LMTX (hydromethylthionine) / TauRx - LARVOL DELTA

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

LEVOSIMENDAN INHIBITS DISULFIDE TAU OLIGOMERIZATION AND AMELIORATES TAU PATHOLOGY IN TAUP301L-BIFC MICE. (ADPD 2024) - "Our data present the potential of levosimendan as a disease-modifying drug for tauopathies."

Preclinical • CNS Disorders

24-MONTH TOPLINE RESULTS FROM PHASE 3 LUCIDITY TRIAL IN AD SHOW COMBINED DISEASE-MODIFYING AND SYMPTOMATIC ACTIVITY FOR HYDROMETHYLTHIONINE MESYLATE (HMTM) (ADPD 2024) - "HMTM combines slowing of neurodegeneration and symptomatic benefit. It is an accessible, safe, oral treatment for MCI-AD to mild/ moderate AD which could be delivered with minimal patient and physician burden worldwide."

P3 data • P3 data: top line • CNS Disorders • NEFL • Plasma NfL

TauRx to Present Two-Year Data from Phase III Trial of HMTM in Alzheimer’s Disease at the AD/PD 2024 Conference in March (Businesswire) - "TauRx Pharmaceuticals Ltd...announced today that the company will present the 24-month data from its Phase III LUCIDITY trial of hydromethylthionine mesylate (HMTM) at the upcoming AD/PD 2024 Alzheimer's & Parkinson's Diseases Conference from 5-9 March 2024, in Lisbon, Portugal....At the conference, TauRx will present the data during a moderated panel discussion at 13:50 CET on 7 March...and host an additional question and answer session on 9 March."

P3 data • Alzheimer's Disease • CNS Disorders

Exploring the Anti-Hypoxaemia Effect of Hydromethylthionine: A Prospective Study of Phase 3 Clinical Trial Participants. (PubMed, Int J Mol Sci) - "We hypothesise that this facilitates a transition from the low oxygen affinity T-state of heme to the higher affinity R-state. HMTM has potential as an adjunctive treatment for hypoxaemia."

Journal • P3 data • Alzheimer's Disease • CNS Disorders • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Friends and Foes in Alzheimer's Disease. (PubMed, Med Princ Pract) - "Trials with humanized aducanumab, lecanomab and donanemab revealed limited success in AD patients. Therefore, research is also focused on the identification of biomarkers for early AD detection. In this respect, the plasma measurement of neurofilament light chain in patients treated with hydromethylthionine mesylate may well open a new way to prevent the formation of tau tangles and represents the first treatment for AD at its roots."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cytomegalovirus Infection • Epstein-Barr Virus Infections • Infectious Disease • Inflammation • Inflammatory Arthritis • Lyme Disease • Pneumonia • Respiratory Diseases • NEFL • Plasma NfL • SYK

Chronic administration of GV1001 improved motor and cognitive function and ameliorated tau aggregates in TauP301L-BiFC Mouse (4R-tau model): implication to a phase 2 clinical trial for PSP in Korea (MDS Congress 2023) - "Present data show that GV1001 improves motor and recognition deficits by inhibiting the hyper-phosphorylation and aggregation of human 4R tau in TauP301L-BiFC, a novel mouse model for PSP. Based on the experiments, a phase-2a double-blind randomized placebo-controlled trial of GV1001 in PSP patients has been launched in South Korea. A total of 75 patients are going to be randomized to placebo, 0.56 mg, and 1.12 mg groups in 5 centers and to get subcutaneous injections of the investigational drug every 2 weeks for 6 months."

Late-breaking abstract • P2 data • Preclinical • CNS Disorders • Cognitive Disorders • Parkinson's Disease • Progressive Supranuclear Palsy

Back-translation of clinical tau-aggregation inhibitor trials to experimental models: negative interactions of dementia therapies (AAIC 2023) - "A significant number of recruits, however, remained on symptomatic treatment and a post-hoc analysis confirmed this sub-cohort was selectively resilient against the tau aggregation inhibitor hydromethylthionine (HMT; previously termed LMT). We successfully back-translate the clinical trials on HMT into the preclinic using L1 tau transgenic mice . Data suggest not only a reduced cognitive efficacy of HMT in subjects pre-exposed to the choline esterase inhibitor rivastigmine, but also offer mechanistic explanations for potential interactions at presynaptic function and for transmitter release."

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

Causal association of cardiovascular risk factors with Alzheimer’s disease (AAIC 2023) - " Baseline brain FDG-PET images of participants with a diagnosis of AD from two large clinical trials of hydromethylthionine were classified into “typical AD” and “mixed” patterns through visual analysis... It is well known fact that the cardiovascular risk factors are commonly associated with cerebrovascular disease but contrary to our expectations cardiovascular risk factors have a causal association with typical AD."

Clinical • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Vascular Neurology