The long-term goal of this program is to develop a disease-modifying, small molecule drug for Alzheimer?s disease (AD) and AD related dementias (ADRD) with tau pathology. There is a critical unmet need for a disease-modifying drug (DMD) for AD. Chronic treatment strategies require safe, effective, and economically feasible approaches such as small molecule drugs. This program is progressing to fill this need with a DMD that, if successful, will have a tremendous impact on the more than five million Americans who currently have AD (projected to be 16 million by 2050) and their caregivers, and will help reduce the current cost of $259 billion (projected to be $1.1 trillion by 2050) to our nation. The Company is developing a small molecule DMD for AD that targets the initial step in tau aggregation leading to the formation of tau oligomers, the toxic tau aggregates responsible for neuronal loss and impairment of memory formation. We hypothesized that by targeting the first step in tau self-association all forms of tau aggregates should be reduced. In fact, we have demonstrated proof-of-concept in vivo, in a blinded study independently performed by Peter Davies, Ph.D., a thought leader in the field of tau biology and therapeutic discovery. The lead compound from our program inhibited tau aggregation in transgenic mice expressing human tau (htau), best representing tau aggregation in AD. Importantly, the lead has good CNS drug-like properties and has demonstrated a good safety profile in preliminary safety screens in vitro and in vivo. The preventive study of the lead in JNPL3 mice of the funded program (5R44AG053150-03) is to determine the efficacy of the compound on pathological tau accumulation. However, the analysis of inflammatory markers for microglyosis and astrocytosis were not included in this study. JNPL3 mice develop an inflammatory response in conjunction with the accumulation of tau of aggregated and hyperphosphorylated tau. Astrogliosis (as measured by GFAP reactivity) in brainstem, diencephalon, and basal telencephalon has been characterized in this mouse model (Lewis et al., 2000). We hypothesize that reduction of tau pathology by treatment with the lead compound should reduce the inflammation caused by tau pathology. In tasks 1-3, we propose to supplement the analysis of tau pathology in JNPL3 with the additional characterization of inflammatory markers to evaluate the efficacy of the lead compound. Tasks 4-7 for this Supplemental Aim are for the advancement of chemistry of the lead compound being tested in the efficacy studies of the PhIIb and supplement the chemistry work being performed. These tasks are for increasing the nonclinical safety studies (NCSS) batch size from 0.5 Kg to 1.0 Kg and for polymorph analysis of the salt form of the lead compound to be used in the pre-clinical safety studies for this lead compound.
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. This program is highly important because it is progressing to fill this need with a small molecule disease-modifying drug that, if successful, will have a tremendous impact on the more than five million Americans who currently have AD (projected to be 16 million by 2050) and their caregivers, and will help reduce the current cost of $259 billion (projected to be $1.1 trillion by 2050) to our nation (Alzheimer's Association 2017 Alzheimer's Disease Facts and Figures). The proposed Supplemental Aim 4 is for the characterization of inflammatory markers to better evaluate the efficacy of the lead compound, for increasing synthesis of the batch size of the lead compound for non-clinical safety studies and for the analysis of the salt forms of the lead compound.
