Background

This inhibitor of the O-GlcNAcase (OGA) enzyme is being developed as a potential treatment for tauopathies, including Alzheimer's disease.

O-GlcNAcylation, 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-GlcNAcylation 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 reported to similarly inhibit aggregation of α-synuclein protein in vitro (Marotta et al., 2015; Levine et al., 2019). This modification appears to promote formation of an α-synuclein fibril strain that does not propagate and is not neurotoxic in vivo (Balana et al., 2024). 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.

Findings

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 up to 16 mg 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 was to enroll 17 healthy volunteers to undergo PET scans before and after a single oral dose of LY3372689. The primary outcome was 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 (Shcherbinin et al., 2020).

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. Complete results were presented at CTAD in 2021. Fourteen days of treatment with 1, 3, or 7 mg once daily produced dose-dependent pharmacokinetics and no safety signs.

In August 2020, a fourth Phase 1 started to assess brain OGA binding after multiple doses of LY3372689. Twelve healthy volunteers were to undergo PET scans with ¹⁸F-LSN3316612 to determine occupancy after the first and last dose. The trial was completed in October 2020 with just four participants. According to results presented at CTAD 2021, after 14 days of dosing at 1 mg LY3372689, brain OGA occupancy was 84 percent at trough plasma drug concentrations.

In September 2021, a Phase 2 trial began to evaluate LY3372689 in 330 people with early symptomatic Alzheimer’s disease. Participants had to have had a gradual and progressive memory change for at least six months, and meet flortaucipir-PET scan criteria. A two-step screening process of plasma p-tau217, followed by tau-PET, was used to randomize 327 participants with moderate to high brain tau pathology (Mar 2024 conference news). Based on pharmacokinetics and PET data, the trial tested a low dose of 0.75 mg, an unspecified high dose, or placebo, with treatment lasting between 76 and 124 weeks. The primary outcome was change from baseline on the Integrated Alzheimer’s Disease Rating Scale (iADRS) in participants with moderate levels of tau pathology. Secondary outcomes include the same measure in the entire study group, plus other measures of cognition and function, tau-PET and MRI, and pharmacokinetics. The study ran at 69 locations in North America, Australia, Japan, and Poland, and finished in July 2024. In an investor call on August 8, the company announced that both high and low doses of the drug had failed to meet the primary endpoint. More results will be presented at CTAD in October 2024.

From February to April 2023, Lilly ran a study of the absorption and metabolism of orally administered radiolabeled LY3372689 in eight healthy adult men.

For details on LY3372689 trials, see clinicaltrials.gov