Moving Beyond the Standard of Care: How Novel Approaches Could Become the Future of Diabetic Retinopathy Treatment
Introduction
An initial diagnosis of diabetic retinopathy (DR) can often be a surprise – for many patients, symptoms or impact on vision are not yet evident upon diagnosis during an eye exam.
The current management strategy for early-stage DR is active surveillance, also known as “watch-and-wait,” until symptoms progress and vision becomes impacted. Active intervention is usually only undertaken once a sight-threatening complication arises or vision deteriorates further, at which point patients usually undergo invasive and sometimes painful treatments.
While there are millions of early-stage DR patients who could potentially benefit from a proactive, non-invasive therapy that preserves vision, rather than seeking to reverse or stall the disease’s effects later on, there are currently no approved options. OcuTerra is working to change that.
OTT166, currently under evaluation in the Phase 2 DR:EAM clinical trial, is a novel small molecule selective integrin inhibitor that OcuTerra has purpose engineered to reach the retina via eye drop application. It is designed to be administered in the early stages of disease, by the patient at home. If approved, OTT166 has the potential to dramatically change the treatment paradigm by enabling non-invasive treatment that preserves vision and prevents disease progression.
Available treatments
The most common treatments for DR are laser photocoagulation or intravitreal anti-VEGF injections. Laser photocoagulation uses directed laser light to stop the growth of new blood vessels and decrease fluid buildup. While effective, this treatment comes with significant side effects including scarring and loss of function in areas of the retina that are exposed to the laser, leading to loss of peripheral and low-light vision.
With a VEGF inhibitor, the medication is injected directly into the back of the eye and must be repeated on a regular basis. A patient typically receives an initial course of five injections every four weeks and after that, they will require further injections for the rest of their life, usually once every 2 to 4 months depending on the severity of disease. This procedure carries some of the same complications associated with any invasive procedure – most notably the risk of infection1 – as well as diminishing responses to subsequent repeated dosing2. Moreover, intravitreal injections can be distressing, leading to non-compliance with repeated injections, and the resulting exacerbation and progression of disease is often a reality.
Alternative treatment approaches
All of this begs the question – why is intravitreal injection still the standard of care for DR? Why hasn’t a less invasive, more proactive treatment option emerged?
One reason is that intravitreal injection enables direct delivery of drug to the retina. The resulting high, local concentrations allow for peak delivery of the therapeutic agent and minimize systemic exposure that could result in potentially harmful off-target drug effects. In addition, these injections circumvent the blood-retina barrier, an obstacle that prevents most systemically delivered therapeutics from reaching the retina, reducing or eliminating their effectiveness.
But with the increasing prevalence of DR – cases in the U.S. are projected to reach over 11 million by 20303 – there is a pressing need for the development of novel therapies that can exploit a non-invasive route of administration.
As well as intravitreal injection, two non-invasive routes exist – systemic delivery or topical eye drop, as summarized in Table 1. Systemic delivery, achieved either through an oral drug or an intravenous injection, has been associated with higher patient compliance but has major limitations due to its indirect delivery4. To overcome the blood-retina barrier and achieve therapeutic concentrations at the retina, patients typically require high doses with potential for off-target toxicity.
Eye drop formulations offer many advantages, including the fact that they can be administered by the patient at home and circumvent the compliance problems that plague injections. Applied directly to the eye, the medication is delivered in the local concentrations required for therapeutic effect at the retina. Knowing that physiological barriers can potentially pose an obstacle with this delivery route, OcuTerra purpose engineered OTT166 to have an optimum balance of physiochemical properties to allow it to distribute to the retina in high concentrations after topical administration.
Table 1: Comparison of oral, eye drop, and intravitreal delivery4
| Intravitreal Injection | Oral/Systemic | Topical |
|---|---|---|
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OTT166 and the DR:EAM Clinical Trial
OcuTerra’s novel eye drop-based therapeutic, OTT166, has been studied in two multi-center, randomized, Phase 1b trials, where it has shown favorable safety and tolerability profiles and clear evidence of biological activity. It is currently under evaluation in the DR:EAM Phase 2 trial, which is further studying the safety and efficacy of OTT166, as well as identifying an optimum dosing regimen for future planned Phase 3 trials.
As an integrin inhibitor, OTT166 expands beyond the anti-VEGF paradigm that has defined medical retina therapy for more than a decade. By selectively inhibiting the actions of key RGD-binding integrin subtypes (αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, α5β1, and α8β1), OTT166 can potentially block multiple pathways of disease that are not addressed by anti-VEGF alone – it is designed to impede several growth factors responsible for new blood vessel growth (angiogenesis), vascular leakage (macular edema), inflammation and reduce fibrosis, a long-term complication of retinal disease present even in patients who have undergone anti-VEGF injection treatment. In a promising category of retinal therapeutics, OTT166 stands apart as a differentiated, first-in-class eye drop candidate.
By developing therapies that can be administered earlier and non-invasively, OcuTerra is aiming to give patients a viable option to slow or even prevent disease progression, addressing a tremendous unmet need for people with ophthalmic disease. As our team continues the DR:EAM Phase 2 trial, we believe that a better treatment paradigm for patients with DR is not only possible, but within sight.
Please stay tuned and follow along as we continue to move forward on this exciting journey!
References
Gupta, N., Mansoor, S., Sharma, A., Sapkal, A., Sheth, J., Falatoonzadeh, P., Kuppermann, B., & Kenney, M. (2013). Diabetic retinopathy and VEGF. The open ophthalmology journal, 7, 4–10. https://doi.org/10.2174/1874364101307010004
Yang, S., Zhao, J., & Sun, X. (2016). Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review. Drug design, development and therapy, 10, 1857–1867. https://doi.org/10.2147/DDDT.S97653
American Diabetes Association. (2022, May). May is Healthy Vision Month…did you know? . American Diabetes Association. Retrieved April 7, 2023, from https://diabetes.org/sites/default/files/2022-04/FOD_HVM_0.pdf
Gaudana, R., Ananthula, H. K., Parenky, A., & Mitra, A. K. (2010). Ocular drug delivery. The AAPS journal, 12(3), 348–360. https://doi.org/10.1208/s12248-010-9183-3