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 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.    

Dr. Dale Bredesen and “The End of Alzheimer’s in our Time”

No, I have not read this book, so I can only comment on the Bredesen protocol – his “ReCODE Program” – based on what I have been able to learn about it from other sources, as well as from a summary by Dr. Bredesen of his thinking about the underlying causes of Alzheimer’s.   

My short take on Dr. Bredesen and his protocol is that he is not a total crackpot.   He has pointed to several factors each of which may in some way contribute to the neurologic changes that cause the symptoms of AD.  He has then formulated a complex protocol that purports to address each of these factors, and gone on to claim that adherence to this protocol will banish Alzheimer’s disease.   In my opinion (and also the opinions of several experts) he has immensely exaggerated his claims, likely for the purpose of selling his protocol for about $1400 per shot – and that’s just for the protocol, supplements and actual treatment are extra.

Bredesen asserts that Alzheimer’s is a protective response to the three basic threats to the brain, these being inflammation, a shortage of essential hormones and nutrients, and toxins in the brain.   Inflammation, according to Bredesen, is caused not only by a response to invading pathogens, but is also (and this appears to be a principal focus of his protocol) a response to foods containing trans-fats, gluten, and – in particular – sugar.    With regard to nutrients in the brain, he mentions brain-derived neurotropic factor (BDNF) as essential.   We may assume that his protocol emphasizes supplements that boost BDNF.   And finally, with regard to toxins, his protocol  includes “identification of the toxic exposure, removal of the source, and then such measures as detoxifying foods such as cruciferous vegetables, hydration with pure water, and sauna-based removal of a specific class of toxins.”       

Dr. Bredesen’s protocol is supported by three papers, which have been to some degree discredited in a paper in Lancet Neurology by Dr Joanna Hellmuth, a neurologist with training in cognitive and behavioral therapy, practicing at the University of California San Francisco Memory and Aging Center.   (Hellmuth J. “Can We Trust The End of Alzheimer’s?  Lancet Neurol 2020;19(5);389-390).   She points out that the evidence upon which Dr Bredesen bases his protocol is suspect.   None of these studies included placebo-controlled trials.   They were not designed to put Dr. Bredesen’s hypothesis to a test, but merely to report that some patients treated by the ReCODE protocol showed some improvement.   They omit details about which elements of the protocol were followed, as well as information about the dose or treatment duration.  They include no mention of participant inclusion and exclusion criteria, and no data on any non-responders.

Furthermore, there is no explanation about how testing measures were conducted and evaluated, so it is unknown whether the improvements in testing scores reflect true changes due to the intervention, or on the other hand chance variations in performance, or practice effect from repeat testing (i.e., the person being tested takes the same test over and over again and gets better at taking the test).  Finally, Dr. Bredesen’s papers were published in journals with scientific sounding names, but little or no editorial oversight.   These journals publish whatever is submitted, but for a fee.   We should note, however, that Dr. Bredesen has published a great many papers in the general area of neurology and Alzheimer’s disease beyond those that he cited in support of his protocol.

Whether this protocol will prevent, or perhaps even reverse AD, is at best a guess.   It doesn’t seem to include potentially harmful supplements or activities, so we might put it in the “might help – won’t hurt” basket, although saunas might be a bit risky for some people.   (The only pain might be in your bank account.)   Overall, the protocol (from what we can learn about it from the outside looking in) seems to line up with the healthy life-style principles that have been observed to contribute to a decreased incidence of AD, whereas a number of factors have been found to correlate highly with AD.   For example, in a previous Doc Gumshoe manifesto, I cited a number of these that had been found to have statistically significant links with AD and dementia, such that a fairly large percentage of dementia could be attributed to these factors.  These included poor education, hearing loss, hypertension, obesity, smoking, depression, physical inactivity, elevated cholesterol, and traumatic brain injury.   And, on the benefit side, a Mediterranean diet appeared, statistically, to minimize AD and dementia.   Incidentally, we should note that nearly all the components of Dr. Bredesen’s protocol can be accessed without a fee.   One should not have to pay a hefty fee to adopt a diet that excludes saturated fats, gluten, and sugar.

