RASP and Immune-Mediated Disease
Levels of RASP are generally observed to be elevated in ocular and systemic inflammatory disease, and thus represent therapeutic targets for immune-modulation.
Because of the inherent toxicity of RASP, most, if not all, living organisms contain enzymes that convert RASP into non-toxic molecules. Under normal and healthy conditions physiological RASP are metabolized by enzymes preventing reactions with other molecules or proteins.
Aside from the stimulation of inflammation, there is no generally accepted biological role of high levels of RASP. Some physiologic molecules have RASP forms, including retinaldehyde (a form of Vitamin A) and pyridoxal and pyridoxal phosphate (forms of Vitamin B6), but the activity of physiological RASP is highly restricted by chaperone and other proteins that prevent reaction with other molecules, including our RASP inhibitors. Thus, pharmacotherapeutic RASP inhibition is expected not to adversely affect normal physiologic processes.
Our most advanced RASP inhibitor, reproxalap, which has been administered to hundreds of patients across numerous completed clinical trials, has been observed to be generally well-tolerated and has not resulted in any serious adverse events to date.
Reproxalap – Our Novel RASP Inhibitor Platform
Reproxalap, our lead clinical candidate, is a novel small molecule RASP inhibitor that covalently binds free aldehydes and diminishes excessive RASP levels. The broad activity and unique mechanism of action (MOA) of reproxalap offers therapeutic promise in a wide array of distinct conditions.
Reproxalap’s MOA has been validated with the demonstration of clinical relevant activity in multiple mechanistically distinct late-phase clinical indications.
In in vitro and animal studies, reproxalap does not appear to affect most cellular components, including most receptors, enzymes, ion channels, or other proteins. Reproxalap has been shown to outcompete cellular constituents to covalently bind and trap RASP. Reproxalap-RASP adducts to be rapidly degraded in cellular environments, after which neither reproxalap nor RASP are detectable.
Outside of biological systems, reproxalap-RASP adducts have shown to be non-reactive and stable, suggesting that reproxalap-RASP binding may be effectively irreversible. By forming covalent drug-RASP adducts that are then degraded, reproxalap and other RASP inhibitors have the potential to substantially lower RASP levels.