LMTX (hydromethylthionine) / TauRx - LARVOL DELTA

From Target Engagement to Translational Disconnect: A Systematic Review and Narrative Synthesis of Direct Tau-Targeted Clinical Trials in Alzheimer's Disease and Primary Tauopathies. (PubMed, Pharmacol Res) - "Tau-targeted therapies highlight a translational gap between biological activity and clinically meaningful benefit across multiple therapeutic mechanisms. Emerging evidence suggests that disease-stage timing, biomarker interpretation, tau heterogeneity, and aging-related factors may contribute to this disconnect. Future strategies will likely require earlier, and more biologically stratified intervention approaches, improved biomarker validation, and combination paradigms addressing the multifactorial complexity of neurodegenerative disease."

Journal • Review • Alzheimer's Disease • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy

Analyzing the influence of fractional orders of FitzHugh-Nagumo and Fisher equations. (PubMed, Sci Rep) - "In a close comparative analysis, both q-HMTM and MVIM provide highly precise results, where MVIM in some instances has a little better accuracy. The results affirm the effectiveness of these methods in addressing new complex systems of a fractional-order that occur in biological, physical, and engineering scenarios."

Journal

Assessment of clinical and neuroimaging efficacy of treatment targeting tau pathology in mild cognitive impairment and mild to moderate Alzheimer's disease with hydromethylthionine mesylate using external control data. (PubMed, J Prev Alzheimers Dis) - "Comparisons of HMTM treatment with CPAD, ADNI, and meta-analytic controls provide evidence consistent with clinical benefit HMTM. It has the potential to offer an accessible oral treatment option which could be delivered with minimal patient/physician burden."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Atypical population pharmacokinetics of hydromethylthionine in patients with Alzheimer's disease explains unexpected phase 3 trial results. (PubMed, Br J Clin Pharmacol) - "The exposure increase at 12 months and the dual pharmacology of HMT explain the unexpected symptomatic activity of low dose MTC. The data suggest it is not possible to maintain comparable urinary discolouration without therapeutic activity in a standard placebo-controlled trial design."

Journal • P3 data • PK/PD data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer's disease. (PubMed, J Prev Alzheimers Dis) - "Although HMTM 16 mg/day arrested progression of neurodegeneration and reduced grey matter atrophy at 52 weeks, symptomatic activity in the control arm precluded separation of treatment arms at 52 weeks on primary clinical endpoints. In participants with MCI, significant clinical separation was seen only at 78 and 104 weeks. This effect has been confirmed in a further study. HMTM was well tolerated and has the potential to offer an accessible oral treatment option with a benign safety profile which could be delivered with minimal patient/physician burden."

Biomarker • Journal • P3 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Pain • NEFL • Plasma NfL

Hypertension is the Main Vascular Risk Factor for Cognitive Impairment, Microvascular Pathology and Brain Atrophy in Alzheimer's Disease. (PubMed, Curr Alzheimer Res) - "Although hypertension is the main risk factor for cerebrovascular disease, contrary to our expectation, hypertension is common in typical AD than the mixed subtype, and this association is driven by the hitherto unsuspected contribution of microvascular pathology to cognitive impairment in typical AD."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Dementia • Diabetes • Dyslipidemia • Hypertension • Metabolic Disorders • Vascular Neurology

Drug Development. (PubMed, Alzheimers Dement) - P1 | "AS-S603 is a first-in-class oral treatment for AD, uniquely targeting both Aβ and tau aggregates. It provides significant cognitive benefits in preclinical studies, suggesting its potential to alter disease progression. Clinical studies will validate its safety and efficacy, positioning AS-S603 as a transformative treatment for AD."