Here’s how I summed it up:

“As we review the factors that seem to contribute to Alzheimer’s and AD dementia, a profile of the likely victim takes shape.   She (most likely a woman) is poorly educated (a high-school dropout), obese, a smoker, eats mostly junk food, is physically inactive, and perhaps is afflicted with one or more chronic conditions such as diabetes, high cholesterol or hypertension – conditions which, of course, are more prevalent in obese sedentary smokers.   Our victim is also more likely to be African-American or Hispanic.   She might be able to improve her chances of avoiding Alzheimer’s dementia if she lost weight, quit smoking, joined a gym, and so forth.   But that’s a lot harder than it sounds.

In contrast, consider a very good friend of ours, who is highly educated, trim and fit, a life-long non-smoker who successfully manages his type 2 diabetes through diet and exercise alone.   Nonetheless, he has Alzheimer’s disease, likely due to his genetic inheritance.   He remains highly active and able to participate in conversations, which he ably steers to avoid the gaps in his cognition.   He is receiving one of the very few drugs approved for AD – there are five in all, including one combination, and none of them make any pretense at reversing the disease course or doing anything more than perhaps slowing progression.

I can’t think of a single thing that our friend could have done to prevent the development of AD.   There will certainly be individuals like our friend, who, despite all efforts to the contrary including mental and physical exercises and the healthiest possible lifestyle, ultimately go on to develop Alzheimer’s disease.   But they can probably stave it off and gain more years of living while in full possession of their wits.   In fact, that’s the situation for the rest of us.   What we want is for our mental capacities to remain optimal even as our physical capacities dwindle.”

What about Dr Marik’s COVID-19 protocol?

I’m not going to say a whole lot about this, since it was covered it some detail in my previous piece, which posted on 28 January.   Dr Marik’s protocol, named MATH+, consists of methylprednisolone, ascorbic acid, thiamine, heparin, plus a statin, zinc, vitamin D, famotidine, melatonin, and magnesium.   His group, Front Line COVID-19 Critical Care Alliance (FLCCC) recently added ivermectin to the protocol.   FLCCC promotes methylprednisone instead of dexamethasone on the grounds that it is a more potent anti-inflammatory.   As physicians who directly treat COVID-19 patients, they claim that their protocol “works,” helping many of their patients avoid the most serious symptoms.

Evidence that ivermectin actually works to treat COVID-19 is scarce.   An Australian study reported that the drug stopped replication of the coronavirus in vitro, and a few other studies have reported some benefit.   However, these were not randomized placebo-controlled studies.

Is there anything new about Anavex and blarcamesine?

>My guess is that the question about Anavex/blarcamesine is more about the performance of Anavex Life Sciences (AVXL) stock than about the possible efficacy of their lead drug.   As I keep saying, Doc Gumshoe is extremely reluctant to weigh in on stock performance, and if he should (accidentally) happen to drop any hints about the performance of a pharmaceutical stock, you, dear readers, should ignore it.

As for the potential merits of blarcamesine, which is also known as Anavex 2-73, here’s what is known at present.

There are some indications that blarcamesine may be effective in three disease areas: Alzheimer’s, Parkinson’s, and Rett syndrome.   The drug reportedly binds two receptors in the brain – the sigma-1 receptor and the muscarinic receptor.   It has been demonstrated to have memory-preserving and neuroprotective effects in mice that have been treated to have deficits in those areas.   It has also been suggested that blarcamesine/Anavex 2-73 may block hyperphosphorylation of tau protein, thereby mitigating the adverse effects of those tau tangles.   

Rett syndrome is one of those rare diseases that pharmaceutical companies can sometimes employ as a way into regulatory approval.   At present, there is no cure for Rett syndrome, and it can lead to severe impairment in practically everything that we human beings try to do.   Thus, if blarcamesine were determined to be an effective treatment for Rett syndrome and thereby received FDA approval, it would be a big boost in the effort to win approval for other diseases or conditions.   

