Therapeutics

NPT520-34

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Overview

Name: NPT520-34
Therapy Type: Small Molecule (timeline)
Target Type: alpha-synuclein, Inflammation (timeline), Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis, Parkinson's Disease
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 1), Parkinson's Disease (Phase 1)
Company: Neuropore Therapies, Inc.

Background

This orally available, small-molecule antagonist of toll-like receptor 2 (TLR2) is in development for the treatment of Parkinson’s disease and ALS. TLR2 is a pattern-recognition, innate immune receptor expressed on neurons and glial cells. It recognizes aggregated proteins, downregulates autophagy, and its expression rises in Parkinson’s. The rationale for NPT520-34 is that it facilitates clearance of misfolded protein aggregation via boosting autophagy (Dzamko et al., 2017; Kwon et al., 2019; Kouli et al., 2019; Fiebich et al., 2018).

According to information on the company’s website, NPT520-34 attenuates neuroinflammation mediated by microglia and astrocytes, and reduces levels of neuropathic proteins including α-synuclein, superoxide dismutase-1, and Aβ. No preclinical data have been published for NPT520-34.

According to a presentation at the 2020 AAT-AD/PD Focus Meeting, NPT520-34 was originally discovered in a screen for compounds that enhance autophagic clearance of α-synuclein in cells. In the L61 α-synucleinopathy mouse model, treatment with this compound reportedly lowered the accumulation of toxic proteins and markers of inflammation, preserved dopamine signaling in the brain, and improved grip strength and walking. In the Line 41 β-amyloidosis model, the compound was reported to lower plaques and inflammation; in the SOD1-G93A amyotrophic lateral sclerosis mouse model, treatment reduced aggregates and inflammation in the spinal cord, and prolonged survival (Apr 2020 conference news).

Findings

Starting in May 2019, a single-site Phase 1 trial assessed the safety, tolerability, and pharmacokinetics of NPT520-34, given in capsule form to 49 healthy volunteers. Volunteers received single doses of 125, 250, 500, or 1000 mg, or multiple doses of 250 or 500 mg, or placebo, daily for 14 days. Results were presented at the 2020 AAT-AD/PD conference (Apr 2020 conference news). The drug displayed dose-linear pharmacokinetics, with a half-life of eight hours. The company reported no deaths, serious adverse events, or discontinuations due to drug effects. The most common adverse event was headache.

In August 2019, the U.S. FDA granted NPT520-34 orphan drug status for ALS (see press release).

For details on NPT520-34 trials, see clinicaltrials.gov.

Last Updated: 08 May 2020

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References

News Citations

  1. Parkinson's Therapies Seek to Stem Progression

Research Models Citations

  1. Thy1-αSyn “Line 61” Mouse
  2. mThy1-hAPP751 (TASD41)
  3. SOD1-G93A (hybrid) (G1H)

Paper Citations

  1. Dzamko N, Gysbers A, Perera G, Bahar A, Shankar A, Gao J, Fu Y, Halliday GM. Toll-like receptor 2 is increased in neurons in Parkinson's disease brain and may contribute to alpha-synuclein pathology. Acta Neuropathol. 2017 Feb;133(2):303-319. Epub 2016 Nov 25 PubMed.
  2. Kwon S, Iba M, Masliah E, Kim C. Targeting Microglial and Neuronal Toll-like Receptor 2 in Synucleinopathies. Exp Neurobiol. 2019 Oct 31;28(5):547-553. PubMed.
  3. Kouli A, Horne CB, Williams-Gray CH. Toll-like receptors and their therapeutic potential in Parkinson's disease and α-synucleinopathies. Brain Behav Immun. 2019 Oct;81:41-51. Epub 2019 Jul 2 PubMed.
  4. Fiebich BL, Batista CR, Saliba SW, Yousif NM, de Oliveira AC. Role of Microglia TLRs in Neurodegeneration. Front Cell Neurosci. 2018;12:329. Epub 2018 Oct 2 PubMed.

External Citations

  1. press release
  2. clinicaltrials.gov

Further Reading

Papers

  1. Lax N, Fainstein N, Nishri Y, Ben-Zvi A, Ben-Hur T. Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer's disease mice. J Neuroinflammation. 2020 Feb 14;17(1):55. PubMed.
  2. Jana M, Palencia CA, Pahan K. Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer's disease. J Immunol. 2008 Nov 15;181(10):7254-62. PubMed.
  3. Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE. CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci. 2009 Sep 23;29(38):11982-92. PubMed.
  4. Doorn KJ, Moors T, Drukarch B, van de Berg WD, Lucassen PJ, van Dam AM. Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson's disease patients. Acta Neuropathol Commun. 2014 Aug 7;2:90. PubMed.
  5. Zhou C, Sun X, Hu Y, Song J, Dong S, Kong D, Wang Y, Hua X, Han J, Zhou Y, Jin G, Yang X, Shi H, Zhang Z, Hua F. Genomic deletion of TLR2 induces aggravated white matter damage and deteriorated neurobehavioral functions in mouse models of Alzheimer's disease. Aging (Albany NY). 2019 Sep 11;11(17):7257-7273. PubMed.
  6. Costello DA, Carney DG, Lynch MA. α-TLR2 antibody attenuates the Aβ-mediated inflammatory response in microglia through enhanced expression of SIGIRR. Brain Behav Immun. 2015 May;46:70-9. Epub 2015 Jan 22 PubMed.
  7. McDonald CL, Hennessy E, Rubio-Araiz A, Keogh B, McCormack W, McGuirk P, Reilly M, Lynch MA. Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer's disease. Brain Behav Immun. 2016 Nov;58:191-200. Epub 2016 Jul 12 PubMed.