Background

OLX-07010 is a small-molecule inhibitor of tau self-association that is being tested for Alzheimer’s disease. The rationale for this approach is that blocking this initial step in tau aggregation will prevent the acute toxicity of oligomers (e.g., Fá et al., 2016; Tian et al., 2013), as well as the subsequent formation of fibrils and tangles, and propagation of pathology through the brain.

Much of the publicly available information on this compound comes from meeting presentations. A high-throughput screen for tau self-association, using full-length, non-mutated tau under what were characterized as physiologically relevant pH and protein concentrations, identified several classes of small-molecule leads. Hits were refined for activity in cell-based assays of tau aggregation, and brain penetration (e.g., see AAIC abstracts Moe et al. 2016, Moe et al., 2017).

A published report of preclinical work details the results of feeding OLX-07010 for four months at daily doses of 10, 40 or 100 mg/kg to human tau-expressing htau mice, starting before tau pathology appeared in brain. The middle dose produced the highest brain levels of compound, and reduced soluble tau oligomers, as well as insoluble and phosphorylated tau in brain, compared to untreated mice (Davidowitz et al., 2020). Positive effects on tau and motor behaviors in the JNPL3 tau mutant mice were reported at meetings (e.g. Moe et al., 2021 AAIC). Results of multiple dosing toxicology studies in rats and dogs indicated oral bioavailability greater than 50 percent, and liver effects in both species at higher doses (Moe et al., 2022 AAIC).

Findings

In January 2023, Oligomerix began a first-in-human, Phase 1 study to evaluate safety, tolerability, and pharmacokinetics of OLX-07010 in 88 healthy adults. Volunteers age 18 to 50 will receive single and multiple doses of 25 and 75 mg capsules; an older cohort between 51 and 75 will receive single doses. Funded by the National Institute on Aging, the trial is set for completion in December 2023.

For details on OLX-07010 trials, see clinicaltrials.gov.