The syndrome occurs almost exclusively in very young girls, emerging sometime after six months of age, and persisting through life.   The signal symptom is near constant repetitive hand movements, but it also affects the patient’s ability to speak, walk, eat, and even breathe easily.   The cause of Rett syndrome appears to be any of perhaps 900 different mutations on the X chromosome on a gene called MECP2.   

As I am writing this, Anavex Life Sciences has received Fast Track designation from the FDA for Anavex 2-73 / blarcamesine for the treatment of Rett syndrome.   This designation followed the announcement on 15 December 2020 of a Phase 2 randomized double-blind placebo-controlled clinical trial of blarcamesine in adult female patients with Rett syndrome.   The primary endpoint of the trial was safety, and the oral liquid once-daily dose of the drug was well-tolerated.  Adverse events were similar between blarcamesine and placebo (13.3% vs. 10%).   

All the secondary efficacy endpoints of the trial demonstrated statistically significant and clinically meaningful sustained improvements in the subjects treated with blarcamesine compared with those treated with placebo.   The outcome measures were the Rett Syndrome Behaviour Questionnaire, where the 66.7% of treated subjects demonstrated significant improvement, versus 10% of the subjects on placebo (P = 0.048), and the Clinical Global Impression Improvement Scale, where 86.7% of the blarcamesine-treated subjects showed significant improvement, versus 40% of the subjects on placebo (P = 0.014).

The FDA Fast Track program is designed to expedite the development and review of a new drug to address unmet medical needs in the treatment of a serious and life-threatening condition for treatment of which it demonstrates some potential.  The purpose of the program is to get important new therapies to the patients earlier.

Even before the Fast Track designation, blarcamesine also has an Orphan Drug designation from the FDA for the treatment of Rett syndrome, and may be considered for accelerated approval.   It is currently being evaluated for Rett syndrome in two other placebo-controlled trials: the Phase 2 AVATAR trial in adult Rett syndrome and the Phase 2/3 EXCELLENCE trial in pediatric patients.

In August 2020, Anavex Life Sciences received Special Access Scheme Approval for blarcamesine from the Australian government for the treatment of patients with Alzheimer’s disease, based on the completion of more than 5 years of daily dosing of the drug in AD patients and recommendation by their physicians.   This was based on a Phase 2b/3 trial at 16 sites in Australia which enrolled 450 subjects with mild cognitive impairment or early dementia, plus evidence of Alzheimer’s pathology based on PET scans or cerebrospinal fluid.   The trial assesses concentrations of amyloid β40 (Aβ40) and Aβ42, total and phosphorylated tau protein, and other possible markers of Alzheimer’s disease. 

Blarcamesine is also being studied in subjects with Parkinson disease dementia in a proof of concept Phase 2 controlled trial.   This is the first double-blind study of Parkinson disease dementia; interim results confirm that it is safe and well-tolerated in these subjects.   The multicenter trial is has been reported by Anavex to show “clinically meaningful, dose-dependent, and statistically significant improvements in the Cognitive Drug Research computerized assessment system analysis.”  According to Anavex Life Sciences, the full study results are expected to be submitted for presentation at a medical conference and for publication in a peer-reviewed medical journal.   No date has been set.

A few weeks ago, on January 11^th, it was announced that Anavex Life Sciences received a research grant of $995,862.51 from the Michael J Fox Foundation for Parkinson’s Research to develop blarcamesine for the treatment of Parkinson’s.   According to Anavex, the award will be used to “explore utilization of PET imaging biomarkers to enable measurement of target engagement and pathway activation of the sigma-1 receptor (SIGMAR1) with clinically relevant doses in people with Parkinson’s disease.”  This is the second grant Anavex received from the foundation; the previous grant fully funded a preclinical study that established the drug as a potentially disease-modifying treatment for Parkinson’s.

