Highlighting recent studies and positive Phase 3 trial results, experts explored promising developments in retinal eye drops, addressing issues of patient compliance, safety and efficacy. While acknowledging the challenges in drug delivery and the need for further study, they emphasized the potential of topical drops as a valuable addition to existing treatment options for retinal diseases.
Though anterior segment diseasest are generally treated with topical eye drops, it’s a different ballgame when it comes to the posterior segment. Current retinal drug delivery systems
are mainly invasive and include injections, hydrogels inserts and implants that promote prolonged drug delivery.
Injections, are the most commonly used in modern ophthalmology. However, they require frequent applications by a specialized ophthalmologist, have major patient compliance issues and a high burden of treatment, and are associated with various side effects.1
Using eye drops that effectively reach the back of the eye could emerge as a major player in the treatment options for retinal diseases. Topical drug delivery remains one of the safest, easiest and most comfortable treatment methods, as it is non- invasive and allows the patient to self-apply. This treatment modality thus holds much promise in the fight against retinal diseases.
Topical drug delivery to the posterior segment
According to a recent study published in Frontiers of Neuroscience, eye drops developed by Columbia University researchers could be a more effective and lower-burden therapy for retinal vein occlusion (RVO), a common eye disease currently treated with anti-vascular endothelial growth factor (anti-VEGF) or corticosteroid injections into the eye.2
The study, titled Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in a mouse model of retinal vein occlusion, showed that caspase-9, an enzyme that triggers cell death, is overactive in blood vessels injured by RVO.
According to the investigators, the eye drops studied contained an experimental drug that blocks caspase-9, improving the health of blood vessels in the retina and reducing toxic signaling that damages the neurons.
Commenting on the recent study, Malaysian ophthalmologist Dr. Manoharan Shunmugam expressed that if these eye drops prove to be as effective as current treatment modalities, they could certainly enhance patient compliance and the administration of such therapies. However, he had some concerns.
“There are multiple caveats in this study. While caspase-9 inhibition shows promise in this particular animal model, the development of effective treatments for retinal diseases is a complex process. Factors such as drug delivery, safety and long-term efficacy need to be carefully studied in human subjects. Therefore, there is still some time to go,” he said.
DIAMONDs out of the rough?
More positive developments in retinal eye drops have also emerged with the positive early Phase 3 results of the DIAMOND trial for the candidate of OCS-01 (OCULIS) in diabetic macular edema (DME). The promising data was presented during the 23rd EURETINA Congress in October 2023.3 DIAMOND investigators showed that the trial met primary and secondary endpoints with robust statistical significance.
Specifically, the primary efficacy endpoint of mean change in best corrected visual acuity (BCVA) versus baseline at week 6 showed a statistically significant increase in visual acuity in the OCS-01arm compared to the vehicle arm (OCS- 01: 7.2 letters vs. vehicle: 3.1 letters, p=0.007), which was sustained through week 12 (OCS-01: 7.6 letters vs. vehicle: 3.7 letters, p=0.016).
For the secondary endpoints, a statistically significantly higher percentage of patients achieved ≥15-letter improvement in BCVA and better improvement in retinal thickness in the OCS-01 arm versus vehicle arm (OCS-01 25.3% vs. vehicle: 9.8%, p=0.015); and patients in the OCS-01 treatment arm also showed significant improvement in retinal thickness as compared to vehicle (OCS-01: -63.6 μm vs. vehicle: +5.5 μm, p<0.0001).
OCS-01 is a novel, high- concentration (15 mg/ml), topical formulation of dexamethasone, developed to reach the retina via an eye drop. If approved, OCS-01 would become the first topical eye drop for the treatment of DME and address a massive unmet need for non-invasive therapeutic options in this blinding disease.
Challenges in topical drug delivery
Dr. Sashwanthi Mohan, a cataract and vitreoretinal specialist from India noted that while retinal eye drop treatments like caspase-9 inhibitors and OCS-1 eye drops may serve as good non-invasive and convenient treatment options, there are nevertheless various challenges or issues that need to be addressed.
“Using topical drops for retinal disease treatment presents several challenges, including the need for efficient drug delivery to the retina, overcoming the blood-retina barrier, consistent and accurate dosing, dealing with potential side effects, achieving adequate drug concentration and retention and ensuring patient compliance over long treatment periods,” she explained.
