Emixustat is a small molecule notable for its establishment of a new class of compounds known as visual cycle modulators (VCMs). Formulated as the hydrochloride salt, emixustat hydrochloride, it is the first synthetic medicinal compound shown to affect retinal disease processes when taken by mouth. Emixustat was invented by the British-American chemist, Ian L. Scott, and is currently in Phase 3 trials for dry, age-related macular degeneration (AMD). The compound is also being investigated as a potential therapy for proliferative diabetic retinopathy, diabetic macular edema and Stargardt disease. In 2008, Acucela Inc. partnered with Otsuka Pharmaceutical Company for the development of emixustat (ACU-4429) in an agreement totaling $263 million in cash and milestone payments. Emixustat hydrochloride is a non-retinoid small molecule inhibitor of RPE65 (retinal pigment epithelium-specific 65 kDa protein, also known as retinoid isomerohydrolase). It is thought to reduce visual chromophore biosynthesis and prevent the accumulation of toxic retinal byproducts. Mechanism of action A significant factor in the pathogenesis of age-related macular degeneration (AMD) is thought to be the toxic byproduct, N-retinylidene-N-retinylethanolamine (A2E). A2E is a major chromophore in lipofuscin and causes singlet oxygen production when exposed to high-energy light. A2E is formed from the release of all-trans-retinol within the outer segment disks of human photoreceptors. All-trans-retinol is an important component in the Visual Cycle, the mechanism by which light energy is converted into electrical energy within the eye. In the visual cycle, exposure to light causes 11-cis-retinal to isomerize to all-trans-retinal (as part of the rhodopsin complex). The isomerisation results in the release of chemical energy, which is processed into an electrical signal (by a series of different cells) that is transmitted to the brain. The all-trans-retinal is released from opsin, reduced to all-trans-retinol, then transported from the photoreceptor cells back to the RPE cells, where it is stored for recycling and future use as retinol palmitate. The transportation of all-trans-retinal back to RPE cells is not 100% efficient, and a small amount of all-trans-retinal can escape. This condenses with membrane-bound ethanolamine to form a Schiff's base. A second molecule of all-trans-retinal reacts with the Schiff's base and forms A2E. The formation of A2E is largely associated with the rod photoreceptor cells. These cells account for approximately 95% of human photoreceptors, and turn over cis to trans retinol constantly under normal lighting conditions. Emixustat hydrochloride is a synthetic small molecule non-retinoid designed to stop the Visual Cycle by