Catscratch is this our company? >What about TauRX?
Doc Gumshoe first discussed TauRX back in December 2015, and has kept track of that company and its approach to the treatment of Alzheimer’s disease in several postings since then. I’ll summarize and update.
As you surely know, there are two competing doctrines about the cause of Alzheimer’s disease – amyloid beta (Aβ) and tau protein. The essential difference between Aβ and tau protein is that while the Aβ structures impede communication between neurons by congregating in the synapses, tau protein fibrils cause neuron death by forming tangles in the axons, which are the conduits through which neurons obtain nourishment. In brief, Aβ does its dirty work outside the neurons while tau protein kills neurons from within by starving them.
A leader in the search for an agent that prevents or at least slows tau protein aggregation is TauRX Therapeutics, Ltd, of Aberdeen, Scotland. TauRX is a biotech spun off from the University of Aberdeen in Scotland, where its clinical trials are being conducted, although its official headquarters are based in Singapore, likely for tax reasons. Their Alzheimer’s disease (AD) candidates are derived from a parent compound, methylene blue, which has been around for decades, and which has been used to treat malaria and methemoglobinemia, a blood disease in which normal hemoglobin is replaced by a form containing ferric rather than ferrous iron, which is less able to transport oxygen. TauRX’s first formulation based on methylene blue (methylthioninium chloride) was Rember, which has been replaced by a successor, LMTX, formerly labeled TRx0237. LMTX and Rember have the same mode of action, but LMTX is a stabilized, reduced form of the parent compound in order to improve the drug’s absorption, bioavailability, and tolerability. Rember and LMTX, as well as the current successor, LMTM, are tau-aggregation inhibitors (TAIs).
The most prominent advocate for the tau hypothesis is Prof. Claude M. Wischik, of the University of Aberdeen School of Medicine and Dentistry, who is also the founder of TauRX Therapeutics. He is unabashedly scornful of the Aβ hypothesis, and outspokenly positive about the prospects for LMTX/LMTM. He points out that clinical trials of agents that target Aβ have failed time and again. On the other hand TauRX’s tau-aggregation inhibitors have been reported to have positive results in a number of clinical trials and at several different dosages.
In trials designated as TRx-015 and TRx-005, analysis of the results demonstrated that patients who were taking LMTM as monotherapy experienced a significant decrease in disease progression in comparison with placebo, and the rate of brain atrophy diminished by 33% and 38% respectively in the two trials. In another trial, a subset of patients with mild AD experienced a highly significant difference (P < 0.001) in cerebral blood flow, which is essential to neuronal function. While TauRX presses ahead with clinical trials in their proprietary formulation of methylthioninium, researchers are tinkering with the basic molecule to try to find structures that have a better pharmacodynamic profile – i.e., permit better absorption and reach higher concentrations. These are characteristics that lead to better efficacy.
Both trials also determined that the benefit of the 8mg/day dose, originally given to the control cohorts, was similar to the higher doses and had fewer side effects. To confirm whether there is a benefit to LMTM as a monotherapy, TauRX is currently running another Phase II/III trial called LUCIDITY investigating two low doses (8 mg and 16mg) of LMTM vs. placebo. The trial is looking to recruit 375 participants with early Alzheimer’s disease. It employs FDG-PET imaging and a composite cognitive/functional clinical psychometric scale to confirm the efficacy of LMTM. In this study LMTM is given as a monotherapy at doses of 8 mg/day (taken as 4 mg twice daily), and a slightly higher dose of 16 mg/day (taken as 8 mg twice daily) which is considered to be the optimal dose, is also being tested. Both doses are compared with placebo. Results of the blinded phase of the trial are expected by mid-2022.
Early studies with Rember/LMTX showed that the absorption of the active component of the drug is somewhat limited when given in combination with food. The finding led to the development of the second generation tau-aggregation inhibitor, LMTM, which does not require conversion to the absorbable form, and has greater efficacy than the previous version.
In many of the earlier clinical trials, LMTX was given along with another drug that aims to reduce Aβ deposits in the brain. A recent finding is that the concurrently given drug has the effect of promoting the excretion of LMTX, thereby lowering the concentration and limiting its efficacy. A clinical trial has been underway in which LMTX is given as monotherapy, so that it remains in the patient’s system to do its work as a TAI. Results were expected to be ready in December 2020, but as yet have not been released.
>Doc Gumshoe has no information about TauRX’s stock, which I’m sure many Gumshoe denizens would be interested in knowing about. However, a Doc Gumshoe reader sent in the following comment:
“TauRx is a private company but there is a way to participate in its eventual success. The largest shareholder of TauRX, and one of its early investors, is a company called Genting Bhd. It is a Chinese-owned Malaysian conglomerate operating in multiple sectors, from palm tree oil to real estate to casinos. The stock is listed on the Singapore and Malaysian stock exchanges (symbol GEBHY) and, with some 20% of TauRX, could benefit handsomely from the latter trade sale or listing. Genting has invested $120m in TauRX over the years. If TauRX is sold for a few tens of billions, Genting would probably make 10x its invested capital. This would more than double the market cap of Genting and therefore double its share price.”
Professor Wischik’s dismissal of amyloid beta as the underlying cause of Alzheimer’s is perhaps a characteristic of the way some scientific investigators function. They formulate a hypothesis, assemble a powerful trove of data to support it, and attempt to disqualify any alternative theories. They tend to defend their own hypothesis until it has been definitively disproved. In a sense, that’s the way scientific knowledge grows: put up your answer to the problem and let everybody else take a shot at it. The hypotheses that survive this process then become accepted science.
The mere fact that to date treatment for Alzheimer’s based on the Aβ hypothesis has not been demonstrated to be successful does not disprove that hypothesis. It has been suggested many, many times that the clinical studies in AD have been done in patients whose disease is too far advanced for the treatment to achieve meaningful results. Some plaque is already present in those patients, and losses in cognition have already taken place. As Doc Gumshoe noted in a piece posted just before Christmas, early detection of the brain changes that precede and predict AD would vastly improve treatment.
My own take on the tau versus Aβ hypotheses is that both have a likely role in the disease process. The Aβ gums up the space between neurons while the tau tangles starve the neurons of nourishment. Neither one rules out the other.