Therapeutics

LY3372689

Overview

Name: LY3372689
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)

Background

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.

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 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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References

Paper Citations

  1. . PET quantification of brain O-GlcNAcase with [18F]LSN3316612 in healthy human volunteers. EJNMMI Res. 2020 Mar 14;10(1):20. PubMed.
  2. . Post-translational modifications of tau protein in Alzheimer's disease. J Neural Transm. 2005 Jun;112(6):813-38. PubMed.
  3. . O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10804-9. PubMed.
  4. . Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012 Apr;8(4):393-9. PubMed.
  5. . Increased O-GlcNAcylation reduces pathological tau without affecting its normal phosphorylation in a mouse model of tauopathy. Neuropharmacology. 2014 Apr;79:307-13. Epub 2013 Dec 8 PubMed.
  6. . Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice. Mol Neurodegener. 2017 May 18;12(1):39. PubMed.
  7. . Increasing brain protein O-GlcNAc-ylation mitigates breathing defects and mortality of Tau.P301L mice. PLoS One. 2013;8(12):e84442. Epub 2013 Dec 23 PubMed.
  8. . α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson's disease. Proc Natl Acad Sci U S A. 2019 Jan 29;116(5):1511-1519. Epub 2019 Jan 16 PubMed.
  9. . Pharmacological inhibition and knockdown of O-GlcNAcase reduces cellular internalization of α-synuclein preformed fibrils. FEBS J. 2020 May 4; PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

No Available Further Reading