Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer’s Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial

Abstract

Background:LMTM is being developed as a treatment for AD based on inhibition of tau aggregation.Objectives:To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD.Methods:Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error.Results:The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy.Conclusions:The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.

Current and Future Treatments in Alzheimer Disease: An Update

“…83 Methylene blue's derivative TRx0237 (LMTX) which was studied in phase 3 failed finally to show efficacy, and based on the analysis of the results, a new phase 2/3 study named LUCIDITY was started 1 year ago in subjects with mild AD with a lower dose of the agent. 84 Microtubule stabilizers. The microtubule-stabilizing agent davunetide was studied in a phase 2 trial but it did not meet the clinical end points.…”

“…First results presented report that the agent was not well tolerated by the participants. 84 IONIS MAPTRx (BIIB080), a microtubule-associated protein tau RNA inhibitor, an antisense oligonucleotide, is assessed in a phase 2 clinical study that is still in the recruiting process of patients with mild AD (NCT02623699). 86 Targeting posttranslational modifications of Tau.…”

FRET-based Tau seeding assay does not represent prion-like templated assembly of Tau fibers

“…Earlier attempts to prevent tau pathology were directed at pathological changes of Tau within neurons, assuming they were the carriers of toxicity. Examples are the inhibition of kinases or activation of phosphatases to reduce hyperphosphorylation (Medina, 2018), or inhibitor compounds to block aggregation (Wilcock et al, 2018, Wischik et al, 2014, Pickhardt et al, 2015, Pickhardt et al, 2007, Pickhardt et al, 2005 Overall these attempts were not successful. The "prion-like" hypothesis shifted the emphasis to the transfer of tau between cells, which could conceptually be intercepted by Tau-specific antibodies , Congdon et al, 2016, Gu et al, 2013, Novak et al, 2017.…”

Cysteine-Independent Inhibition of Alzheimer's Disease-like Paired Helical Filament Assembly by Leuco-Methylthioninium (LMT)

“…1:0.1, is approximately the same as that required to reverse the proteolytic stability of PHFs isolated from AD brain tissues [20,21]. The evidence we have presented showing that LMT is the active moiety at the site required for inhibition of aggregation of the core tau unit of the PHF may be part of the explanation for the clinical evidence suggesting that the stable reduced form of the MT moiety (LMTM, hydromethylthioninium mesylate), appears to be effective at a dose 20-fold lower than the minimum effective dose previously identified using the oxidised MT + form [19,34]. A global clinical…”