On 5 April 2025 at the AD/PD 2025 International Conference on Alzheimer’s and Parkinson’s Diseases, held in Vienna, Austria, during a symposium on “Tauopathies: challenges in targeting tau,” TauRx Therapeutics presented further analysis of data from its Phase III LUCIDITY (NCT03446001) trial, not previously presented, confirming the efficacy of LMTX (hydromethylthionine mesylate [HMTM]) for the treatment of mild cognitive impairment (MCI) and mild-to-moderate Alzheimer’s disease. LMTX is an oral small molecule that inhibits tau aggregation and has a secondary symptomatic effect of increasing levels of acetylcholine in the hippocampus. It is currently in pre-registration in the UK.
Despite its late stage, TauRx has faced unique challenges in the development of LMTX. It has not been possible for TauRx to run a placebo-controlled trial in which the participants remain blind to their treatment arm due to the properties of the drug, which causes urinary discolouration, and as such, the pivotal LUCIDITY trial was not placebo-controlled, following guidance from regulators who discourage use of a “true placebo.” Due to the lack of traditional efficacy data compared with placebo in a randomised trial, key opinion leaders (KOLs) previously interviewed by GlobalData have been generally less optimistic about the prospects of LMTX. To get around this challenge, TauRx has conducted an analysis using placebo trial data from contemporary Alzheimer’s disease trials available in the Critical Path in Alzheimer’s Disease (CPAD) database.
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Patients from the LUCIDITY trial who had received 16mg/day LMTX for 18 months were closely matched to subjects in the CPAD database on measures including age, sex, smoking history, APOE genotype, positive amyloid-positron emission tomography (PET) scan, Clinical Dementia Rating (CDR) score, and Mini-Mental State Examination (MMSE) score at baseline.
Data presented at AD/PD 2025 showed that LMTX treatment resulted in an 82% reduction in cognitive decline measured by change from baseline in Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog13) score compared with matched placebo at 18 months. This increased to 115% reduction when just the early Alzheimer’s patient population (moderate patients excluded) was analysed. Further, there was a 35% reduction in the progression of brain atrophy, measured using whole brain volume, at 18 months in LMTX-treated patients compared with matched placebo. This also increased when just the early Alzheimer’s patient population was evaluated, to 54%. Finally, LMTX treatment resulted in a 77% reduction in global clinical decline, measured using CDR-sum of boxes (SB), at 24 months compared with matched placebo, increasing to 82% in just the early Alzheimer’s population.
Overall, 71% of patients treated with LMTX had the same or better global CDR rating after two years compared with 52% for matched placebo. These results were consistent with findings presented at AD/PD 2024 that compared patients from the LUCIDITY trial with historical matched individuals with MCI or Alzheimer’s from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
TauRx submitted a marketing application for LMTX for the treatment of MCI and mild-moderate Alzheimer’s in the UK in July 2024, and in December 2024 the company announced that it had received a request for further information with a response due to be submitted in February 2025. If approved, LMTX has the potential to become the first orally available disease-modifying therapy (DMT) in the UK, and given the status of Eisai/Biogen’s Leqembi (lecanemab) and Eli Lilly’s Kisunla (donanemab) in the UK — approved but not reimbursed — the first widely available DMT. It would also be the first DMT approved that targets tau. Compared with the two approved DMTs, LMTX has several key advantages: not only is it an oral drug allowing for easy administration that can fit into existing care pathways, LMTX also has a benign safety profile with no risk of amyloid-related imaging abnormalities compared with published placebo frequency.
Ultimately, the success of LMTX will likely depend on clear communication of its efficacy to physicians less familiar with trial results that are not placebo-controlled, with real-world evidence of clinically meaningful benefit for patients also playing an important role in increasing confidence in prescribing the drug.
