetonide]. Of course, in the clinical investigation stages are microparticles. Dr Korobelnik, can you say a few words about microparticles and nanoparticles?
Jean-Franҫois Korobelnik, MD: What I can say is that durability is the new challenge. We have pathways we have identified inhibiting VEGF that are very effective, and we need long-lasting drugs. Anything that can help those drugs last longer in the eye has to be explored. Now it’s the early stages of trials, and we have to look for safety and for stability of the proteins; it’s a very big challenge. Anything that can work clinically will be more than welcome. Will it be microparticles, nanoparticles, micro things, whatever? I am open to this. The thing is that it must be stable, sterile, effective, and long lasting.
Albert J. Augustin, MD: What about microneedles?
Jean-Franҫois Korobelnik, MD: I do not have a specific opinion on this one; I am not much aware of it. Are you?
Albert J. Augustin, MD: It is a painless application. They must be long enough to overcome the ocular barriers. We are at least able to establish a localized drug delivery; we minimize pain, tissue damage and reduce the risk of infection hopefully, so they can contribute to increased patient compliance. It is the same with nanoparticles that are in clinical investigations. This is also true for microelectromechanical systems: micro machines that apply electrical current to deliver charged drug particles; iontophoresis, electroporation. These are interesting approaches, and we should know that those devices, so to speak, are under investigation. Sooner or later I’m sure some of them will come into clinical investigation at a minimum. Near [to clinical use] are port delivery systems, such as permanent refillable eye implants, which continuously deliver a customized formulation of ranibizumab over a month or even longer. Dr Peto, can you speak on this port delivery system that is under investigation?
Tunde Peto, MD, PhD: A port delivery system for long duration and stable drug delivery, so that we would not have the peaks and troughs, would be excellent. We have been asking for this for a long time; of course every time when you get what you ask for, then new challenges arise. The system, as it is under investigation, needs to be put in preferably by a vitreoretinal surgeon. In some countries, finding enough people to do this operation will be a real issue. If we can cut across this barrier and be able to put the drugs in, that will really help our clinics if the patient doesn’t have to always have an extra injection. For those patients in an average population and not in a clinical trial, how are we going to make sure they will remain safe, and that it will not be a route for infection to get into the eye? This will also be a potential challenge.
Albert J. Augustin, MD: What do you think about continuous anti-VEGF application? I think we all know that VEGF is also a kind of survival factor, at least it is contributing to a positive interaction between photoreceptors and RPE [retinal pigment epithelium] cells. If you continuously block the vascular endothelial growth factor with such a drug, can this be a drawback? Do you expect anything?
Tunde Peto, MD, PhD: From clinical trials and clinical examinations, we do know that a lot of patients develop macular atrophy with repeated injections, especially many injections, 5 to 7 years down the track after starting those injections. There is always the possibility that some of these patients might have developed it anyway, but we do need to be mindful that we are blocking the positive effect as well; we might again have a few extra negative results that we didn’t quite anticipate. Having said that, atrophy tends to be slower progressing; it does not tend to give you such a huge swing in visual acuity than, for example, in AMD [age-related macular degeneration], and another bleed, or a huge amount of fluid. It might be that the sort of mechanisms patients might have for increasing color contrast or getting used to a slowly deteriorating vision might be different to a sudden loss of vision that they currently experience.
Jean-Franҫois Korobelnik, MD: Albert, if I may comment on this point?
Albert J. Augustin, MD: Yes.
Jean-Franҫois Korobelnik, MD: I understand your concern about continuous VEGF inhibition. On the other hand, we have been injecting some patients for 10 years. They have received dozens of injections, with a very high spike of anti-VEGF agents in the eye and in the retina. I do not know if these repeated spikes are better or worse than a continuous low dose of VEGF inhibitor in the eye. It is definitely something we must look at. It may be a problem, but so far in the trials it is not clearly established; maybe a low dose is better than very high spikes.
Tunde Peto, MD, PhD: I completely agree that we do not have a clear understanding or a clear answer as to what might be best for our patients.
Albert J. Augustin, MD: I just wanted to raise attention; we do not know yet. There also seems to be a difference between patients with diabetes, venous occlusion, and AMD. Obviously if the RPE is diseased, they are more susceptible to such a kind of atrophy compared to patients with diabetes or venous occlusion.
Transcript edited for clarity.