Novel Compounds for Reducing Brain A-Beta Levels via Enhanced Systemic Clearance

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DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized by progressively worsening dementia eventually leading to death. It affects over five million people in the United States and costs the healthcare system over $200 billion per year. Currently there is no available therapy for slowing, reversing or preventing the disease. There is strong evidence suggesting that AD starts with the accumulation of the 4.5 kDa peptide, amyloid beta (Aβ), in the brain leading to concentration-dependent Aβ self-assembly into neurotoxic oligomers. Aβ accumulation in sporadic AD is related to a decreased net clearance rate of Aβ from the brain rather than Aβ overproduction. Despite the strong correlation between Aβ accumulation and AD progression, most amyloid-targeted therapeutic approaches have failed to demonstrate significant clinical benefits. However, most Aβ-targeted therapies have focused on removing specific forms of Aβ (e.g. plaques or oligomers), inhibiting Aβ production, or shifting the equilibrium distribution of Aβ between the brain and the periphery. Few, if any, attempts have been made to enhance Aβ brain clearance rates by sustainably increasing the irreversible systemic clearance and degradation of Aβ. Akston proposes to address this critical need by developing therapeutic candidates that specifically bind and remove Aβ from the body at a high enough rate to increase the net clearance of Aβ from the brain into the periphery and reduce the overall steady state amyloid burden throughout the body. The company will leverage its key scientists' extensive experience in chemical modification of biomolecules for targeted biodistribution. Therapeutic candidates that are chemically-engineered with various targeting moieties will be infused intravenously in aged beagle dogs to select a candidate with the highest potential to reduce peripheral Aβ levels. The main goal of this one-year Phase 1 feasibility study is to demonstrate that this candidate, when infused intravenously for two weeks in aged beagle dogs, can significantly reduce brain and CSF Aβ levels. This candidate could then be evaluated in large-animal and human clinical testing to determine if increased systemic A clearance can reverse or stall the degradation in cognitive function associated with AD.