In a novel approach to managing Aβ accumulation in the brain, HPP854 has been developed to inhibit the enzyme responsible for Aβ-generation; BACE-1.
BACE is an aspartyl protease that has been identified to have β-secretase activity. BACE is a type-1 transmembrane protein. It is widely distributed in the body with the highest concentrations in the brain. BACE initiates Aβ production by cleaving APP to generate APPβ and C99, a critical step for subsequent cleavage of C99 at the transmembrane region by γ-secretase to release Aβ1-40 and Aβ1-42. BACE knockout mice develop normally and show no phenotypic changes, and they show low or unmeasurable levels of Aβ peptides in the brain.
While APP levels in the brain seem to be relatively stable with aging in Alzheimer’s disease patients, it has been reported that the expression and activity of BACE in the brain increases with aging. Reducing BACE activity could be the most efficient way to lower Aβ accumulation in the brain. Therefore, it is desirable to develop an orally active small molecule BACE inhibitor to reduce the over production of Aβ in the brain under physiological and pathophysiological conditions.
Using TransTech Pharma’s Translational Technology®, HPP854 was identified as a potent and selective inhibitor of BACE that is active in a series of in vitro and in vivo studies.
Indeed, in animal studies dosing orally with HPP854, Aβ1-40 and Aβ1-42 peptide in the brain were significantly decreased both acutely and chronically in a dose-dependent manner.
HPP854 is in phase I clinical trials.