Name: LMTM
Synonyms: TRx0237, LMT-X, Methylene Blue, Tau aggregation inhibitor (TAI)
Chemical Name: Methylthioninium chloride (MTC)
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease, Frontotemporal Dementia
U.S. FDA Status: Alzheimer's Disease (Phase 3), Frontotemporal Dementia (Phase 3)
Company: TauRx Therapeutics Ltd
Approved for: Methylene Blue predates FDA. Used for treatment of malaria and methemoglobinemia.


TRx 0237 (LMTX™) is a second-generation tau protein aggregation inhibitor for the treatment of Alzheimer's disease (AD) and frontotemporal dementia. It is a replacement formulation for Rember®the first company's first proprietary formulation of methylthioninium chloride (MTC). Both TRx 0237 and Rember are purified forms of Methylene Blue, an old drug that predates the FDA and is being widely used in Africa for the treatment for malaria, as well as for methemoglobinemia and other conditions. TRx 0237 and Rember share the same mode of action, but TRx 0237 has been designed as a stabilized, reduced form of MTC to improve the drug's absorption, bioavailability, and tolerability. 

The rationale behind both TRx 0237 and Rember TM is that these compounds prevent tau aggregation or dissolve existing aggregates to interfere with downstream pathological consequences of aberrant tau in tauopathies including Alzheimer's and other neurodegenerative diseases. Tau pathology is widely considered to be downstream of Aβ pathology and is more closely linked to cognitive deficits in Alzheimer's disease. Mutations in the tau gene cause frontotemporal dementia, not Alzheimer's disease, but tau is considered a central drug target for all tauopathies, including Alzheimer's.

Prior to the first publicized Phase 2 trial on Rember TM in 2008, one peer-reviewed paper to support this rationale had been published, which reported that Methylene Blue interfered with the tau-tau binding necessary for aggregation (see Wischik et al., 1996). No peer-reviewed papers have been published on Rember TM or TRx 0237. However, since 2008, numerous independent academic investigations of the commercially available parent compound, Methylene Blue, have reported potentially beneficial effects on a growing list of cellular and system-level endpoints, including tau fibrillization in vitro (see Crowe et al., 2013), autophagy (e.g. Congdon et al., 2012), neuroprotection via mitochondrial antioxidant properties (e.g. Wen et al., 2011), as well as on Aβ clearance and proteasome function in transgenic AD mouse models (see Medina et al., 2011), and spatial learning and brain metabolism in rats (see Deiana et al., 2009; Riha et al., 2011)One mechanistic study found that Methylene Blue oxidizes cysteine sulfhydryl groups on tau in a way that keeps tau in the monomeric state (see Feb 2013 news).

Some studies reported a generalized anti-aggregation effect for Methylene Blue against aggregation-prone proteins, such as prion protein and TDP-43 (e.g. Cavaliere et al., 2012; Arai et al., 2010). However, findings are mixed, with other papers reporting no inhibition of tau- and polyglutamine-mediated neurotoxicity in vivo (see van Bebber et al., 2010).


No information on Phase 1 trials of TRx0237 is available. A four-week Phase 2 safety study of 250 mg/day of TRx0237 in patients with mild to moderate Alzheimer's disease began in September 2012 but was terminated in April 2013, reportedly for administrative reasons.

In November 2012, TauRx started a phase 3 study comparing 200 mg/day of LMTM to placebo in a planned 800 patients with a diagnosis of either all-cause dementia or Alzheimer's disease mild enough to score above an MMSE of 20. The trial ran at more than 90 sites in North America and Europe. As primary outcomes, it used standard cognitive (ADAS-Cog 11) and clinical (ADCS-CGIC) batteries, as well as temporal lobe brain metabolism as measured by FDG-PET and safety parameters. Results were presented—and disputed—at the 2016 CTAD meeting. Participants on LMTM declined on cognition (ADAS-Cog) and functional scales (ADCS ADL) as rapidly as did patients on placebo, which contained a low dose of active compound for coloring purposes (Dec 2016 conference news). 

Another Phase 3 trial compared 150 and 250 mg/day of TRx0237 to placebo in 891 patients with mild to moderate Alzheimer's disease with an MMSE of 14 or higher. Started in 2013, this trial involved more than 80 sites in North America, Australia, Europe, and Asia. It used clinical (ADCS-CGIC), cognitive (ADAS-Cog 11), and safety measures as primary outcomes. Negative results from this trial were presented at the 2016 AAIC conference in Toronto (see Jul 2016 conference news).

