As an introduction to this piece, I’ll repeat that what Doc Gumshoe is looking for is credible information about the effectiveness and safety of medical treatment options, mostly drugs, but sometimes other forms of treatment as well. There is an implicit assumption that good news about the safety/efficacy of a drug equals good news about the prospects of the pharmaceutical company that markets the drug, and, of course, good news about the stock price. But what I’ve tried to emphasize many times is that there’s many a slip twixt cup and lip. Biogen remains a strong company even after the FDA severely pruned its approval of Aduhelm, but I bet lots of people lost lots of money guessing that its rocket-propelled rise would continue. So, please know that what I’m dispensing is not primarily investment-related. It probably has some impact on investment, but a lot of other factors – factors that I know zero about – have a lot more impact. With that in mind, please read on.

Most of the questions that I’m attempting to respond to came up in the Alzheimer’s disease piece that posted about a month ago, which makes sense, since AD is certainly a concerning matter, and there’s no definite treatment option that makes a definitive difference. The one question to which I have no answer – not the merest hint of an answer – concerns the drug that has been hailed as “the Holy Grail of medicine” by no less a body than the Nobel Committee. Despite extensive Googling, I have not been able to trace that quote to its source. I have no idea which drug it might be.

Lots of drugs and treatments have, at one time or another, been given the Holy Grail accolade. For instance, stem cells; implanting pig organs in human patients; the discovery of the hepatitis C virus; and neutraceuticals. Take your pick. I’m guessing that the quest for the Holy Grail will go on and on and on.

As for the drugs that I’ll discuss here, none of them come close to Holy Grail status, but some are more interesting than others.

HMTM from TauRx Pharmaceuticals

HMTM is hydromethylthionine mesylate, the most recent formulation of methylene blue, which has been the basis of TauRx’s drug development program since its inception as a pharmaceutical company. Before HMTM there was TRx0237, which was a slightly different methylene blue formulation – leuco-methylthioninium bis-hydromethanesulfonate, if you need to know – also known as LMTM.

In the most recent Doc Gumshoe about Alzheimer’s, I did a last-minute add-on to highlight the latest news about the LUCIDITY trial, which was a Phase 3 trial in HMTM. Preliminary results from that trial, announced a little over a month ago, suggested that cognition in participants receiving the drug declined at a rate substantially lower than is typical in patients with Alzheimer’s, based on published research. The safety profile was positive. These results were based on a 12-month follow-up period in the blinded phase of the trial, which involved 598 subjects. The 12-month double-blind period will be followed by a one-year open label phase.

What is especially interesting about the TauRx drugs is that these drugs are aimed not at amyloid beta (Aβ), which is the target of most of the Alzheimer’s candidate drugs, but at the tangles formed by tau protein. The essential difference between the amyloid beta and tau protein hypotheses is that the Aβ structures impede communication between neurons by congregating in the synapses, whereas tau protein fibrils lead to neuron death by forming tangles in the axons that are the conduits for nourishment for neurons.

When the normal chemical structure of tau protein is altered by the addition of extra phosphorus radicals, it forms tangles of fibers inside neurons, and in particular, in the axons that connect neurons with the central nervous system. This is fundamentally different from what Aβ does, which is to accumulate in sheets in the space between synapses and prevent the passage of information from one neuron to the next. The damage wreaked by tau neurofibrillary tangles (these are now commonly abbreviated NFTs) consists in particular of starving neurons of nourishment, which is transported via the axons.

In brief, Aβ works its mischief outside the neurons, while tau kills neurons from within. That is the mechanism that the TauRx agents target. HMTM and TRx0237 are both derivatives of a fairly common compound, methylene blue, which has been used for the treatment of 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 researchers are working on variations of the compound to improve absorption and distribution.

The early clinical trials in these compounds have been definitely encouraging. One study in particular reported a highly significant (P < 0.001) increase in cerebral blood flow in patients with mild Alzheimer’s. In that Phase 3 study, which involved over 1,900 patients, TRx0237 was found to reduce both cognitive decline and brain atrophy. These benefits varied, depending on the amount of the agent that was absorbed; thus the modification of TRx0237 leading to the present formulation.

Based on the current results of the on-going LUCIDITY trial, the UK Medicines & Healthcare Products Regulatory Agency (MHRA) granted TauRx an Innovation Passport, which is the first stage of Innovative Licensing and Access Pathway (ILAP), which is intended to accelerate development and approval times.

About the company TauRx Therapeutics

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.

