TITLE: Development and Commercialization of a Tau Oligomer Inhibitor for AD/RD PROJECT SUMMARY - SBIR/STTR Commercialization Readiness Pilot (CRP) Program (PAR-19-333) The long-term goal of this program is to develop a disease-modifying, small molecule drug for Alzheimer?s disease (AD) and related dementias (ADRD). There is a critical unmet need for a disease modifying drug for AD. Chronic treatment strategies require economically feasible approaches such as small molecule drugs. Our small molecule leads target tau self-association into oligomers for neurodegeneration and are therefore highly differentiated from the competition. Tau oligomers are the acutely toxic species of tau protein and their reduction will modify the course of AD. Our in vivo efficacy studies were blinded and independently performed by Peter Davies, Ph.D., a key opinion leader in the tau targeting field. In preventive studies in transgenic mice, the lead compound inhibited tau aggregation in transgenic mice expressing either human tau (htau), best representing tau aggregation in AD, or aggregation-prone, mutated tau (P301L) in the JNPL3 mouse model of inherited tauopathy. These results demonstrated that our lead compound reduced self-association of tau and inhibited formation of insoluble tau aggregates. The activity translated from in vitro and cellular assays to an in vivo model of tau aggregation validating our screening approach and showing that targeting oligomer formation can inhibit the entire tau aggregation pathway. In vitro pharmacology tests (non-GLP) such as Ames, hERG, and DiscoverX Safety47? panel showed good safety profiles, and the compound was highly stable in human liver microsomal stability studies. In vivo safety testing in rats (non-GLP) showed a maximum tolerated dose (MTD) of 1,000 mg/kg, and no adverse effects were found in a 14-day dose range finding study at 400 mg/kg. GLP safety studies that will support our package for FDA (Grant # AG062021) will be performed on the stable, free-base polymorph of the formulated compound. The cGMP manufacture and formulation of our lead for use in clinical development is also in progress (Grant # AG066384). This application is for commercialization activities and technical and consulting work necessary for an IND submission. There is no overlap in funding for these activities with our awarded grants. Commercialization tasks will include the development of a pre-launch commercial plan including a target product profile (TPP), market research, pricing, comprehensive analyses of the market, customers and competition, and plans for public relations and project management. Technical work includes evaluation of the GMP batch for stability and development of a pharmacokinetic/pharmacodynamic (PK/PD) model using acute dosing. We will also provide additional support for the program by a Consulting Toxicologist and a Chief Medical Officer. An intellectual property plan will be made spanning IND to clinical development.
There is a critical unmet need for a disease modifying drug for AD; of the ten leading causes of death in the United States, only AD cannot be prevented, slowed or cured and that is increasing in incidence. This program is highly important because it is progressing to fill this need with a disease modifying drug that, if successful, will have a tremendous impact on the more than 5.8 million Americans who currently have AD (projected to be 14 million by 2050) and their caregivers, and will also help reduce the current cost of $290 billion (projected to be $1.1 trillion by 2050) to our nation (Alzheimer's Association 2019 Alzheimer's Disease Facts and Figures). Long- term treatment for chronic diseases such as AD requires economically feasible approaches such as small molecule drugs, especially for preventive and early therapeutic strategies.
