Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6CBA-Tg(Thy1.2-hAPParc)
Last Updated: 06 Mar 2018
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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 Rember was TauRx's first-generation compound; it has since been replaced by TRx0237.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., 2009; Riha 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., 2014, Hochgräfe 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).
Last Updated: 18 May 2015
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Name: RG7129
Synonyms: RO5508887, BACE Inhibitor
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Roche
This is an orally administered inhibitor of the β-secretase BACE1, the sheddase enzyme that cleaves APP and sets up subsequent γ-secretase cleavage leading to generation of Aβ species. The rationale behind this approach is that it will test the amyloid-cascade hypothesis of Alzheimer's disease and act as a disease-modifying therapy.
Three Phase 1 trials have been completed. In January 2012, a trial conducted in Strasbourg, France, concluded a test of RG7129 in 50 healthy men to assess safety and pharmacological parameters of single ascending doses given with or without food. This trial assessed plasma levels of amyloid biomarkers. In September 2012, a trial concluded evaluation of a 14-day course of multiple ascending doses in 36 patients, also in Strasbourg. This trial assessed RG7129 pharmacologic parameters across the adult age range starting at 18. In June 2013, a trial in 42 participants in the United States concluded, which investigated the pharmacodynamics and pharmacokinetics of single doses of RG7129 in plasma and cerebral spinal fluid of healthy men. No results have been reported thus far.
In October 2013, Roche terminated development of this compound. Liver toxicity has been mentioned as the reason, but Roche issued no official explanation.
Last Updated: 27 Mar 2015
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