The most prominent advocate for the tau hypothesis is Prof. Claude M. Wischik, of the University of Aberdeen School of Medicine and Dentistry, and also of TauRx Therapeutics. He is unabashedly scornful of the Aβ hypothesis, and outspokenly positive about the prospects for TRx0237. For a taste of his rhetoric, here’s a bit from his paper in Biochemical Pharmacology (88: 2014):

“A recent meeting hosted by the New York Academy of Sciences had the title: “A Truce in the βAP-tist/Tau-ist War?” A truce only needs to be called when one side no longer sees any hope of outright victory. The extraordinary history of repeated clinical trial failures at phases 2 and 3 based on the β-amyloid hypothesis does suggest a need for βAP-tists to find a way out of an untenable situation. For long-term Tau-ists such as the authors, it is early days in the campaign, as we are only conducting the very first tau-based phase 3 clinical trial. It would be understandable that we would see no need for a truce at this stage.”

Dr Wischik is not content with expressing his support for the tau hypothesis – which, after all, is to a considerable degree his baby. No, he also takes out the cudgels and wallops the Aβ hypothesis (he’s calling it beta amyloid, βA for short, and thus the “βAP-tist/Tau-ist War”). The paper I cited above lists 27 clinical trials targeting aspects of the Aβ hypothesis, and marking most of them as “failed.” Yes, it is true that most of these trials failed to meet their objectives, but that certainly does not put the Aβ hypothesis to rest. A distinct possibility is that by the time the subjects in these trials started treatment, the accumulation of Aβ had reached the point where prevention or slowing of further accumulation would not make much difference. One of the problems with treating AD is that by the time symptoms appear – that is, overt signs of dementia – treatment that addresses Aβ may just be too late. I do not accept Dr Wischik’s premise that the advocates of the Aβ hypothesis need “to find a way out of an untenable situation.”

This is not to say that the evidence for the tau hypothesis is not reasonably good. The evidence that the neurofibrillary tangles really do starve neurons of their necessary nourishment is very solid. The process has been observed many times by researchers who are not part of TauRx. The methylene blue derivatives thus far developed demonstrate a clear beneficial effect on improving cerebral blood flow as well as slowing cognitive decline and brain atrophy. We’ll see where it goes from here.

At this point, TauRx Therapeutics is privately held.

(ed. note: There are at least two publicly-traded companies that own stakes in TauRx, if you’re curious — the very small and mostly mining-focused merchant banking company Dundee (DC.A.TO in Canada, DDEJF OTC in the US) owns 3.7% of TauRx, and the Malaysian gaming company Genting Berhad (GEBHY for the US ADR) owns a little over 20% of TauRx… it is not the primary focus of either company, but Genting, in particular, often sees at least a bit of a share price reaction when there’s big news out of TauRx).

Anavex 2-73 (blarcamesine) from Anavex Life Sciences

The first time Doc Gumshoe wrote about Anavex (AVXL) was in a piece that posted on December 21, 2015. That was more than six years ago. Here’s what I said back then:

Anavex 2-73, from Anavex, has been discussed by Travis on a couple of occasions in the past. The company keeps proclaiming that their drug does wonders in enhancing cognition. In the opinion of the ever-skeptical Doc Gumshoe, their claims are hooey. For example, this past month they announced – to great fanfare – the results of a small uncontrolled clinical trial in which they gave about 50 patients their drug, following which they gave them the usual tests of cognition. The patients did a little better, but there is no way of knowing whether this was because of the drug or a placebo effect. All of the patients in the trial got Anavex 2-73, and it would be entirely to be expected if these patients, pleased and excited to be in a clinical trial of an exciting new drug, actually did do a little better on those instruments. The absence of a placebo group ramps up my skepticism quotient by a factor of ten at least, and the ballyhoo of their announcement by another ten. Anavex has another candidate, Anavex 3-71, which targets the same receptors. So far it has been tested in mice only. This is a Wait and See proposition.

Anavex 2-73 is still their lead drug and it is still in relatively early-stage clinical trials. Interim results of trials in Rett syndrome and Parkinson’s disease are being released. For example, the company released what they described as highly positive results from a Phase 2 trial in 132 patients with Parkinson’s. The measures used to judge the results were scores on the Movement Disorder Society’s United Parkinson’s Disease Rating Scale, and the patients taking Anavex 2-73 increased their scores by about 11 points, or 18.9% from baseline. The scores of patients taking placebo declined by about 3.5 points from baseline.

The drug’s target is a receptor called SIGMAR1, which is involved in the transport of lipids and proteins within the cell and plays a role in the development of neurodegenerative diseases. In addition to Rett syndrome and Parkinson’s, SIGMAR1 is involved Alzheimer’s, infantile spasms, and two relatively rare syndromes, Angelman’s and Fragile X.

