Therapeutics

LM11A-31-BHS

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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). It reduced tau pathology in mice expressing amyloid precursor protein or the P301L tau mutant (Yang et al., 2020; Yang et al., 2020). 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). LM11A-31 was 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), chemotherapy-induced peripheral neuropathy (Friesland et al., 2014), HIV-induced neurodegeneration (Xie et al., 2021, Killebrew et al., 2021), peripheral nerve injury (McGregor et al., 2021, Aby et al., 2021), and acute stroke (Nasoohi et al., 2023; Nguyen et al., 2022). 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). 

LM11A-31 has been evaluated in mouse models of strep meningitis and of erectile dysfunction, and in cats infected with feline immunodeficiency virus (Zhang et al., 2021, Yin et al., 2021, Fogle et al., 2021).

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

Findings

No Phase 1 trial was registered for LM11A-31-BHS, but the company states that the compound is safe and well-tolerated based on a safety trial conducted in healthy young and elderly adults (Dec 2017 news). That trial was funded by the ADDF, the Alzheimer’s Association, and private investors. A second Phase 1 study ran in healthy adults in Spain (company website).

In February 2017, a Phase 1/2 trial of LM11A-31-BHS started enrolling 242 people with mild to moderate Alzheimer’s disease, confirmed with CSF Aβ biomarkers. Participants were randomized to receive 400 or 800 mg drug or placebo daily for six months. The primary outcome was safety on clinical, electrophysiological, and laboratory measures; secondary outcomes include CSF biomarkers of tau, phosphorylated tau, Aβ, and acetylcholinesterase activity. Also included as secondary outcomes were cognitive assessments of working memory, word fluency, processing speed, and executive function. The trial ran at 21 centers in Austria, Czechia, Germany, Spain, and Sweden, with funding from the U.S. National Institute on Aging and philanthropic support. It finished in June 2020.

At the November 2021 CTAD conference, safety and biomarker results were presented. Sixteen of the 242 participants discontinued dosing due to adverse events. These occurred more frequently on the high dose and included three serious adverse events. Dose-dependent increases in nasopharyngitis, gastrointestinal symptoms, and transient asymptomatic eosinophilia were seen. CSF biomarkers of Aβ, tau, synaptic function, and inflammation all moved in the direction of an expected benefit, with Aβ40 and 42, SNAP25, neurogranin, and YKL40 significantly changed in the treatment groups. Trend changes in hippocampal volume and cognition were not statistically significant but favored drug. A slowing of decline in FDG-PET in regions of interest did not reach significance, but a voxel-wise analysis found slower decline in most voxels in the treatment group compared to placebo. Trial results were published after peer review (Shanks et al., 2024). Additional exploratory biomarker results were presented at the October 2024 CTAD conference. In untreated patients, plasma pTau-217 increased by 29.1 percent per year, and LM11A-31-BHS significantly slowed this rise. Proteomics analysis confirmed significant changes in CSF YKL-40, neurogranin, and total tau, consistent with earlier results that used antibody-based detection methods. Treatment also slowed changes in proteomic networks related to AD progression.