Journal • Alzheimer's Disease • CNS Disorders

Effects of hydromethylthionine mesylate and rivastigmine in a pharmacological mouse model of Alzheimer's disease. (PubMed, Behav Pharmacol) - "The results from clinical trials have indicated that the tau aggregation inhibitor hydromethylthionine mesylate (HMTM) produces disease-modifying effects in Alzheimer's disease (AD) patients when administered alone, but less of an effect when administered in conjunction with cholinesterase inhibitors (ChEIs). Furthermore, coadministration of rivastigmine with HMTM ameliorated the impairments induced by scopolamine. These findings extend our previous observations with MTC and confirm that HMTM also has a dual mode of action, disease modification through tau aggregation inhibition, but also having symptomatic effects through its normalisation of cholinergic activity."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Hybrid molecules with dual inhibition of acetylcholinesterase and Tau hyperphosphorylation: design, inhibitory activity evaluation, apoptosis assessment, and mechanistic exploration. (PubMed, Chem Biol Interact) - "To address this need, the present study designed a series of hybrid molecules by integrating three pharmacophoric scaffolds with established P-Tau-modulating activity (phenothiazine, dibenzazepine and benzothiazepinones) into AChE-inhibiting frameworks: indanone (derived from the clinical AChE inhibitor Donepezil) or 9-chloro-1,2,3,4-tetrahydroacridine (derived from Tacrine, another clinically approved AChE inhibitor)...Notably, the indanone-phenothiazine hybrid compound C11 stood out as the most promising candidate, it achieved the lowest P-Tau/total Tau (T-Tau) ratio (5.30 × 10-6) in okadaic acid (OA)-induced SH-SY5Y cells, outperforming hydromethylthionine mesylate (5.40 × 10-6), a leading clinical candidate for Tau aggregation inhibition...Concurrently, C11 modulated the expression of glycogen synthase kinase-3β (GSK-3β), a critical kinase driving P-Tau formation."

Journal • CNS Disorders

Development and validation of a deep learning model for individualized survival prediction in advanced cervical cancer. (PubMed, Discov Oncol) - "Our study developed a novel, practical, personalized prognostic model for advanced cervical cancer, this individualized survival prediction system may also help clinicians to design more balanced and reasonable clinical trials."

Journal • Cervical Cancer • Hematological Disorders • Oncology • Solid Tumor

Tau(350-362) is a key region that drives modulates inhibition of fibrillogenesis by hydromethylthionine. (PubMed, J Mol Biol) - "Here, a chiral spectral circular dichroism fingerprint shows that HMT binds to tau350-362 and we reveal that HMT inhibits assembly. We conclude that the region important for assembly and inhibition is formed by the inner C-shaped region of tau and suggest that the central region involved in filament assembly may associate with HMT to prevent self-assembly."

Journal • Alzheimer's Disease • CNS Disorders

FDG-PET Image Classification in Alzheimer's Disease: from Traditional Visual Analysis to Advanced Transfer Learning. (PubMed, Nucl Med Mol Imaging) - "Baseline FDG-PET data were collected as part of two large scale Phase III clinical trials of a novel tau aggregation inhibitor drug, Leuco-Methylthioninium (LMTX®)...The average accuracy to distinguish the two subtypes after 5-fold cross validation was found to be 97.5%. This study is first of its kind to distinguish two subtypes of AD through visual interpretation of FDG-PET images and exploring the findings with a semi-quantitative method followed by transfer learning, which has been used to predict the two subtypes with high accuracy, sensitivity and specificity."

Journal • Alzheimer's Disease • CNS Disorders

TRx0237 induces apoptosis and enhances anti-PD-1 immunotherapeutic efficacy in anaplastic thyroid Cancer. (PubMed, Int Immunopharmacol) - "Therefore, our study suggests that TRx0237 showed anticancer effects by inducing apoptosis and improving the efficacy of anti-PD-1 immunotherapy. TRx0237 is a potential agent for the treatment of ATC."

