First-in-Class Semaphorin 3a Small-Molecule Inhibitor for the Treatment of Diabetic Retinopathy and Diabetic Macular Edema
Abstract
In the US, 9.5% of the population is diagnosed with diabetes and ~25% of those patients develop eye complications as a comorbidity.[1] Diabetes is forecast to grow 54% between 2017 and 2030[2] in the US. However, it is not only a US disease. The diabetes epidemic is a global healthcare crisis, affecting people from all walks of life.[3] Chronic diabetic patients who have hypertension and fluid retention, eventually develop diabetic retinopathy (DR), which has a spectrum of severity. Diabetic macular edema (DME) is a more severe form of diabetic retinopathy that affects ~12% of DR patients and causes 10,000 new cases of blindness per year.[4] DME’s physiological manifestation include fluid buildup in the macula leading to thickening and swelling of the macula and eventually causing irreversible damage. Clinically, patients with DME report blurry vision, floaters, double vision and if left untreated, eventual blindness. Treatment of DME includes focal and grid laser therapy (pan-retinal photocoagulation; PRP) to cauterize the “leaky” vasculature and intravitreal (IVT) anti-VEGF (anti-Vascular Endothelial Growth Factor) drugs therapy (Lucentis, Iluvien, and Eylea). PRP reduces the neovascularization in the near term but has no effect on the underlying cause of DME: low oxygen levels (hypoxia) and runaway new blood vessels formation (angiogenesis).[5] Anti-VEGF therapy does address the underlying cause of angiogenesis, but the response rate and durability of anti-VEGF therapy is <25%[6]. Additional therapies are needed for this unmet public health issue. Levels of Semaphorin 3a (Sema3a), a protein released by dying circulatory network and nerve cells, has been shown predictive of diabetic retinopathy severity.[7] Sema3a is also upregulated in the vitreous (fluid of the eye ball) of diabetic macular edema (DME) patients. It has also been shown that the inhibiting Sema3a in the vitreous can reduce the “leakiness” of DME, the hallmark of the disease and its progression. Company X will test its drug development candidate Compound 2 in studies to determine if: (1) inhibiting Sema3a with Compound 2 will modify DME disease progression and (2) how effective Compound 2 is in modifying DME disease progression versus standard of care anti-VEGF drugs. With successful testing of Compound 2, Company X can advance into safety studies required for Investigational New Drugs (IND) and subsequent human clinical studies and hopefully the market. [1] 2017 CDC Diabetes statistical report; https://www.cdc.gov/diabetes/pdfs/data/statistics/nationaldiabetes-statistics-report.pdf. [2] Popul Health Manag. 2017 Feb 1; 20(1):6-12. [3] Nature volume 414, pages 782-787 (2001). [4] Geriatrics. 2009;64(2):16-20; Ophthalmology. 2008;115(11):1859-1868; Cell Biosci. 2014;4:27. [5] Ophthalmology. 1989 Oct;96(10):1518-22. [6] Clin Ophthalmol. 2017; 11: 393-401. [7] IOVS June 2016 Vol. 57 No. 7 2984.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010064
Entities
People
- Nathan Josephsohn
Organizations
- United States Army