Anavex recently issued a press release touting the success of Anavex 2-73 in Rett syndrome, which primarily affects girls and young women in such areas as general mood, breathing problems, hand behaviors, body rocking, and repetitive face movements. The trial was originally a Phase 2 trial, but in the two weeks prior to the press release, they changed it to a Phase 3 trial and changed the endpoints on the FDA’s clinical trial database. Before the edits, Anavex was evaluating the drug’s efficacy based on pharmacokinetic activity and plasma concentration. But when they saw the results – 72.2% over-all symptom improvement in the cohort taking Anavex 2-73, and 38.5% in the placebo arm – they decided to change the endpoints and elevate the trial to Phase 3.

Outside observers point out that changing endpoints in the course of a trial may have unpredictable effects on the outcomes. The measurement of symptoms such as the typical Rett symptoms was likely less rigorous than if symptoms had been the primary endpoint. Also, the high percentage of symptom improvement in the placebo arm casts doubt on the attribution of the symptom improvement in the treatment art to the active drug.

Some critics have voiced their concern that the FDA may be unduly swayed by the fact that Anavex 2-73 targets a previously ignored receptor, SIGMAR1, and may be moved to grant premature approval to the drug, much as the FDA approved aducanumab/Aduhelm based not so much on the benefits it brought to Alzheimer’s patients, but to the fact that it targeted BACE rather than the usual AD targets. As you may remember, the FDA’s initial approval of Aduhelm was considered by many (including Yours Truly) to be a blunder.

From where Doc Gumshoe sits, Anavex is still a wait-and-see proposition.

Viagra and dementia

Viagra, as nearly everyone on Planet Earth knows, is a drug meant to prevent erectile dysfunction (ED) and thereby facilitate sexual intercourse. Why should this drug – sildenafil – or any of its cousins such as tadalafil, vardenafil, avanafi and others, have an effect on cognition?

The evidence that Viagra does have such an effect comes from a study published around six months ago in Nature Aging. The study was based on claims data from 7,230,000 men, and a conclusion was that men taking Viagra were 69% less likely to develop Alzheimer’s diseases, which is the most common form of dementia.

The mechanism through which Viagra and its related ED drugs produce erections is straightforward: vasodilation – relaxation of the constricting effect of the veins and arteries in the penis, allowing them to fill with blood and thus producing an erection. The ED drugs may also be used to treat arterial pulmonary hypertension by means of the same mechanism. So if the ED drugs work by increasing blood flow to the lungs and the penis, might they also work to increase cognition by increasing blood flow to the brain?

The current ED drugs are members of a class known as phosphodiesterase 5 (PDE5) inhibitors, which function as donors of nitric oxide (NO). Nitric oxide in turn increases levels of cyclic guanosine monophosphate (cGMP), which is the messenger that controls the erectile process. Using the NO / cGMP connection has demonstrated some cognitive benefits in mice, and research is currently underway to develop NO donors that pass the blood-brain barrier more effectively than the current generation of ED drugs and might therefore be more effective as anti-Alzheimer’s drugs.

But if men who take Viagra are already 69% less likely to develop AD than men who do not take Viagra, why not just use Viagra and the other PDE5 inhibitors as anti-Alzheimer’s drugs?

An answer – perhaps not the answer, but an answer – is that the results of that study in 7-plus million men are open to question. This was not a study in two comparable groups, where other possible differences that might affect the outcome were adjusted. There were two cohorts – one took Viagra, the other did not. Did the not-Viagra cohort not require an ED drug because they mostly did not experience ED, or did they not require an ED drug because they did not have much sexual activity? The Viagra users, one would assume, were apt to be younger and more sexually active, and probably more physically fit. These were medical claims data-bases, remember, and would probably skew to an older population.

In any case, when drugs are taken for different purposes, there frequently have to be adjustments in dosage, and sometimes in the formulation of the drug itself.

However, despite these reservations, on balance the information is pretty encouraging. We should look for further developments along those lines.

Cassava’s simufilam and testimony from Hilary Metz

In my June 22 posting about Alzheimer’s disease, I discussed simufilam and some distinctly negative assertions about Cassava Sciences (SAVA), including this:

“Cassava has been the subject of citizen petitions requesting FDA action to halt simufilam trials, alleging research misconduct having to do with clinical trial biomarker data. In 2021 several independent scientists reported instances of data manipulation in published studies. Cassava denied wrongdoing, but admitted to errors in a poster. In March of this year, the journal PlosOne retracted five papers by a Cassava academic collaborator named Hoau-Yan Wang, and in November of 2021 the journal Molecular Neurodegeration retracted a paper, also by Wang.