For details, see clinicaltrials.gov

Last Updated: 15 Nov 2024

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References

News Citations

  1. In the Running: Trial Results from CTAD Conference

Paper Citations

  1. Shanks HR, Chen K, Reiman EM, Blennow K, Cummings JL, Massa SM, Longo FM, Börjesson-Hanson A, Windisch M, Schmitz TW. p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial. Nat Med. 2024 Jun;30(6):1761-1770. Epub 2024 May 17 PubMed.
  2. Sotthibundhu A, Sykes AM, Fox B, Underwood CK, Thangnipon W, Coulson EJ. Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor. J Neurosci. 2008 Apr 9;28(15):3941-6. PubMed.
  3. Knowles JK, Rajadas J, Nguyen TV, Yang T, Lemieux MC, Vander Griend L, Ishikawa C, Massa SM, Wyss-Coray T, Longo FM. 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.
  4. Massa SM, Xie Y, Yang T, Harrington AW, Kim ML, Yoon SO, Kraemer R, Moore LA, Hempstead BL, Longo FM. Small, nonpeptide p75NTR ligands induce survival signaling and inhibit proNGF-induced death. J Neurosci. 2006 May 17;26(20):5288-300. PubMed.
  5. Yang T, Knowles JK, Lu Q, Zhang H, Arancio O, Moore LA, Chang T, Wang Q, Andreasson K, Rajadas J, Fuller GG, Xie Y, Massa SM, Longo FM. Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment. PLoS One. 2008;3(11):e3604. PubMed.
  6. James SE, Burden H, Burgess R, Xie Y, Yang T, Massa SM, Longo FM, Lu Q. 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.
  7. Knowles JK, Simmons DA, Nguyen TV, Vander Griend L, Xie Y, Zhang H, Yang T, Pollak J, Chang T, Arancio O, Buckwalter MS, Wyss-Coray T, Massa SM, Longo FM. 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.
  8. Nguyen TV, Shen L, Vander Griend L, Quach LN, Belichenko NP, Saw N, Yang T, Shamloo M, Wyss-Coray T, Massa SM, Longo FM. 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.
  9. Yang T, Tran KC, Zeng AY, Massa SM, Longo FM. Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies. Sci Rep. 2020 Nov 23;10(1):20322. PubMed.
  10. Yang T, Liu H, Tran KC, Leng A, Massa SM, Longo FM. Small-molecule modulation of the p75 neurotrophin receptor inhibits a wide range of tau molecular pathologies and their sequelae in P301S tauopathy mice. Acta Neuropathol Commun. 2020 Sep 5;8(1):156. PubMed.
  11. Simmons DA, Knowles JK, Belichenko NP, Banerjee G, Finkle C, Massa SM, Longo FM. 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.
  12. Xie Y, Meeker RB, Massa SM, Longo FM. Modulation of the p75 neurotrophin receptor suppresses age-related basal forebrain cholinergic neuron degeneration. Sci Rep. 2019 Mar 27;9(1):5273. PubMed.
  13. Simmons DA, Belichenko NP, Ford EC, Semaan S, Monbureau M, Aiyaswamy S, Holman CM, Condon C, Shamloo M, Massa SM, Longo FM. 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.
  14. Haefeli J, Ferguson AR, Bingham D, Orr A, Won SJ, Lam TI, Shi J, Hawley S, Liu J, Swanson RA, Massa SM. A data-driven approach for evaluating multi-modal therapy in traumatic brain injury. Sci Rep. 2017 Feb 16;7:42474. PubMed.
  15. Shi J, Longo FM, Massa SM. A Small Molecule P75(NTR) Ligand Protects Neurogenesis after Traumatic Brain Injury. Stem Cells. 2013 Aug 13; PubMed.
  16. Tep C, Lim TH, Ko PO, Getahun S, Ryu JC, Goettl VM, Massa SM, Basso M, Longo FM, Yoon SO. 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.
  17. Friesland A, Weng Z, Duenas M, Massa SM, Longo FM, Lu Q. 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.
  18. Xie Y, Seawell J, Boesch E, Allen L, Suchy A, Longo FM, Meeker RB. Small molecule modulation of the p75 neurotrophin receptor suppresses age- and genotype-associated neurodegeneration in HIV gp120 transgenic mice. Exp Neurol. 2021 Jan;335:113489. Epub 2020 Sep 29 PubMed.