A third Phase 3 trial evaluated TRx0237 in the behavioral variant of frontotemporal dementia, the most common form of this disease. Begun in August 2013, this trial targeted enrollment of 180 people with probable bvFTD who have frontotemporal atrophy confirmed by MRI and whose MMSE is above 20. The trial compared 200 mg/day to placebo for the drug's ability to show clinical benefit on activities of daily living as measured by the modified ADCS-CGIC Alzheimer's scale and the revised Addenbrooke's Cognitive Examination (ACE-R), a widely used psychometric tool in FTD clinical research. This trial was to be conducted at 45 sites in North America, Europe, Australia, and Singapore. At the 2016 ICFTD conference in Munich, this trial was reported to have missed its co-primary endpoints (Sep 2016 conference newscompany press release).

These three Phase 3 trials used “active placebo” tablets that include 4 mg of TRx0237 as a urinary and fecal colorant to help maintain blinding; hence the placebo group received a total of 8 mg/day of TRx0237. TRx0237's predecessor compound, Rember TM, colors urine and feces, and the blinding of its Phase 2 trial has been questioned. Hence a colorless TRx0237 was developed; however, it, too, turns blue once metabolized in the body (for details and Q&A with TRx0237's founding scientist, Claude Wischik, see Oct 2012 news). 

In January 2018, TauRx started another phase 2/3 trial aiming to enroll 180 people with all-cause dementia and Alzheimer's disease, at 55 sites in North America, Belgium, Poland and the UK. The trial will compare a 6-month course of 4 mg of LMTM twice daily—the amount of LMTM previously admixed to 'active placebo' in the prior phase 3 trials—to a different kind of placebo. Primary outcomes include 18F-FDG-PET imaging and safety; secondary outcomes include structural MRI, as well as measures of cognition and activities of daily living. This trial is set to run until February 2019.

For all clinical trials with TRx0237, see

Clinical Trial Timeline

  • Phase 2
  • Phase 2/3
  • Phase 3
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029
TauRx Therapeutics Ltd NCT01626391
TauRx Therapeutics Ltd NCT01689233
TauRx Therapeutics Ltd NCT01689246
TauRx Therapeutics Ltd NCT01626378
TauRx Therapeutics Ltd NCT03446001

Last Updated: 11 Nov 2016


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News Citations

  1. Tau Inhibitor Fails Again—Subgroup Analysis Irks Clinicians at CTAD
  2. In First Phase 3 Trial, the Tau Drug LMTM Did Not Work. Period.
  3. First Round of FTD Therapeutics Fell Short, But Many More Are Up and Running
  4. Will Tau Drug Show Its True Colors in Phase 3 Trials?
  5. Does TauRx Drug Work by Oxidizing Tau?

Therapeutics Citations

  1. Rember TM

Paper Citations

  1. . Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11213-8. PubMed.
  2. . Aminothienopyridazines and Methylene Blue Affect Tau Fibrillization via Cysteine Oxidation. J Biol Chem. 2013 Apr 19;288(16):11024-37. PubMed.
  3. . Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy. 2012 Apr;8(4):609-22. PubMed.
  4. . Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem. 2011 May 6;286(18):16504-15. PubMed.
  5. . Methylene blue reduces aβ levels and rescues early cognitive deficit by increasing proteasome activity. Brain Pathol. 2011 Mar;21(2):140-9. PubMed.
  6. . Methylthioninium chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine. Psychopharmacology (Berl). 2009 Jan;202(1-3):53-65. PubMed.
  7. . Beneficial network effects of methylene blue in an amnestic model. Neuroimage. 2011 Feb 14;54(4):2623-34. PubMed.
  8. . Binding of methylene blue to a surface cleft inhibits the oligomerization and fibrillization of prion protein. Biochim Biophys Acta. 2013 Jan;1832(1):20-8. Epub 2012 Sep 25 PubMed.
  9. . Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy. Neuropathology. 2010 Apr;30(2):170-81. PubMed.
  10. . Methylene blue fails to inhibit Tau and polyglutamine protein dependent toxicity in zebrafish. Neurobiol Dis. 2010 Sep;39(3):265-71. PubMed.

External Citations

  1. company press release

Further Reading


  1. . "Lest we forget you--methylene blue...". Neurobiol Aging. 2011 Dec;32(12):2325.e7-16. PubMed.
  2. . Neuroprotective actions of methylene blue and its derivatives. PLoS One. 2012;7(10):e48279. PubMed.
  3. . Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models. FEBS Lett. 2009 Jul 21;583(14):2419-24. PubMed.
  4. . Methylene blue induces macroautophagy through 5' adenosine monophosphate-activated protein kinase pathway to protect neurons from serum deprivation. Front Cell Neurosci. 2013 Jan 1;7:56. Epub 2013 May 3 PubMed.