Therapeutics

Rember TM

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Overview

Name: Rember TM
Synonyms: Methylene Blue, Tau aggregation inhibitor (TAI), TRx-0014
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.

Background

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 for the treatment for malaria, as well as for 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 Rember was TauRx's first-generation compound; it has since been replaced by TRx0237.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 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 8 (see Aug 2008 conference story), 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 (see Congdon et al., 2012), neuroprotection via mitochondrial antioxidant properties (see 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., 2009Riha 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 story).

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).

Findings

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 or memantine. The primary outcome was cognition as measured by the ADAS-Cog test battery. This trial was reported to have shown signs of benefit for the two lower doses in moderate though not mild AD, but the methodology for how the different doses were analyzed was questioned, as was the trial's blinding.

The trial continued into an open-label extension of 111 patients up to one year. 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.

TauRx has subsequently 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).

For extensive coverage on the Rember Phase 2 trial, see Aug 2008 conference story and follow-up story and Q&A with Claude Wischik.

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References

Therapeutics Citations

  1. TRx0237

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. Does TauRx Drug Work by Oxidizing Tau?

Paper Citations

  1. . 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.
  2. . 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.
  3. . Aminothienopyridazines and Methylene Blue Affect Tau Fibrillization via Cysteine Oxidation. J Biol Chem. 2013 Apr 19;288(16):11024-37. PubMed.
  4. . Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy. 2012 Apr;8(4):609-22. PubMed.
  5. . Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem. 2011 May 6;286(18):16504-15. PubMed.
  6. . Methylene blue reduces aβ levels and rescues early cognitive deficit by increasing proteasome activity. Brain Pathol. 2011 Mar;21(2):140-9. PubMed.
  7. . Methylthioninium chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine. Psychopharmacology (Berl). 2009 Jan;202(1-3):53-65. PubMed.
  8. . Beneficial network effects of methylene blue in an amnestic model. Neuroimage. 2011 Feb 14;54(4):2623-34. PubMed.
  9. . Binding of methylene blue to a surface cleft inhibits the oligomerization and fibrillization of prion protein. Biochim Biophys Acta. 2012 Sep 25; PubMed.
  10. . 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.
  11. . 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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