The sole clinical trial in which simufilam was reported to produce positive results in cognition has been criticized on the ground that it lacked a placebo group, and also that the patients with Alzheimer’s were not followed long enough to confirm that the reported improvements in cognition were genuine.”

In response to this, a reader posted a suggestion that I look/listen to an interview with Hilary Metz, whose father (at the time of the interview, which was about six months ago) was in a simufilam open-label trial of persons with Alzheimer’s. Ms Metz’s description of how her father was doing on simufilam seemed honest, open-minded, and by no means one-sided. In her view, her father was on the whole doing better, although there were certainly worse days among the better days. She expressed concern that when if trial morphed into a placebo-controlled phase, her father would wind up in the placebo cohort and the benefits from simufilam would cease. She acknowledged that simufilam was not going to cure her father’s AD, but she expressed confidence that treatment with simufilam would slow the progression of the disease such that she and her mother would have perhaps five or even ten more years of connection with her father.

Ms Metz expressed considerable anger at a writer for The New York Times who wrote an article about Cassava, in particular what the article described as Cassava’s misconduct. Ms Metz was outraged that the writer showed no interest in contacting any of the participants in the simufilam clinical trial, but kept the focus on the alleged misdeeds of the pharmaceutical company. She characterized the writer as simply obeying the commands of the newspaper to blacken Cassava’s reputation without admitting that their lead drug might be doing some good.

I have been a daily reader of the Times for many, many years, and I don’t think the paper had it in for Cassava when it published that piece. The Times regularly reports on business matters, including those occasions when a company releases news in an effort to produce an immediate effect on its stock price. As Stock Gumshoe readers certainly know, that kind of thing happens all the time. In Cassava’s case, the Times focused on the validity of the news that had contributed to the steep (and temporary) peak in Cassava’s stock price – certainly a legitimate topic of journalism.

This is not to say that simufilam might not deliver some genuine benefits to patients with Alzheimer’s.

INmune Bio

INmune Bio (INMB) has three drug candidates, all in fairly early clinical trial stages. The company’s website states that their focus is on harnessing the innate immune system to treat cancer; however, they state that one of their drugs, XPro1595 may possibly be useful in treating Alzheimer’s disease.

Their leading candidate at this moment is INKmune, which, according to their statement, primes natural killer cells (NK cells, thus the name INKmune) to attack cancer cells. They point out that NK cells are typically primed by one of the proteins in the interleukin group – IL-2, IL-12, or IL-15 – but that in some cancers, this process sometimes fails. INKmune has been developed to compensate for that deficit.

Another candidate is INB03. This drug is a protein biologic, developed to reverse resistance to trastuzumab (Herceptin, from Genentech), which is widely used to treat HER2 positive cancers. At this point INB03 is in trials with animals only.

INMune Bio was invited to present data at the HER2 Targeted Therapy Summit in Boston, starting on June 16th.

A third candidate is XPro1595, which targets a soluble form of tumor necrosis factor, sTNF. TNF has been implicated in the pathogenesis of some neurological diseases such as Alzheimer’s. On June 22, the US Patent and Trademark Office issued a patent on XPro1595 for the treatment of central nervous system diseases. (As I have pointed out, the interval between the patent on a drug and approval to market it can be lengthy. The patent prevents pirates from stepping in and beating the original developer of the drug to the payoff. And without doubt, there are pirates out there, on the lookout for opportunities to take advantage of a drug developer’s early and unprotected research.)

As you can see, all three of these candidates are in early stages of research and development. Clinical Trials.gov lists a total of four trials for INmune Bio’s candidates – one completed, one terminated, one recruiting, and one not yet recruiting. The completed clinical trial was a search for TNF as a biomarker in Alzheimer’s and did not evaluate the effectiveness of XPro1595, but did confirm TNF in Alzheimer’s patients.

It’s impossible to predict the progression of any of these candidates. INmune Bio is very cautious in its statements, as can be seen from the following excerpt from their company website:

“Clinical trials are in early stages and there is no assurance that any specific outcome will be achieved. Any statements contained in this statement that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. Any forward-looking statements contained herein are based on current expectations but are subject to a number of risks and uncertainties. Actual results and the timing of certain events and circumstances may differ materially from those described by the forward-looking statements as a result of these risks and uncertainties.”

