Combination Therapy for Simultaneous Multidimensional Treatment of Retinal Vascular Diseases

Overview

Global trends indicate a notable rise in the number of individuals vulnerable to visual impairments. Currently, age-related macular degeneration (AMD) stands as the most prevalent cause of blindness in developed nations, affecting approximately 196 million people worldwide. Among the working-age population (16-64 years old), diabetic retinopathy (DR) is the leading cause of blindness, impacting around 93 million individuals across the globe. The underlying pathophysiology of these diseases primarily involves the abnormal growth of blood vessels in the retina or choroid, resulting in the formation of fragile, leaky vessels resembling tufts. This condition gives rise to retinal exudates, hemorrhages, atrophy, and in severe cases, retinal detachment.

The standard treatment approach involves using anti-vascular endothelial growth factor (VEGF) agents. However, only up to 50% of patients respond sufficiently to this treatment, and the visual benefits for AMD patients often diminish after 2-3 years of therapy. Furthermore, this treatment places a significant economic burden on the healthcare system, necessitates frequent patient visits over many years, and carries notable adverse effects, including retinal breaks/detachment, endophthalmitis, hemorrhages, uveitis, cataracts, and retinal atrophy, which can ultimately lead to blindness in advanced cases. The limitations of current intravitreal anti-VEGF monotherapy injections, coupled with the significant involvement of multifactorial pathways in the development of retinal vascular diseases, emphasize the urgent need for a multidimensional simultaneous treatment approach.

Our solution

Recent research conducted at Hadassah led by of Dr. Samer Khateb in collaboration with Prof. Itay Chowers and Prof. Ofra Benny has shed light on the significant involvement of non-VEGF pathways in the development of retinal vascular diseases. Unlike previous studies focused solely on VEGF, this multidimensional approach utilizes small molecule inhibitors (SMIs), which target key proteins responsible for the multifactorial causes of various retinal vascular diseases. The team’s innovative strategy demonstrated a synergistic effect of the SMI combination in both in vitro models and an ex vivo mouse choroid sprouting model, which mimics angiogenesis. Notably, the SMI combination exhibited profound inhibition of angiogenesis in a laser-induced choroidal neovascularization (CNV) model, in vivo, an experimental model that closely imitates wet AMD (wAMD) in humans. These findings highlight the potential of this novel therapeutic approach to address the complexities of retinal vascular diseases beyond the scope of VEGF pathways.

Development Status

• Development of a slow, extended-release ophthalmic rod into which the SMIs combination will be incorporated.
• Expansion of the in vivo data to reinforce efficacy and safety results, and to assess the effectiveness for additional types of retinal vascular diseases.

Market potential

The global AMD market alone was valued at approximately USD $9.84 billion in 2021, and these figures are projected to grow significantly in the future due to increased life expectancy leading to a higher prevalence of age-related retinal diseases.

Presently, there is no known cure for retinal vascular diseases such as AMD and DR. The majority of treatments developed in recent decades have primarily focused on blocking VEGF-mediated neovascularization using biologic agents such as Avastin®, Eylea®, Beovu®, and Vabysmo®. However, several challenges persist in the current treatment landscape, including the high manufacturing costs associated with anti-VEGF monoclonal antibodies, the short-term effectiveness of these treatments and the fact that a substantial proportion of patients experience only partial or no response. Targeting multiple factors simultaneously offers the potential for optimal disease control, at a relatively low cost and with improved outcomes for patients.

IP

PCT filed