IO biomarker • Journal • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma

ON THE EFFICACY OF THE TAU AGGREGATION INHIBITOR HYDROMETHYLTHIONINE: DIFFERENT DOSING REGIMENS AND SYMPTOMATIC ACTIONS (ADPD 2025) - "Furthermore, co - administration of rivastigmine also ameliorated the scopolamine defi cit. Beneficial effects of HMT on cognitive performance were observed following intermittent and shorter treatment regimens of only one administration per week. Furthermore, like previous observations from our group with methylthioninium chlo ride, HMT was effective in a symptomatic model of AD confirming multiple mechanisms of action."

Clinical • Alzheimer's Disease • CNS Disorders

CONFIRMATION OF EFFICACY OF ORAL TAU AGGREGATION INHIBITOR HYDROMETHYLTHIONINE MESYLATE (HMTM) IN EARLY TO MODERATE ALZHEIMER'S DISEASE (ADPD 2025) - "Conclusions HMTM 16 mg/day is effective in reducing clinical decline and brain atrophy progression over 78 weeks, with benefits lasting 2 years. HMTM provides a safe and accessible oral treatment option for MCI-AD to mild/moderate AD which could be delivered with minimal patient and physician burden."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Hydromethylthionine sustains truncated tau-dependent inflammation-lowering effects in mouse brain. (PubMed, FEBS J) - "Tauopathies are a heterogeneous mixture of neurodegenerative disorders, including Alzheimer's disease and frontotemporal dementia (FTD), characterised by the accumulation of tau filaments in brain tissue. These findings indicate that HMT has a beneficial effect in reducing neuroinflammation that accompanies a decrease in the accumulation of truncated tau species and that these benefits are not susceptible to interference by memantine. In turn, the nature of drug interference between HMT and memantine seems to be independent of tau and related to microglia reactivity."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Inflammation • Oncology • TNFA

Rivastigmine interferes with the pharmacological activity of hydromethylthionine on presynaptic proteins in the line 66 model of frontotemporal dementia. (PubMed, Brain Res Bull) - "The most prominent differences appeared in proteins of the SNARE complex (SNAP-25, VAMP-2, SNTX-1), but rivastigmine also interfered with the HMTM-dependent reduction in tau accumulation. These data extend our previous findings with L1 mice and provide evidence for a synaptic mechanism of interference between symptomatic and disease-modifying dementia therapies and an explanation for similar drug interactions observed in clinical trials."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration

Mechanism of Methylene Blue Inducing the Disulfide Bond Formation of Tubulin-Associated Unit Proteins. (PubMed, JACS Au) - "Methylene blue (MB) has recently completed a Phase-3 clinical trial as leuco-methylthioninium (LMT) bis(hydromethanesulfonate) for treating Alzheimer's disease...Moreover, MT+ preferentially oxidized C291 and C322 in the lysine-rich R2 and R3 domains. Under in vivo brain physoxia conditions, LMT may convert to MT+, possibly interfering with tau fibrillation via disulfide bond formation."

Journal • Alzheimer's Disease • CNS Disorders

TauRx Submits UK Marketing Authorisation Application for HMTM as a Treatment for Alzheimer’s Disease (Businesswire) - "TauRx Pharmaceuticals Ltd...has announced the submission of a UK Marketing Authorisation Application (MAA) for hydromethylthionine mesylate (HMTM) for treatment of mild cognitive impairment (MCI-AD) and mild to moderate stages of dementia due to Alzheimer’s disease...The MAA is based on the totality of evidence available from the recently released 24-month Phase 3 LUCIDITY data and two earlier Phase 3 trials in mild to moderate AD. These studies have been consistent in showing benefit on measures of decline in cognition, ability to perform normal activities of daily living, and reduction in the rate of brain shrinkage."

