Anti-integrin therapy with ALG-1001 (Luminate, Allegro Ophthalmics) represents a novel approach to treatment of diabetic macular edema (DME) that addresses the multifactorial pathophysiology of the disease by targeting an early point in its pathogenic pathway.
As an inhibitor of three integrin receptors, a5b1, avb5, and aMb2, ALG-1001 interferes with cell cycle signaling that is induced by diabetes-related retinal oxidative stress and leads to the production of cytokines, growth factors, and other molecules that mediate neovascularization, vascular leakage, inflammation, and damage to the neuroretina.
This broad range of effects explains why analyses of results from phase II clinical trials showed that whether given as monotherapy or sequentially after a single intravitreal anti-VEGF injection, ALG-1001 demonstrated particular benefit for improving vision and anatomic outcomes in patients who were suboptimal responders to previous anti-VEGF therapy.
“Integrin-targeted therapy has an established role in oncology and autoimmune disease, but ALG-1001 is a first-in-class molecule in ophthalmology,” said Vicken Karageozian, MD, president and chief medical officer, Allegro Ophthalmics, San Juan Capistrano, CA.
“Unlike anti-VEGF agents that address a downstream actor in DME, ALG-1001 works higher up in the pathogenic pathway at the source of the problem,” he said. “By stabilizing the retina’s response to the hypoxic and oxidative stress that occurs with diabetes, it essentially works to turn off the faucet that is producing all of the mediators of diabetic eye disease.”
ALG-1001 is a synthetic RGD class peptide that acts to downregulate the PI3K pathway by binding to and inhibiting the a5b1, avb5, and aMb2 integrin receptors. Both a5b1 and avb5 are intimately involved in the regulation of neovascular remodeling, neovascular construction, and vascular leakage, whereas aMb2 modulates inflammatory pathways involving both leukocyte adhesion and migration and complement 3.
“Stimulation of the PI3K pathway in the retina signals cells to respond to diabetes-induced stress,” he said. “Anti-integrin therapy with ALG-1001 stabilizes this cell signaling pathway to turn off inflammation, stop production of proangiogenic and other deleterious growth factors, and stabilize the neuroretina.”