This inhibitor of the O-GlcNAcase (OGA) enzyme is being developed as a potential treatment for tauopathies, including Alzheimer's disease.
O-GlcNAc-ylation, i.e. addition of N-acetylglucosamine to serine and threonine residues, is a post-translational modification that regulates the function of many proteins. In particular, N-GlcNAc-ylation of tau reduces its propensity to form toxic aggregates (Gong et al., 2005; Liu et al., 2004). OGA catalyzes removal of O-GlcNAc. OGA inhibitors promote tau glycosylation, prevent aggregation, and appear to stabilize tau in a soluble, nonpathogenic form.
In preclinical work in three different mutant human-tau-expressing transgenic mice, the OGA inhibitor thiamet G was reported to increase N-GlcNAc-modified tau, reduce the number of tau neurofibrillary tangles, and decrease neuronal cell loss in three different mouse strains expressing P301L mutant human tau (Yuzwa et al., 2012; Graham et al., 2014; Hastings et al., 2017). One lab found that thiamet G treatment resulted in better motor skills, higher body weight, and longer lifespan (Borghgraef et al., 2013).
N-GlcNAcylation was recently reported to similarly inhibit aggregation of α-synuclein protein in vitro (Levine et al., 2019). Thiamet G or OGA knockdown reduced the uptake of synuclein fibrils by cells (Tavassoly et al., 2020). Fibril uptake is a proposed mechanism for the spread of tau pathology in the brain.
No preclinical results have been published for LY3372689.
Between February and June 2019, Lilly conducted Phase 1 safety testing of in LY3372689 in healthy adults. The crossover design evaluated two drug doses and placebo during three study periods in each of 23 participants. A total of six doses were tested. According to a presentation at the 2020 AAIC, the drug was well-tolerated at all doses, without serious adverse events or discontinuations due to an adverse event. The pharmacokinetics were deemed adequate for once-a-day dosing.
In May 2019, the company began a second Phase 1 study to measure binding of LY3372689 in the brain by way of displacement studies of the OGA-specific PET ligand 18F-LSN3316612 (Lee et al., 2020). The study will enroll 17 healthy volunteers to undergo PET scans before and after a single oral dose of LY3372689. The primary outcome is percent of OGA occupancy before and after dosing. At the 2020 AAIC, the investigators reported results of the first three dose cohorts involving 12 participants, claiming to see a plasma-concentration related increase in brain OGA occupancy, which reached greater than 90 percent after the highest dose.
In October 2019, a third Phase 1 study began to evaluate the safety, tolerability, and pharmacokinetics of a two-week course of multiple doses of LY3372689 in 54 healthy volunteers. Adverse events and pharmacokinetics were primary outcomes; this study finished in February 2020.
In August 2020, a fourth Phase 1 started to assess brain OGA binding after multiple doses of LY3372689. Twelve healthy volunteers are undergoing PET scans with 18F-LSN3316612 to determine occupancy after the first and last dose. The trial will run through October 2020.
For details on LY3372689 trials, see clinicaltrials.gov
Last Updated: 16 Sep 2020
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- Tavassoly O, Yue J, Vocadlo DJ. Pharmacological inhibition and knockdown of O-GlcNAcase reduces cellular internalization of α-synuclein preformed fibrils. FEBS J. 2020 May 4; PubMed.
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