“Using topical drops for retinal disease treatment presents several challenges, including the need for efficient drug delivery to the retina, overcoming the blood-retina barrier, consistent and accurate dosing, dealing with potential side effects, achieving adequate drug concentration and retention and ensuring patient compliance over long treatment periods.”– Dr. Sashwanthi Mohan
Notably, topical drug delivery to the posterior segment is limited by poor bioavailability and short residence time due to the complex anatomy of the eye. These ocular barriers, which include the tear film, cornea, conjunctiva, vitreous, blood-aqueous barrier and blood- retina barrier, protect the eye from potentially harmful molecules from the external environment, but at the same time, reduce the effective delivery of medications.3 Hence, only a small portion of the applied dose (about 5%) can penetrate the internal structures of the eye.4
Like glaucoma drops, retinal drops are also affected by the issue of poor drug absorption. “However, their design and formulation differ due to the distinct anatomical structures involved,” added Dr. Mohan.
“The goal of glaucoma eye drops is to reduce intraocular pressure in the anterior chamber of the eye, and they often use penetration enhancers to improve absorption. On the other hand, retinal eye drops must navigate various ocular barriers, including the blood- retina barrier, to reach the retina at the back of the eye. Strategies to enhance absorption in retinal drops may involve nanotechnology, penetration enhancers, vehicle delivery and pro-drug formulations, among others, to optimize drug delivery to the retinal tissue,” she continued.
Dr. Mohan also noted that the development of effective drugs and the conduct of rigorous clinical trials for long-term safety and efficacy remain a challenge in making topical retinal drops an effective management modality for retinal diseases.
And even if these challenges are overcome, Dr. Mohan believes topical drops would not replace existing treatment modalities, but instead complement them.
“The potential for eye drops to replace other treatment modalities like injections, hydrogel, lasers and surgeries in ophthalmology depends on factors such as the complexity and severity of the retinal disease, treatment safety and efficacy, patient variability, side effects and regulatory approval processes,” she said. “While eye drops offer advantages like non-invasiveness and ease of use, they may not fully supplant other therapies, as different retinal conditions may require tailored or more targeted treatments, and individualized approaches may involve a combination of different modalities. Topical eye drops can potentially serve as a valuable addition to the existing options rather than completely replacing them,” she further explained.
Patient acceptance and compliance
Compared to intravitreal injections, topical drops offer the advantage of higher patient acceptance while negating the risk of injection-related complications. There are, however, still issues with patient compliance, noted Dr. Shunmugam.
“Patient compliance issues would prevail for eye drops as they do in glaucoma cases. On the other hand, compliance issues also arise with intravitreal injections due to the poorer acceptance of such injections or experience bias based on the patient’s individual encounter with an intravitreal injection, which has a wide operator-dependent variable that can be difficult to quantify,” he commented.
Nevertheless, this can be overcome with good patient education and compliance monitoring. “Since retinal diseases often require continuous treatment, ensuring that patients consistently administer their drops as prescribed is crucial. To mitigate compliance issues, patients should be educated about the importance of treatment adherence, provided with clear instructions for drop administration and any concerns or side effects should be addressed immediately. Additionally, simplifying dosing schedules, using reminder tools and involving family members can help improve patient compliance with retinal drop regimens, ultimately increasing the chances of successful treatment outcomes,” Dr. Mohan advised.
In essence, topical drops hold great promise, but there is much that remains to be explored.
“Topical drops offer the potential for early intervention and reduced invasiveness compared to injections or surgeries. However, matters regarding the diverse retinal diseases to treat, effective drug delivery to the retina, appropriate drug formulation and rigorous testing for safety and efficacy must be properly addressed,” Dr. Mohan concluded.
1. Löscher M, Seiz C, Hurst J, Schnichels S. Topical Drug Delivery to the Posterior Segment of the Eye. Pharmaceutics. 2022;14(1):134.
2. Avrutsky MI, Chen CW, Lawson JM, Snipas SJ, Salvesen GS, Troy CM. Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in a mouse model of retinal vein occlusion. Front Neurosci. 2023;17:1209527.
3. Positive Phase 3 Stage 1 DIAMOND Trial Results of OCS-01 in Diabetic Macular Edema Presented at 23rd EURETINA Congress. GlobeNewswire. Available at https://www.globenewswire.com/news-release/2023/10/10/2757269/0/en/Positive-Phase-3-Stage-1-DIAMOND-Trial-Results-of-OCS-01-in-Diabetic-Macular-Edema-Presented-at-23rd-EURETINA-Congress.html. Accessed on November 9, 2023.
4. Wu KY, Joly-Chevrier M, Akbar D, Tran SD. Overcoming Treatment Challenges in Posterior Segment Diseases with Biodegradable Nano-Based Drug Delivery Systems. Pharmaceutics. 2023;15(4):1094.
Editor’s Note: A version of this article was first published in PIE Magazine Issue 28.