ABERDEEN, Scotland and SINGAPORE, 1 June 2015 – With the publication of a key article in The Journal of Biological Chemistry, TauRx Pharmaceuticals Ltd. continues to build a growing body of evidence supporting the rationale for tau aggregation inhibition in the treatment of neurodegenerative diseases such as Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD). This latest of six connected papers, five of them published in the past six months describes the robust scientific research programme behind the development of LMTXTM, the second-generation tau aggregation inhibitor (TAI) currently in three large global Phase 3 clinical trials.
“Taken together, these six papers reflect more than 10 years of clinical and preclinical research dedicated to discovering more about the genesis and relentless spread of the tau pathology through the brain of AD patients,” said Dr. Charles Harrington, Chief Scientist of TauRx and lead author of the latest article, “Cellular models of aggregation-dependent template-directed proteolysis to characterize tau aggregation inhibitors for treatment of Alzheimer’s Disease” (Harrington et al., Journal of Biological Chemistry 2015, 290/17: 10862-10875). “Together, they provide a strong basis for our belief that LMTXTM should be capable of affecting the course of the disease, reducing the rate of spread of the pathology and potentially permitting an improved quality of life to these patients as well as to their immediate families and their caregivers.”
Professor Claude Wischik, co-founder and Executive Chairman of TauRx and lead author of two of the articles, said: “Since the completion of our Phase 2 studies and the announcement of our highly promising results back in 2008, we have been working towards our goal of bringing forward a tau-targeted approach into final stage clinical trials. Now these publications provide the long-awaited data from our efforts, which collectively chronicle that journey.”
Despite the strong efficacy signals seen on clinical and functional molecular imaging endpoints at the minimum effective dose in the Phase 2 study, a major confounding issue was the apparent failure of response at the highest dose. “This took a considerable body of work to resolve, and publishing the Phase 2 results without fully explaining the dose-response problem would simply have clouded the issue,” he explained. “As we have now shown in Baddeley et al. (2015), the underlying problem is that the bioavailability of the active methylthioninium (MT) moiety is limited when it is dosed in the oxidised MT+ form, as we did using the chloride salt (methylthionium chloride, MTC, commonly known as ‘methylene blue’). With further work, we were able to show that the minimum effective dose of 138 mg MT/day was simply the highest bioavailable dose administered in the Phase 2 study. Solving this problem then permitted us to publish the Phase 2 data in full as Wischik et al. in the Journal of Alzheimer’s Disease (2015).”
This then led to the question of how to provide MT in a form with better bioavailability and tolerability. “We were able to show that the problem is the redox state of the MT moiety, and we had to discover how to produce MT in a stable reduced form, which we have done with our second-generation TAI, LMTXTM,” he said. “This is a novel chemical entity that is able to deliver MT to the brain more efficiently.” The discovery, synthesis and biological characterisation of LMTXTM forms the main subject of the most recent paper (Harrington et al., 2015). “We were also able to define for the first time the critical concentration of MT required for it to act as a Tau Aggregation Inhibitor (TAI).” It turns out that this concentration (~ 0.15 µM) is very close to the steady state brain concentration the team reported in Baddeley et al. (2015) at the minimum effective dose of 138 mg MT/day (0.18 µM). This concentration also overlaps the brain concentrations required to reverse both the pathology and the behavioural deficits in the two new tau transgenic mouse models they developed and reported (Melis et al., 2015a, b).
“The story we have to tell is unavoidably complex and the amount of research work that our multidisciplinary scientific team has undertaken to understand and explain the story has been enormous,” Professor Wischik said. “Rather than send this information out in parts over an extended period of time through several disconnected updates, we made a conscious decision to wait until we could assemble the critical pieces of the jigsaw into a coherent whole. The body of papers we have now published supports our central contention that abnormal aggregation of tau protein is the main driver of clinical dementia, and that LMTXTM provides the first fully viable TAI as a novel basis for treatment and prevention of AD.”
He added: “In about one year’s time, we should know whether the first two of our three Phase 3 studies to complete have generated the data that will support our claim that LMTXTM could be the first truly disease-modifying drug for AD. Looking forward to what we believe will be a successful outcome, 2015 will be the last year in which it is possible to argue a strong version of the amyloid-? theory, and 2016 will mark a need for a fundamental paradigm shift in regards to both treatment and prevention of AD. Until then, we plan to prepare the ground for this shift and to continue the task of sharing our research output with the AD research community via our 2015-2016 publication programme. We anticipate that this will comprise a further 4-5 papers covering additional work in the areas of the pharmacokinetics and mechanism of action of LMTXTM.”
The six publications, now available on the TauRx website at www.taurx.com, are as follows:
About TauRx Therapeutics Ltd
TauRx Therapeutics Ltd is a spin-out company from the University of Aberdeen, Scotland, and was established in Singapore in 2002 with the aim of developing new treatments and diagnostics for a range of neurodegenerative diseases. The company’s tau aggregation inhibitor, LMTXTM, is currently in global Phase III clinical trials for Alzheimer’s and Frontotemporal Dementia (FTD). LMTXTM targets aggregates of abnormal fibres of tau protein that form inside nerve cells in the brain, giving rise to ‘tau tangles’. TauRx’s primary research facilities are headquartered in Aberdeen. For more information, please visit: http://www.taurx.com.
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