Transformational next generation high affinity trispecific fab protein to address unmet needs in Ophthalmology

PROJECT SUMMARY There is an urgent need for new, improved ophthalmologic treatments to tackle the burden of age-related macular degeneration (AMD). AMD is the leading cause of legal blindness in older adults in the western world. It affected 196 million people globally in the year 2020 and approximately 11 million individuals in the US. There are two forms of AMD, nonexudative (dry) and exudative (wet), both of which cause loss of vision by damaging the macula, the central region of the retina that is responsible for visual acuity. The exudative form of AMD, also known as wet AMD (wAMD) is less prevalent, accounting for 20% of cases, but is responsible for 80-90% of severe vision loss associated with AMD. Many retinal diseases, including wAMD, Diabetic Retinopathy (DR), Retinal Vein Occlusion (RVO), Ocular Histoplasmosis Syndrome, and Myopic Macular Degeneration cause abnormal growth of new retinal and choroidal blood vessels (neovascularization), and tissue swelling (macular edema). Choroidal and retinal neovascularization results in loss of vision due to bleeding, scar tissue formation, and macular edema. Choroidal and retinal neovascularization and macular edema are associated with elevated vitreous levels of vascular endothelial growth factor-A (VEGF-A). Anti-VEGF agents are a group of medications that, when injected into the eye, reduce retinal neovascularization and macular edema. Current Anti-VEGF treatment medicines require frequent injections, often leading to vision loss due to poor adherence to treatment regimens. It is also well documented that compensatory mechanisms for neovascularization are activated with the suppression of VEGF-A. There has been increased interest in targeting alternate or multiple angiogenic pathways in retinal vascular disease to achieve better outcomes and lower treatment burden for this population. Two additional targets which are upregulated with VEGF-A suppression and also have clinical evidence to support therapeutic use are Angiopoietin-2 (Ang-2) and Vascular Endothelial Growth Factor-C (VEGF-C). RevOpsis Therapeutics has developed RO-104, a first -in class trispecific surrobody that targets VEGF-A, VEGF-C and Ang-2 for the treatment of retinal diseases. RO-104 has been extensively tested in vitro and in vivo in smaller mammals (rats and rabbits), shows comparable half-life and higher affinity for VEGF-A and Ang-2, with higher synergistic binding to Ang-2, than the current standards of care and first in class binding to VEGF-C with the ability to bind all three targets simultaneously. Improved efficacy of RO-104 will allow it to lessen the burden of treatment by reducing the needed dosing frequency and address the 40% of patients that are suboptimal responders to VEGF-A monotherapy. In this SBIR Phase II project, RO-104 will be used to perform pivotal investigational new drug (IND)-enabling preclinical studies to evaluate its in vivo toxicology, pharmacokinetics and dose-range establishment using a relevant preclinical animal model. The completion of this project will support a Phase IIb application that will complete IND-enabling toxicity and efficacy studies. This will allow the filing of an IND application, enabling future clinical trials.