MHRA filing • Alzheimer's Disease • CNS Disorders

Rescue of synaptosomal glutamate release defects in tau transgenic mice by the tau aggregation inhibitor hydromethylthionine. (PubMed, Cell Signal) - "In this case, directionally opposite abnormalities in glutamate release resulting from different types of tau aggregation in the two mouse models can be corrected by hydromethylthionine. This may help to explain the activity of hydromethylthionine on cognitive decline and brain atrophy in both AD and behavioural-variant FTD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Frontotemporal Lobar Degeneration

A Review of Recent Advances in the Management of Alzheimer's Disease. (PubMed, Cureus) - "The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab...Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aβ) monomer aggregation into toxic oligomers...The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aβ plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia..."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • Diabetes • Inflammation • Insomnia • Metabolic Disorders • Sleep Disorder

Hydromethylthionine rescues synaptic SNARE proteins in a mouse model of tauopathies: interference by cholinesterase inhibitors. (PubMed, Brain Res Bull) - "Interference of cholinesterase inhibition with HMTM was observed also in a tau transgenic mouse model, where rivastigmine reduced the pharmacological activity of HMTM at multiple brain levels including hippocampal acetylcholine release, synaptosomal glutamate release and mitochondrial activity. These data indicate a reduction in pharmacological activity of HMTM when given as an add-on therapy, a result that is consistent with the responses observed in the clinic. Attenuation of the therapeutic effects of HMTM by cholinergic treatments may have important implications for other potential AD therapies."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Napsin A • SYP

Tau Aggregation-Dependent Lipid Peroxide Accumulation Driven by the hsa_circ_0001546/14-3-3/CAMK2D/Tau Complex Inhibits Epithelial Ovarian Cancer Peritoneal Metastasis. (PubMed, Adv Sci (Weinh)) - "In vivo, treatment with ferrostatin-1 and TRx0237 rescued the inhibitory effect of hsa_circ_0001546 on EOC cell spreading. Therefore, based on this results, ferroptosis caused by Tau aggregation occurs in EOC cells, which is not only in Alzheimer's disease- or Parkinson's disease-related cells and this kind of ferroptosis driven by the hsa_circ_0001546/14-3-3/CAMK2D/Tau complex is LPO-dependent rather than GPX4-dependent is hypothesized."

Journal • Alzheimer's Disease • CNS Disorders • Movement Disorders • Oncology • Ovarian Cancer • Parkinson's Disease • Solid Tumor • CAMK2D • GPX4

Neuroprotection of Cholinergic Neurons with a Tau Aggregation Inhibitor and Rivastigmine in an Alzheimer's-like Tauopathy Mouse Model. (PubMed, Cells) - "Recent evidence suggests that tau protein is a putative target for the treatment of dementia, and the tau aggregation inhibitor, hydromethylthionine mesylate (HMTM), has emerged as a potential disease-modifying treatment. This phenotype is reversible by HMTM, but at the same time appears to be subject to a homeostatic regulation induced by chronic pre-treatment with an acetylcholinesterase inhibitor, which interferes with the efficacy of HMTM. The strongest phenotypic reversal coincided with a normalization of the tau load in the cortex and hippocampus of L1, suggesting that tau accumulation underpins the loss of cholinergic markers in the basal forebrain and its projection targets."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • Pain • CA3 • CHAT

Two Year Sustained Cognitive Benefits of Hydromethylthionine Mesylate (HMTM) Indicated by TauRx's LUCIDITY Trial (Businesswire) - P3 | N=598 | LUCIDITY(NCT03446001) | Sponsor: TauRx Therapeutics Ltd | "TauRx Pharmaceuticals Ltd...presented the 24-month data from its Phase 3 LUCIDITY trial of hydromethylthionine mesylate (HMTM) at the AD/PD 2024 Alzheimer's & Parkinson's Diseases Conference in Lisbon, Portugal....From the data shared today, participants at the early stage of AD receiving HMTM 16 mg/day remained significantly above baseline to 18 months and only returned to baseline values after 24 months. Within this subgroup, progression of symptoms to the dementia stage of the disease was significantly less than in the control group. Additionally, further analysis of this subgroup shows that the control group declined significantly below their baseline despite the switch to 16 mg/day after 12 months in the open label phase (p=0.0308 for the observed cases difference in ADAS-Cog13, being a more accurate measure for early disease)."

P3 data • Alzheimer's Disease • CNS Disorders