Therapeutics

GC021109

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Overview

Name: GC021109
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: GliaCure

Background

GC021109 is one of the first compounds in Alzheimer's clinical research that specifically target microglial cells. Mediators of microglial responses in neurodegenerative diseases with an inflammatory component have attracted renewed interest in drug development research, years after several NSAIDs failed clinical trials.

GC021109 reportedly is a prodrug for an agonist of microglial P2Y6 receptor. This is a metabotropic G-protein coupled receptor, whose natural ligand is adenosine diphosphate, a metabolite of ATP. Astrocytes release the "gliotransmitter" ATP in response to neuronal injury, the presence of cellular debris, and also the presence of Aβ plaques. P2Y6 signaling is thought to be involved in shifting the phenotype of microglia, which tend to surround amyloid plaques, from patrolling to phagocytic (Dong et al., 2010). Aβ42 increased ATP release in cultured astrocytes, and ATP was neuroprotective in slice culture (Mar 2012 news). P2Y6 and its family of purinergic receptors have been most studied in neuropathic pain (Inoue et al., 2009; Bernier et al., 2013; Inoue and Tsuda, 2012). 

GC021109 has been reported in the biotech press to stimulate both microglial phagocytosis and inhibit microglial release of pro-inflammatory cytokines such as IL-12; however, this information is not published in the peer-reviewed literature (Fidler 2014, Xconomy). The only published preclinical work on this compound reports efficacy in a mouse model of asthma (Chetty et al., 2018).

Findings

In September 2014, GliaCure started a Phase 1 trial at one site in New Jersey to compare five different doses, administered once, to placebo in about 44 healthy volunteers. This was a first-in-human safety study. It was completed in December 2014, weeks after GC021109 received Fast Track status by the FDA (press release).

A second Phase 1 tested safety, tolerability and pharmacokinetics of 28 days of multiple ascending doses in 39 people with mild to moderate Alzheimer’s disease. This study included plasma and CSF biomarkers such as IL-12, Aβ, and tau. Funded by the Alzheimer’s Drug Discovery Foundation, it was completed in October 2015. No further information was found on these trials.

See clinicaltrials.gov.

Last Updated: 04 Nov 2022

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References

News Citations

  1. Astrocyte ATP, Transmembrane Chemokine Drive Neuroprotection

Paper Citations

  1. Dong J, Revilla-Sanchez R, Moss S, Haydon PG. Multiphoton in vivo imaging of amyloid in animal models of Alzheimer's disease. Neuropharmacology. 2010 Sep-Oct;59(4-5):268-75. PubMed.
  2. Inoue K, Koizumi S, Kataoka A, Tozaki-Saitoh H, Tsuda M. P2Y(6)-Evoked Microglial Phagocytosis. Int Rev Neurobiol. 2009;85:159-63. PubMed.
  3. Bernier LP, Ase AR, Boué-Grabot É, Séguéla P. Inhibition of P2X4 function by P2Y6 UDP receptors in microglia. Glia. 2013 Dec;61(12):2038-49. Epub 2013 Oct 7 PubMed.
  4. Inoue K, Tsuda M. Purinergic systems, neuropathic pain and the role of microglia. Exp Neurol. 2012 Apr;234(2):293-301. Epub 2011 Sep 17 PubMed.
  5. Fidler B. Blessed By Angels, GliaCure Tests New Alzheimer’s Approach In Humans. Xconomy, September 26, 2014 Xconomy
  6. Chetty A, Sharda A, Warburton R, Weinberg EO, Dong J, Fang M, Sahagian GG, Chen T, Xue C, Castellot JJ, Haydon PG, Nielsen HC. A purinergic P2Y6 receptor agonist prodrug modulates airway inflammation, remodeling, and hyperreactivity in a mouse model of asthma. J Asthma Allergy. 2018;11:159-171. Epub 2018 Aug 1 PubMed.

External Citations

  1. press release
  2. clinicaltrials.gov

Further Reading

Papers

  1. Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF, Spray DC, Reichenbach A, Pannicke T, Pekny M, Pekna M, Zorec R, Verkhratsky A. Glial cells in (patho)physiology. J Neurochem. 2012 Apr;121(1):4-27. PubMed.
  2. Halassa MM, Fellin T, Haydon PG. The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol Med. 2007 Feb;13(2):54-63. Epub 2007 Jan 4 PubMed.
  3. Lai MK, Tan MG, Kirvell S, Hobbs C, Lee J, Esiri MM, Chen CP, Francis PT. Selective loss of P2Y2 nucleotide receptor immunoreactivity is associated with Alzheimer's disease neuropathology. J Neural Transm. 2008 Aug;115(8):1165-72. PubMed.
  4. Inoue K. [Neuropharmacological study of ATP receptors and their role in neuropathic pain]. Yakugaku Zasshi. 2013;133(10):1035-9. PubMed.
  5. Kim B, Jeong HK, Kim JH, Lee SY, Jou I, Joe EH. Uridine 5'-diphosphate induces chemokine expression in microglia and astrocytes through activation of the P2Y6 receptor. J Immunol. 2011 Mar 15;186(6):3701-9. Epub 2011 Feb 11 PubMed.