Doc Gumshoe’s take on INmune Bio is on the whole positive. Clearly, it will be a while before definitive results emerge, but the mechanisms that they are targeting are rational, and the way they are proceeding with their quest is promising. It’s definitely worth keeping an eye on this outfit.

ProMIS Neurosciences

The focus of ProMIS Neurosciences (PMN) is on misfolded proteins as a basic cause of neurodegenerative diseases, in particular Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD). ProMIS made a poster presentation at the American Academy of Neurology Annual Meeting in Seattle which took place in early April 2022. The subject of the presentation gives us a clue as to the complexity of the research that ProMIS is undertaking: “RACK1 Knockdown Alleviates TDP-43-Associated Global Translational Suppression in vitro and Neurodegeneration in vivo”. Sleuthing a bit, I learned that RACK1 is the Receptor of Activated C-Kinase. C-kinase is an enzyme, creatine kinase, which has a number of vital functions. TDP-43, in turn, stands for TAR DNA-binding protein 43, which is involved in the regulation of RNA processing. TAR is a gene sequence.

If you made it through that paragraph, you probably arrived at the same conclusion that I did: that ProMIS is doing research at the extreme boundaries of biotechnology.

Misfolded proteins have essentially the same composition as properly folded proteins, which are folded into a specific shape so that the molecules that make up the protein readily present to the physiologic organs whose function they enable. Misfolded proteins expose toxic portions of the protein, causing potential damage to the organs with which they come into contact.

ProMIS states that they have over 75 patents (issued or pending) for disease-specific misfolded protein targets and for monoclonal antibodies that selectively target those toxic bodies called “oligomers” that are associated with the development of several neurodegenerative diseases, including Alzheimer’s, ALS, and Parkinson’s. Oligomers consist of a few individual molecules, or monomers, while polymers are large complex structures consisting of many monomers.

These are among ProMIS’s planned ventures:

• Developing a safe and effective vaccine against Alzheimer’s disease is a principal objective. The strategy is to induce a specific immune response against toxic Alzheimer’s oligomers. ProMIS is collaborating on this project with the Vaccine and Infectious Disease Organization of the University of Saskatchewan.
• PMN267 is a project to target misfolded forms of TDP-43, mentioned above. ProMIS states that TDP-43 is implicated in the development of amyotrophic lateral sclerosis (ALS), known to some of us as Lou Gehrig’s disease. ProMIS also says that their ALS therapeutic programs target TDP-43 and have shown potential benefits in combating disease progression.
• Another project is to identify drug candidates that show high selectivity for misfolded alpha-synuclein, which some studies have indicated plays a key role in the development of Parkinson’s disease and other neurodegenerative disorders.

ProMIS is evidently wagering that misfolded proteins will turn out to be root causes of those neurodegenerative diseases. Needless to say, the misfolded protein theory has a lot of competition, including genetics, environmental factors, the amyloid beta and tau theories in Alzheimer’s, and others. A statement from ProMIS is as follows:

“The Company’s proprietary target discovery engine is based on the use of two complementary computational modeling techniques. The Company applies its molecular dynamics, computational discovery platform -ProMIS™ and Collective Coordinates – to predict novel targets known as Disease Specific Epitopes on the molecular surface of misfolded proteins.”

ProMIS is headquartered in Toronto, Ontario, with offices in Cambridge, MA.

I was not able to get information about ongoing or planned clinical trials conducted by ProMIS. The search is hugely complicated by the fact that PROMIS is also the acronym for NIH’s Common Fund’s Patient Reported Outcomes Measurement Information System.

Doc Gumshoe’s enthusiasm meter is pointing in a somewhat positive direction in relation to ProMIS. Misfolded proteins are real, and the way molecules work in our physiologic systems depends a good deal on physics – the shape of the molecule, which little bits stick out and which bits are concealed. And of course, the electric charges of those bits. If the wrong bits stick out and the right bits are hidden because the molecule is folded not how it’s usually folded, it could well cause significant harm. ProMIS seems to be going about the research carefully and with purpose. Major results should not be expected in the near future, but we’ll keep our eyes and ears open.

* * * * * * *

You may notice that I left out a few of the subjects that readers posted questions about. They will have to wait until another posting. For the next Doc Gumshoe piece, I’m planning to address the gigantic and consequential topic of inflammation – not so much the acute inflammation that occurs when we sustain an injury, but the chronic inflammation that we live with for a range of reasons, and that can have a distinctly harmful effect on many aspects of our lives. However, whatever questions and comments this current epistle stirs up, please pass it along. Best to all, Michael Jorrin (aka Doc Gumshoe)