All the information about blarcamesine cited above comes from Anavex Life Sciences.   Only four published papers mention blarcamesine, one of which confirms that the markers targeted by the drug are indeed associated with Parkinson’s disease.   The other three papers do no more than mention that the drug is under development.   

Doc Gumshoe’s tentative conclusion is that Anavex-2-73 / blarcamesine is indeed a likely prospect for regulatory approval for the treatment of Rett’s syndrome.   The other two potential indications are somewhat longer shots.

What do we know about the quercetin / zincsupplement?

Quercetin is a flavonoid.   Flavonoids, including quercetin, are very widely distributed in plants and foods, including red wine, onions, green tea, apples, berries, to name just a few.   Some flavonoids are plant pigments, accounting for most yellow, red, and blue pigmentation in plants.   If you happen to look up flavonoids in Google, you will need to search diligently to find an honest definition, because what comes up mostly is advertisements for supplements.   My Dorland’s Medical Dictionary also points out that some flavonoids, called “bioflavonoids” have some physiologic properties.   Quercetin is supposedly one of those.

Quercetin is also found in some plants that are the sources of supplements, such as St John’s wort and Ginkgo biloba.   It is commonly taken orally, supposedly to treat a number of health conditions such as heart disease, cancer, arthritis, diabetes, and bladder infections.   Regarding its possible usefulness in treating COVID-19 infections, there are suggestions that quercetin may have some benefit in managing airway infections.   As to whether there is evidence for any of these uses, the answer appears to be that there is none.

Quercetin appears to have antioxidant and anti-inflammatory effects which might be put to use in managing some health conditions.   However, its usefulness is severely limited by some of its properties, specifically that it is very poorly absorbed, and that even the small fraction of the oral dose that is absorbed is then quickly and extensively metabolized and eliminated.  In other words, almost all of the quercetin that we ingest doesn’t stay in our bodies long enough to be of any use.

In an effort to compensate for this deficiency, some drug-makers have created a quercetin-zinc complex in the hopes that it would have superior pharmacokinetics, meaning those characteristics such as absorption, half-life, metabolism and excretion.   The quercetin-zinc complex has been investigated with regard to its effect on bladder cancer cells in vitro.   This is not the same as an investigation of its effectiveness is actually treating bladder cancer in a human patient.

The results of that investigation were that the quercetin-zinc complex significantly reduced the cancer cell’s ability to migrate and invade other cells (P < 0.05).   Also, the complex was able to kill more than 50% of bladder cancer cells after 24 hours of treatment (P < 0.05).   The authors of the study concluded that the quercetin-zinc complex could serve as a feasible tool for both anti-cancer and anti-metastasis on human bladder cancer cells.   (Lee, Y-H. In Vitro Cell Dev Biol Anim./2019 June;55(6):395-404.doi: 10.1007/s11626-019-00363-2.).

Doc Gumshoe would be hard pressed to venture an opinion as to whether these quercetin-zinc complex tablets would actually do any good in combating bladder cancer.   The effectiveness of the complex as cited in the study quoted above was based on the dose, and packaged supplements are sometimes unclear (and even deceptive) about such matters as dosage and what they actually contain.   If the quercetin-zinc supplement were to be scrupulously compounded and honestly packaged, it might indeed be beneficial.   And since current treatment options for bladder cancer are, to put it mildly, not attractive, the quercetin-zinc complex is something to keep an eye on. 

* * * * * * *

Inevitably, Doc Gumshoe will be returning to the subject of COVID-19, which looks as though it will continue to be with us for most of the rest of this year.   I will be looking at the situation with the different vaccines, which now include Novavax and the AstraZeneca / Oxford vaccine as well as the Russian Sputnik V and several others, and not only how much immunity they confer, but what kinds of immunity, and how it may vary.   Thanks for all the comments / questions.   Be well and stay well!   Best, Michael Jorrin (aka Doc Gumshoe)