Rember TM


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Name: Rember TM
Synonyms: Methylene Blue , methylthioninium (MT), TRx-0014, Tau aggregation inhibitor (TAI)
Chemical Name: 3,7-Bis(dimethylamino)phenothiazin-5-ium chloride
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: TauRx Therapeutics Ltd
Approved for: Methylene Blue predates FDA. Used for treatment of malaria and methemoglobinemia.


Rember® is a purified, proprietary formulation of methylthioninium chloride (MTC), also known as methylene blue. This old drug predates the FDA. It is being widely used in Africa to treat malaria, as well as methemoglobinemia and other conditions. Rember was TauRx's first-generation compound; it has since been replaced by TRx0237.

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 linked more closely 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 of Rember TM in 2008 (see Aug 2008 conference story), one peer-reviewed paper to support this rationale had been published. It reported that methylene blue interfered with the tau-tau binding necessary for aggregation (see Wischik et al., 1996). Since 2008, numerous 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 (see Congdon et al., 2012), neuroprotection via mitochondrial antioxidant properties (see Wen et al., 2011), as well as Aβ clearance and proteasome function in transgenic AD and tauopathy mouse models (see Medina et al., 2011) and spatial learning and brain metabolism in rats (see Deiana et al., 2009Riha et al., 2011). A mechanistic study found that methylene blue oxidizes cysteine sulfhydryl groups on tau to keep tau monomeric (see Feb 2013 news). One preclinical treatment study in tauopathy mice reported anti-inflammatory or neuroprotective effects mediated by the Nrf2/antioxidant response element (ARE); another reported insoluble tau reduction and a learning and memory benefit when given early (see Stack et al., 2014Hochgräfe et al., 2015).

Some studies reported a generalized anti-aggregation effect for methylene blue against aggregation-prone proteins, such as prion protein and TDP-43 (see 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).


The first trial known for Rember was a six-month Phase 2 study that ran between 2004 and 2007. This single-center, dose-ranging study compared hard capsules containing 30, 60, and 100 mg taken three times a day to placebo in 321 people with mild to moderate Alzheimer's disease who were not taking acetylcholinesterase inhibitors or memantine. The primary outcome was cognition as measured by the ADAS-Cog test battery. This trial was presented at a conference as having shown benefit for the two lower doses in moderate, though not mild AD; however, the trial's blinding and methodology for analyzing the high dose was questioned (see Aug 2008 conference news follow-up story, and Q&A with Claude Wischik). 

The trial continued into an open-label extension of up to one year in 111 patients. By that point, participants on the middle dose were reported to have stabilized. Side effects included diarrhea, urinary urgency, and painful urination, as well as dizziness and falls. Overall, the side effect profile was reported to be similar to the three acetylcholinesterase inhibitors, though diarrhea was more common.

The 100 mg dose was ineffective, reportedly because of interactions between the study drug and gelatine in the capsule wall. According to the investigator, this delayed absorption of the drug. MTC contains the chloride salt of the oxidized form of methylthionine. In the low pH of the stomach, enzymes convert it to uncharged leuco-methylthionine (LMT) prior to absorption, but at high doses it is poorly tolerated unless taken with food.

Results from this trial were published in 2014. One study reported a minimum effective dose of 138 mg/day, as well as pharmacokinetic parameters such as the steady-state concentration of MTC achieved in the brain and the reasons for the poor bioavailability of the highest dose (Baddeley et al., 2014). The other paper reported a statistically significant benefit of -5.42 units on the ADAS-cog, as well as a benefit of 3.79 units on the MMSE, in the moderate group on the 138 mg/day dose (see Wischik et al., 2015.)

In the meantime, TauRx had developed TRx 0237 (LMTX™). This second-generation compound is a stabilized, reduced form of MTC that reportedly has better absorption into the intestine, bioavailability, and tolerability. TRx 0237 and Rember share the same mode of action. TRx 0237 is being evaluated in Phase 3 trials for the treatment of Alzheimer's disease and frontotemporal dementia. These trials use tablets, not capsules (see also Wischik and Staff, 2009).


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News Citations

  1. Chicago: Out of the Blue—A Tau-based Treatment for AD?
  2. Vienna (and Burkina Faso): What's New With Methylene Blue?
  3. Will Tau Drug Show Its True Colors in Phase 3 Trials?
  4. Does TauRx Drug Work by Oxidizing Tau?

Therapeutics Citations

  1. LMTM

Paper Citations

  1. . Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease. J Pharmacol Exp Ther. 2015 Jan;352(1):110-8. Epub 2014 Oct 15 PubMed.
  2. . Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease. J Alzheimers Dis. 2015;44(2):705-20. PubMed.
  3. . Challenges in the conduct of disease-modifying trials in AD: practical experience from a phase 2 trial of Tau-aggregation inhibitor therapy. J Nutr Health Aging. 2009 Apr;13(4):367-9. PubMed.
  4. . 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.
  5. . Aminothienopyridazines and Methylene Blue Affect Tau Fibrillization via Cysteine Oxidation. J Biol Chem. 2013 Apr 19;288(16):11024-37. PubMed.
  6. . Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy. 2012 Apr;8(4):609-22. PubMed.
  7. . Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem. 2011 May 6;286(18):16504-15. PubMed.
  8. . Methylene blue reduces aβ levels and rescues early cognitive deficit by increasing proteasome activity. Brain Pathol. 2011 Mar;21(2):140-9. PubMed.
  9. . Methylthioninium chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine. Psychopharmacology (Berl). 2009 Jan;202(1-3):53-65. PubMed.
  10. . Beneficial network effects of methylene blue in an amnestic model. Neuroimage. 2011 Feb 14;54(4):2623-34. PubMed.
  11. . Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity. Hum Mol Genet. 2014 Jul 15;23(14):3716-32. Epub 2014 Feb 20 PubMed.
  12. . Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau. Acta Neuropathol Commun. 2015 May 10;3:25. PubMed.
  13. . 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.
  14. . 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.
  15. . Methylene blue fails to inhibit Tau and polyglutamine protein dependent toxicity in zebrafish. Neurobiol Dis. 2010 Sep;39(3):265-71. PubMed.

Further Reading

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