Therapeutics

LM11A-31-BHS

Overview

Name: LM11A-31-BHS
Synonyms: LM11A-31
Chemical Name: (2S,3S)-2-amino-3-methyl-N-[2-(4-morpholinyl)ethyl]-pentanamide, dihydrochloride
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: PharmatrophiX

Background

LM11A-31 is an orally available, brain-penetrant, small-molecule ligand of the p75 neurotrophic receptor. P75NTF binds nerve growth factor, brain-derived growth factor, and other neurotrophins. Its signaling can promote either neuron survival or death by apoptosis, depending on its ligand and cellular context.

In AD models, P75NTF mediates neurotoxic effects of Aβ (Sotthibundhu et al., 2008; Knowles et al., 2009).

LM11A-31 selectively activates p75NTF survival pathways and inhibits apoptosis signaling (Massa et al., 2006). It blocks Aβ-induced neurodegeneration and synaptic impairment in neuronal and hippocampal slice cultures (Yang et al., 2008). Its neuroprotective actions are not specific for Aβ, as it also counteracts toxicity of anticancer drugs on neurons in culture (James et al., 2008).

LM11A-31 has been studied in multiple mouse models of AD, where it prevented tau phosphorylation and misfolding, microglia and astrocyte activation, loss of cholinergic neurites, and cognitive decline (Knowles et al., 2013; Nguyen et al., 2014). In mouse models with cholinergic neuron deficits, treatment induced recovery of dendrites (Simmons et al., 2014).

In normal mice, LM11A-31 suppressed cholinergic loss during aging (Xie et al., 2019). It was also reported to show efficacy in mouse models of Huntington’s disease (Simmons et al., 2016), traumatic brain or spinal cord injury (Haefeli et al., 2017; Shi et al., 2013; Tep et al., 2013), and chemotherapy-induced peripheral neuropathy (Friesland et al., 2014). In other rodent models, it reduced cognitive impairment caused by sepsis-induced neuroinflammation in mice (Ji et al., 2018), and reduced excessive alcohol intake in rats (Darcq et al., 2016).

Pharmatrophix advanced a modified version of LM11A-31, LMA11A-31-BHS, to clinical trials.

Findings

No Phase 1 trial was registered for LMA11A-31-BHS, but the company states that the compound is safe and well-tolerated based on a safety trial conducted in 2013 and 2014 (company website). That trial was funded by the ADDF, the Alzheimer’s Association, and private investors.

In February 2017, the company began a Phase 2a trial of LMA11A-31-BHS. It is enrolling 190 people with mild to moderate Alzheimer’s disease, confirmed with CSF Aβ biomarkers. Participants are randomized to receive 400 or 800 mg drug or placebo daily for six months. The primary outcome is safety on clinical, electrophysiological and laboratory measures; secondary outcomes include CSF biomarkers of tau, phosphorylated tau, Aβ, and acetylcholinesterase activity. The investigators will also perform cognitive assessments of working memory, word fluency, processing speed, and executive function. The trial is being conducted at 21 centers in Austria, Czechia, Germany, Spain, and Sweden, with funding from the U.S. National Institute on Aging, and philanthropic support.

Last Updated: 22 Jan 2020

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References

Paper Citations

  1. . Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor. J Neurosci. 2008 Apr 9;28(15):3941-6. PubMed.
  2. . The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo. J Neurosci. 2009 Aug 26;29(34):10627-37. PubMed.
  3. . Small, nonpeptide p75NTR ligands induce survival signaling and inhibit proNGF-induced death. J Neurosci. 2006 May 17;26(20):5288-300. PubMed.
  4. . Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment. PLoS One. 2008;3(11):e3604. PubMed.
  5. . Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants. Neurotoxicology. 2008 Jul;29(4):605-12. Epub 2008 Apr 26 PubMed.
  6. . A small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model. Neurobiol Aging. 2013 Aug;34(8):2052-63. PubMed.
  7. . Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in AβPP(L/S) transgenic mice. J Alzheimers Dis. 2014;42(2):459-83. PubMed.
  8. . A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- to late-stage disease progression. PLoS One. 2014;9(8):e102136. Epub 2014 Aug 25 PubMed.
  9. . Modulation of the p75 neurotrophin receptor suppresses age-related basal forebrain cholinergic neuron degeneration. Sci Rep. 2019 Mar 27;9(1):5273. PubMed.
  10. . A small molecule p75NTR ligand normalizes signalling and reduces Huntington's disease phenotypes in R6/2 and BACHD mice. Hum Mol Genet. 2016 Nov 15;25(22):4920-4938. PubMed.
  11. . A data-driven approach for evaluating multi-modal therapy in traumatic brain injury. Sci Rep. 2017 Feb 16;7:42474. PubMed.
  12. . A Small Molecule P75(NTR) Ligand Protects Neurogenesis after Traumatic Brain Injury. Stem Cells. 2013 Aug 13; PubMed.
  13. . Oral administration of a small molecule targeted to block proNGF binding to p75 promotes myelin sparing and functional recovery after spinal cord injury. J Neurosci. 2013 Jan 9;33(2):397-410. PubMed.
  14. . Amelioration of cisplatin-induced experimental peripheral neuropathy by a small molecule targeting p75 NTR. Neurotoxicology. 2014 Dec;45:81-90. Epub 2014 Sep 30 PubMed.
  15. . The p75 neurotrophin receptor might mediate sepsis-induced synaptic and cognitive impairments. Behav Brain Res. 2018 Jul 16;347:339-349. Epub 2018 Mar 28 PubMed.
  16. . The Neurotrophic Factor Receptor p75 in the Rat Dorsolateral Striatum Drives Excessive Alcohol Drinking. J Neurosci. 2016 Sep 28;36(39):10116-27. PubMed.

External Citations

  1. company website

Further Reading

Papers

  1. . Nerve Growth Factor Pathobiology During the Progression of Alzheimer's Disease. Front Neurosci. 2019;13:533. Epub 2019 Jul 1 PubMed.
  2. . Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease. Nat Rev Drug Discov. 2013 Jul;12(7):507-25. PubMed.
  3. . The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo. J Neurosci. 2009 Aug 26;29(34):10627-37. PubMed.