New Developments in Eye Drop Formulation: How OTT166 is Purpose-engineered to Reach the Retina

Introduction 

The current standard of care for patients newly diagnosed with diabetic retinopathy (DR) is “watch-and-wait” – regular monitoring of disease progression until symptoms advance to the point where a sight-threatening complication arises. At this point, active intervention is required, but the options are limited – the most common treatments are laser photocoagulation or intravitreal injections of a therapeutic, usually anti-VEGF. While both of these treatments can be effective, they are invasive and associated with significant side effects and complications which may further impact vision. 

As a result of the distressing nature of intravitreal injections, many patients delay or avoid treatment, which can lead to avoidable exacerbation of disease. In addition, the disease is growing in prevalence; cases in the U.S. are predicted to almost double over the next few years, reaching over 11 million by 20301. A paradigm shift in early preventative therapy for DR is urgently needed. While alternative methods of treatment exist and are in development, such as oral or systemically delivered drugs, as well as eye drops, none are FDA approved for treatment so far. 

Early intervention with eye drops 

Eye drops offer many advantages over alternative delivery routes – in fact, they are recognized as one of the safest and most convenient routes of ocular drug delivery2. As summarized in April’s OcuTerra Insights, eye drop delivery is non-invasive, and the topical route of drug delivery allows for a high local concentration of the drug at the site of action. Eye drops can be self-administered by the patient at home on a regular basis, and the delivery method is associated with higher patient preference and compliance compared to injections3. The ease with which an eye drop can be administered makes these medications ideal for early intervention, with the potential to delay or even prevent further disease development. 

Anatomy of the eye 

The eye is a very complex organ with unique physiological characteristics. In order to reach the retina via the external surface of the eye, a formulation must first overcome physiological constraints such as reflexive blinking and tear production, as well as nasolacrimal drainage which reduce the concentration and bioavailability of the therapeutic. The therapeutic must then get through multiple layers of tissue, specifically the conjunctiva, the sclera and the choroid, before finally gaining access to the retina – though for small molecules this route of distribution can be more facile than transiting the cornea, the aqueous humor and the vitreous.

Numerous formulations and additives have been developed to increase concentration and drug penetration and overcome physiological barriers. For example, scientists have developed viscosity and permeability enhancers that allow eye drop therapeutics to penetrate the outer surface of the eye (the cornea). These modifications are effective in delivering compounds to the anterior portion of the eye – the cornea, conjunctiva, iris and lens4 – but in order to reach tissues in the posterior segment such as the retina, other strategies must be developed.  

OcuTerra’s scientists have engineered OTT166 to alter its physiochemical properties. By incorporating fluorine atoms at specific positions on the molecule, we’ve adjusted the therapeutic’s lipophilicity and solubility while retaining its function as a specific RGD-binding integrin inhibitor, allowing it to penetrate the conjunctiva and transverse the sclera and choroid, and distributing to the site of action in the retina at concentrations sufficient for therapeutic effect5. 

Advancing OTT166 

Historically, delivery of therapeutics to the retina via topical eye drop has been hampered by the physical barriers posed by the unique anatomy of the eye, and thus direct intravitreal injection has become the standard practice for treatment. Through the development of OTT166 as an integrin inhibitor delivered via eye drop, OcuTerra is enabling earlier non-invasive treatment with the goal of preventing disease progression, thereby delaying or completely eliminating the need for intravitreal injections or destructive laser procedures. OTT166 is currently being studied in the Phase 2 DR:EAM trial, evaluating its safety and efficacy in the treatment of diabetic retinopathy. As an inhibitor of multiple specific integrin subtypes (αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, α5β1 and α8β1), OTT166 moves beyond the anti-VEGF paradigm with the potential to block multiple disease pathways that are not addressed by anti-VEGF alone. These include new blood vessel growth (angiogenesis), vascular leakage (macular edema) and well as fibrosis, a long-term complication of retinal disease that anti-VEGF treatments do not address.  

As the DR:EAM study continues, we hope to demonstrate the value of a novel eye drop treatment for early-stage DR. Patients with DR deserve therapeutic options that don’t put them between a rock and a hard place – and OcuTerra is working to provide that. 

References 

  1. 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 

  2. 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   

  3. Jacobs, B., Palmer, N., Shetty, T., Dimaras, H., Hajrasouliha, A., Jusufbegovic, D., & Corson, T.W. (2021) Patient preferences in retinal drug delivery. Scientific reports, 11(1), 7-8. https://doi.org/10.1038/s41598-021-98568-7 

  4. Patel, A., Cholkar, K., Agrahari, V., & Mitra, A. K. (2013). Ocular drug delivery systems: An overview. World journal of pharmacology, 2(2), 47–64. https://doi.org/10.5497/wjp.v2.i2.47    

  5. Boyer, D. S., Kaiser, P. K., Magrath, G. N., Brady, K., Edwards, S., Tanzer, D. J., & Heier, J. S. (2022). The Safety and Biological Activity of OTT166, a Novel Topical Selective Integrin Inhibitor for the Treatment of Diabetic Eye Disease: A Phase 1b Study. Ophthalmic surgery, lasers & imaging retina, 53(10), 553–560. https://doi.org/10.3928/23258160-20220923-02

Brad Good