Identification of pharmacodynamics readouts through acute dosing of a small molecule inhibitor of tau self‐association in a tauopathy mouse model
Year: 2021
Type: article
Abstract: Background The accumulation of tau aggregates correlates with and facilitates disease progression in pure and mixed tauopathies such as Progressive Supranuclear Palsy and Alzheimer’s disease. However, a disease‐modifying‐therapeutic targeting tau aggregation has not yet shown success in the clinic. Our target approach is highly differentiated from other programs that are focused on inhibiting tau aggregation and all downstream cascades. We have selected and optimized small molecules capable of targeting tau self‐association (TSA), the first and rate‐limiting step in tau aggregation. We have demonstrated the efficacy of our lead TSA inhibitor in two mouse models of tauopathy (htau mice; tau‐P301L‐JNPL3 mice) in preventive and therapeutic studies. Treatment with the lead TSA inhibitor blocked tau self‐association and formation of large tau aggregates, reduced overall tau accumulation, and rescued impaired motor function in aged mice with pre‐existing tau aggregates. IND‐enabling studies for the lead TSA inhibitor are completing, and a FDA submission is planned for Q1 2022. In this study, we aim to identify acute measures of efficacy in aged homozygous female tau‐P301L‐JNPL3 mice that will be used to model Pharmacokinetics (PK)/Pharmacodynamics (PD) relationship of our TSA inhibitors. Methods Acute dose range‐finding (ADRF) study was performed using multiple routes of administration. C57BL/6 mice (n=30) were either administered vehicle or a single dose of a selected TSA inhibitor ranging from 2 to 200 mg/kg (n = 3 mice/gender/group). Biospecimens were collected at Cmax. PK studies in C57BL/6 mice will be performed with and without fasting to determine the food effects on bioavailability. Results Serum and brain homogenate samples from the ADRF study are being analyzed to evaluate TSA inhibitor concentrations by LC‐MS/MS. These results will be used to select the dose and route of administration for PK studies in 9 months‐old homozygous female JNPL3 mice. To determine the selective dose for PD evaluations, PK studies will be performed using three doses. Some of the PD measures that will be evaluated are tau self‐association, tau hyperphosphorylation, and motor behavior. Conclusions Understanding PK/PD relationship will be crucial for determining appropriate dosing and target engagement biomarkers in subsequent Phase‐1b studies.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.058326
Authors: Dhruv R. Patel, Chaya Sussman, Mindy Greco, Edward H. Cheesman, Patricia Lopez, Eliot J. Davidowitz, James G. Moe
Institution: Oligomerix (United States)
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4206442883