Doc Gumshoe’s Responses to Comments and Questions

Alzheimer's Disease, COVID protocols, Quercetin and more...

By Michael Jorrin, "Doc Gumshoe", February 11, 2021

Many of the comments to these Doc Gumshoe pieces go like this: “What do you know about such-and-such a drug, or about what this or that person (usually a physician) has to say about cancer, or heart disease, or (especially these days) about COVID-19?” My right-off-the-bat response to most of these would usually be “not much.” Or, possibly, “never heard of it (or him/her).” So I have to do some sleuthing.

Sometimes the queries seem to be more about the prospects for a stock than about a drug or a form of medical treatment. In those cases Doc Gumshoe should, by all rights, remain mum, since insights or expertise about the stock market are definitely not his strong suit. In those matters, Doc Gumshoe defers to Travis, who decidedly knows what he’s talking about.

Here’s a brief digression. One would suppose that if there should happen to be early indications that a new drug is effective at treating a disease – especially if that disease affects lots of people and there isn’t a readily-available first-line treatment option – that would be excellent news for the pharmaceutical outfit that makes the drug, and its stock would go zooming. Yes, one would suppose that, but one might be quite mistaken.

Quite some time ago I got an assignment from a pharma company to produce physician training material on the subject of juvenile rheumatoid arthritis. They had a drug in early stages – Phase 2 trials underway, and interim results were quite promising. They were ramping up to launch a Phase 3 trial, huge and expensive, and to generate ancillary material about the disease to bring pediatricians and general practitioners into the tent. Then, bad news about this Phase 2 trial came trickling out, specifically that the some of the young people that were enrolled in the trial had experienced suicidal ideation. No actual suicides, but the suicidal ideation data was enough. The Phase 2 trial was stopped, the Phase 3 trial was never launched, my client’s stock plummeted, and I only collected about a third of my fee.

On the other hand, also quite some time ago, I did some work for Gilead (GILD) when they were first bringing their HIV drugs to market. We eventually did buy some Gilead stock, but not until after it had experienced its initial zoom. As I have said more than once, when it comes to the stock market I am a babe in the woods.

So now for some recent questions posed by Doc Gumshoe readers.

>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 clin