KU-046 a dual-acting symptomatic plus disease-modifying drug candidate for treatment of Alzheimer's disease

Abstract

Amyloid centric disease modifying approaches for treatment of Alzheimer's such as direct gamma secretase inhibition have been unsuccessful in late-stage clinical trials. This necessitates identification of new approaches for drug discovery. Decreased brain energy production and increased oxidative stress, hallmark events in Alzheimer's disease (AD) may impair cognition as well as induce abeta-42 (aß-42) overproduction. We hypothesized that concurrent modulation of these events can produce symptomatic improvements in cognitive function and disease modification (aß-42 lowering). Accordingly we designed a novel compound, KU-046, which may improve cellular energy as well as inhibit oxidative stress and examined its effects in animal models of cognition and aß-42 lowering. To examine effects of KU-046 on cognition we tested its effects in two different rodent models of cognition, the scopolamine-induced novel object recognition test (NORT) and Morris water maze (MWM) test. To study the effects of KU-046 on aß-42 lowering, we used a rat model as well as aß-42 overproducing transgenic mice Tg2576. In rat NORT study, KU-046 (3,10 and 30 kg/mg dosed orally daily) improved cognition in a dose dependent manner and the effect was greater than donepezil used as a positive control. Similarly in rat MWM test, KU-046 (1,3, 10 mg/kg) improved learning and memory functions comparable to donepezil control. Normal-aged rats were dosed orally (10,25 and 50 mg/kg) which resulted in dose dependent lowering of brain soluble aß-42 by 21%, 45%, and 61% respectively. Sub-chronic treatment of KU-046 (4 weeks, 50 mg/kg) in transgenic Tg2576 mice resulted in significant improvements in cognition in MWM test as well as lowering of brain soluble aß-42 and aß-40 levels. In summary KU-046, an orally deliverable compound improves cognition and lowers aß-42 in disease models. In addition, preclinical therapeutic index of KU-046 (a measure of drug safety) is excellent. We propose that KU-046 represents a first-in-class dual acting (symptomatic and disease modifying) drug candidate with therapeutic profile differentiated from direct secretase inhibitors, amyloid aggregation inhibitors and vaccine approaches.