Better delivery systems needed for retinal diseases
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The most common drugs injected into the vitreous to treat posterior segment disease are steroids and anti-VEGF medication. To keep it simple, I will use trade names when available.
For steroid delivery to the posterior segment, we have Triesence (triamcinolone acetonide injectable suspension, Novartis), Ozurdex (dexamethasone intravitreal implant, Allergan), Yutiq (fluocinolone acetonide intravitreal implant 0.18 mg, EyePoint Pharmaceuticals), Iluvien (fluocinolone acetonide intravitreal implant 0.19 mg, Alimera Sciences) and Vitrasert (ganciclovir). These FDA-approved treatments allow delivery of steroid into the posterior segment, ranging from 30 days to 3 years. Unfortunately, for most treatable posterior segment disease other than chronic uveitis with cystoid macular edema, intravitreal anti-VEGF injection is more effective.
One of the best studies confirming the efficacy of a monthly injection of an anti-VEGF into the vitreous for the treatment of neovascular age-related macular degeneration is the ANCHOR study. In this study, compulsive compliance to 12 monthly injections generated on average an 11.3 letter improvement in visual acuity.
Monthly injections are a significant burden on the provider, the patient and their family, as well as society. For this reason, as-needed and treat-and-extend protocols have flourished in real-world treatment environments. Meta-analysis of real-world PRN and T&E treatments of wet AMD sadly confirms that they are much less effective than monthly injections compulsively delivered.
A timely paper recently published in the August issue of Ophthalmology reviewed nonadherence and nonpersistence in the treatment of neovascular AMD with an anti-VEGF. This review suggested nonadherence and/or nonpersistence occurs in 60% of patients receiving intravitreal injections of an anti-VEGF for neovascular AMD. The risk factors for poor compliance in this study included old age, illness, poorer vision, fear, and difficulty with office visit logistics and travel.
We have a problem with patient compliance in all eye diseases that require long-term therapy, with glaucoma being the classic example, but in this case it is a combination of patient and provider noncompliance, as perfect compliance with a monthly intravitreal injection of an anti-VEGF for every patient who would benefit is nearly impossible to deliver.
One answer is to develop anti-VEGF medications or delivery systems with a longer duration, enhancing their durability. This is the promise of the Genentech Port Delivery System (PDS), described in the accompanying cover story. The PDS system, not yet FDA approved but in phase 3 clinical trial, promises a system that would allow an injection every 6 months to continuously deliver anti-VEGF medication at an appropriate concentration for 180 days.
Once approved, this will provide some interesting new challenges to our patient care delivery model. The patient treated using a PDS will need to be monitored in between visits to the ophthalmologist specialist. Local eye care providers can play a role here, but especially promising to me are home diagnostics that will allow the patient, in collaboration with their treating ophthalmologist, to monitor their status in between visits without professional help. Notal is a leader here, and a home-based OCT device is in development along with the already available Preferential Hyperacuity Perimetry. Of course, the patient can also follow their visual acuity and Amsler grid metamorphopsia daily while at home. I believe the PDS system, if shown safe and effective, will be a step in the right direction.
A second approach is to deliver a second medication that can enhance the durability of the anti-VEGF injection. This is a common approach used in other medical fields, including the medical management of cancer. A promising drug here is tyrosine kinase inhibitor, and several companies, including Ocular Therapeutix and Graybug Vision, are working in this arena.
Finally, gene therapy would be amazing if it could genetically modify the patient’s own ocular cells to generate a continuous and lifelong release of an appropriate concentration of anti-VEGF to treat their disease. While this appeared to be science fiction only a few years ago, many well-funded companies are pursuing this once seemingly impossible dream.
In addition, dry AMD has an incidence and prevalence 10 times greater than wet AMD, and the approaches to its treatment in clinical trials may well also require an intravitreal injection of a complement inhibitor, an antioxidant, an anti-integrin, or an injectable cell or gene therapy. The issue of nonadherence and nonpersistence and the need for a durable treatment will be 10 times greater for dry AMD than for wet AMD, and we ophthalmologists, our patients, their families and even society are already challenged managing wet AMD and macular edema.
Investment into better delivery systems is arguably a more urgent need than investment into new medications. The magic of the innovation cycle fertilized by adequate human and financial capital remains our best hope to manage this critical eye care delivery problem.
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