Background
ALSP’s strategy to combat the ravages of neurodegenerative disease is to deploy its proprietary class of compounds to inhibit papain-like cysteine proteases. The Company’s initial focus on traumatic brain injury (TBI) is increasingly supported by mounting evidence that one of these cysteine proteases in particular, cathepsin B, when inappropriately expressed, as is the case in (TBI) and Alzheimer's disease (AD), and many other neurodegenerative diseases creates a dangerous intersection at which inflammatory, apoptotic, and necrotic pathways are activated. ALSP believes these pathways constitute the underlying pathology of neurodegeneration.
Consequently, the efficient reversal of the over expression of this key enzymes can completely mitigate all of these pathways at once and prevent the neuronal destruction that they mediate. Doing so significantly improves measures of memory deficit and neuro-motor dysfunction in TBI and AD animal models, respectively. The inhibition of these protease not only reduces neuro-inflammation, but also provides potent neuronal protection by multiple mechanisms. Data from TBI and AD models using cathepsin B knock-out animals indicate that this protease plays a dominant role at this toxic intersection and suggests that its inhibition should not have undesired consequences.
Lead Compound
Cathepsin B activity is significantly elevated in TBI and AD. This enzyme has been well studied with respect to its contribution to pathways leading to caspase activation and programmed cell death (apoptosis) of the neuron, to inflammatory pathways that include TNF-a, Il-1β and metallo-proteinase activation, and to tissue necrosis. ALSP’s lead compound, ALP-495, is a potent inhibitor of cathepsin B. Elimination of the drug is primarily through the kidney and the gut without multi-dosing accumulation. Extensive work with ALP-495-related tool compounds suggests that this class of compounds has a wide therapeutic window.