  19. Killebrew DA, Williams KS, Xie Y, Longo F, Meeker RB. Suppression of HIV-associated Macrophage Activation by a p75 Neurotrophin Receptor Ligand. J Neuroimmune Pharmacol. 2022 Jun;17(1-2):242-260. Epub 2021 Jul 22 PubMed.
  20. McGregor C, Sabatier M, English A. Early regeneration of axons following peripheral nerve injury is enhanced if p75NTR is eliminated from the surrounding pathway. Eur J Neurosci. 2021 Jan;53(2):663-672. Epub 2020 Sep 9 PubMed.
  21. Aby K, Antony R, Eichholz M, Srinivasan R, Li Y. Enhanced pro-BDNF-p75NTR pathway activity in denervated skeletal muscle. Life Sci. 2021 Dec 1;286:120067. Epub 2021 Oct 19 PubMed.
  22. Nasoohi S, Tayefeh Ghahremani P, Alehossein P, Elyasizadeh S, BaniArdalan S, Ismael S, Vatanpour H, Ahmadiani A, Ishrat T. The p75 neurotrophin receptor inhibitor, LM11A-31, ameliorates acute stroke injury and modulates astrocytic proNGF. Exp Neurol. 2023 Jan;359:114161. Epub 2022 Jul 2 PubMed.
  23. Nguyen TV, Crumpacker RH, Calderon KE, Garcia FG, Zbesko JC, Frye JB, Gonzalez S, Becktel DA, Yang T, Tavera-Garcia MA, Morrison HW, Schnellmann RG, Longo FM, Doyle KP. Post-Stroke Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Attenuates Chronic Changes in Brain Metabolism, Increases Neurotransmitter Levels, and Improves Recovery. J Pharmacol Exp Ther. 2022 Feb;380(2):126-141. Epub 2021 Dec 10 PubMed.
  24. Ji M, Yuan H, Yuan S, Xia J, Yang J. 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.
  25. Darcq E, Morisot N, Phamluong K, Warnault V, Jeanblanc J, Longo FM, Massa SM, Ron D. The Neurotrophic Factor Receptor p75 in the Rat Dorsolateral Striatum Drives Excessive Alcohol Drinking. J Neurosci. 2016 Sep 28;36(39):10116-27. PubMed.
  26. Zhang D, Zhao S, Zhang Z, Xu D, Lian D, Wu J, He D, Sun K, Li L. Regulation of the p75 neurotrophin receptor attenuates neuroinflammation and stimulates hippocampal neurogenesis in experimental Streptococcus pneumoniae meningitis. J Neuroinflammation. 2021 Nov 2;18(1):253. PubMed.
  27. Yin GN, Ock J, Limanjaya A, Minh NN, Hong SS, Yang T, Longo FM, Ryu JK, Suh JK. Oral Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Improves Erectile Function in a Mouse Model of Cavernous Nerve Injury. J Sex Med. 2021 Jan;18(1):17-28. Epub 2020 Nov 24 PubMed.
  28. Fogle JE, Hudson L, Thomson A, Sherman B, Gruen M, Lacelles BD, Colby BM, Clary G, Longo F, Meeker RB. Improved neurocognitive performance in FIV infected cats following treatment with the p75 neurotrophin receptor ligand LM11A-31. J Neurovirol. 2021 Apr;27(2):302-324. Epub 2021 Mar 4 PubMed.

External Citations

  1. company website
  2. clinicaltrials.gov

Further Reading

Papers

  1. Mufson EJ, Counts SE, Ginsberg SD, Mahady L, Perez SE, Massa SM, Longo FM, Ikonomovic MD. Nerve Growth Factor Pathobiology During the Progression of Alzheimer's Disease. Front Neurosci. 2019;13:533. Epub 2019 Jul 1 PubMed.
  2. Longo FM, Massa SM. 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. Knowles JK, Rajadas J, Nguyen TV, Yang T, Lemieux MC, Vander Griend L, Ishikawa C, Massa SM, Wyss-Coray T, Longo FM. 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.
  4. James ML, Belichenko NP, Shuhendler AJ, Hoehne A, Andrews LE, Condon C, Nguyen TV, Reiser V, Jones P, Trigg W, Rao J, Gambhir SS, Longo FM. [(18)F]GE-180 PET Detects Reduced Microglia Activation After LM11A-31 Therapy in a Mouse Model of Alzheimer's Disease. Theranostics. 2017;7(6):1422-1436. Epub 2017 Mar 24 PubMed.