Here are some responses to your recent questions and comments. As I’ve said before, I’m very appreciative of your questions and comments – they keep me connected to a real world that is not so focused on theoretical, far-off potential treatments and cures. However, my responses to some of your questions do often rely on data that might be viewed as a bit theoretical, e.g., the drug that improved cognition in mice was demonstrated by the ability of the treated mice to find their way through a labyrinth and arrive at the cheese more quickly than the untreated mice. Some folks might say that maybe all the drug did for the mice was improve their sense of smell. Still, the drug makers have to start from somewhere. They require data to proceed with the expensive process of developing and testing a drug, and those data are what Doc Gumshoe looks at.

This being the Stock Gumshoe planetary system, it should not surprise me that many of your questions seem to point to whether the stock of a pharmaceutical outfit is worth a bet. As I have said many, many times, Doc Gumshoe does not venture into those waters. We (my spouse and I) have invested in pharmaceutical stocks a few times, but always with safety and security in mind.

As you surely know, the stock price of a pharmaceutical company goes all over the place in response to what frequently amounts to no more than trickles of news, and often that news comes in the form of statements by the pharmaceutical company itself or by “involved parties,” such as people who were actively involved in the research and other insiders. I do not need to belabor the point that insiders can be handsomely rewarded for disclosing news that has positive implications. Sometimes this works out just fine. The positive news bits are followed by more positive news bits, and they win the hand of the princess and live the rest of their lives in the castle. Other times, not so fine.

The most urgent request came from a reader who took me to task for not keeping up with Anavex and its lead drug, Anavex 2-73, blarcamesine. In my brief response in the comments thread, I noted that I had in fact discussed Anavex in previous posts, and that I would do so again when there were new data.

So, here’s an update on Anavex:

Doc Gumshoe first mentioned Anavex in a piece on December 21, 2015. 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.”

As news releases about Anavex and blarcamasine emerged, I noted them in my posts, generally with a similar skeptical tone. Here’s the most recent Doc Gumshoe discussion on that topic, dating from February 11, 2021:

“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 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 had 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 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 11th, 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 syndrome. The other two potential indications are somewhat longer shots.”

Since that piece was posted almost two years ago, there have indeed been developments in Anavex-2-73 / blarcamesine. About two months ago, on November 7, 2022, Anavex won FDA Orphan Drug status for Anavex-2-73 / blarcamesine, not for Rett syndrome or Alzheimer’s disease, but for a rare disease called Fragile X syndrome, based on preclinical studies in mice. Fragile X syndrome is a rare genetic disease, causing a range of disabilities, mostly in cognition, and resulting in delays in learning to speak, and also anxiety and hyperactive behavior.

Anavex has also released the results of an Anavex-2-73 / blarcamesine trial in Rett syndrome. The company stated that their drug performed better than placebo on the main and secondary endpoints, which included general mood, breathing problems, hand behaviors, repetitive face movements, and body rocking, which are common Rett syndrome signs. On this measure 72.2% in the treatment group experienced some improvement, versus 38.5% in the placebo group. On a different scale rating anxiety and emotional behavior in Rett patients, Anavex said that 52.9% of patients taking Anavex-2-73 /blarcamesine experienced some improvement, while only 8.3% of placebo patients experienced improvement.

Anavex characterized those outcomes as very large and large differences, respectively. What that says to me is that on that primary endpoint, almost three out of four subjects got at least some benefit from the drug. It does not specify the degree of benefit, and I can see how that would be difficult to quantify. But I also see that Anavex is trying very hard to make the trial look like a major success.

Anavex made some changes to the trial specifications while the trial was underway. It started out as a Phase 2 trial, and the main endpoint was measuring the plasma concentration and pharmacokinetic activity of Anavex-2-73 /blarcamesine at seven weeks. These are preliminary goals, but they are essential for the determination of the drug’s activity in the body. Anavex also changed the trial’s designation from Phase 2 to Phase 3, presumably so that the results could be used as a pathway to FDA approval for Anavex-2-73 / blarcamesine as a drug for Rett syndrome.

On the Alzheimer’s front, Anavex claimed that they had new data on their drug, stating that it reduced clinical decline in patients with mild cognitive impairment. They said that 84% of subjects who received Anavex-2-73 / blarcamesine “demonstrated visible improvement” compared with placebo patients. But they didn’t say how much these persons improved – just that they had improved.

Anavex is clearly trying to boost their share price with these announcements, and the reaction from several respected pharmaceutical news sites has been sharply critical. STAT called Anavex’s announcement a “spin job,” and Fierce Biotech threw a “rotten tomato” at Anavex.

To make my own position clear: it seems clear that Anavex-2-73 / blarcamesine has definite merit regarding Rett syndrome, and I should think that would be recognized by the FDA, especially with regard to that disease, for which there is no available treatment. But Anavex is not, and from the economic perspective, cannot be content with that. They want FDA approval as a treatment of some kind for Alzheimer’s. But at present, they aren’t doing themselves any favors by fiddling with their clinical trials. The problems aren’t with the drug itself, but with the company.

Let’s take a look at a couple of other pharmaceutical companies and their candidate drugs that readers asked about.

Cassava Sciences and simufilam / PTI-125

Cassava has been the target of a great deal of severe criticism, and the merits of its lead drug, simufilam / PT125, have been questioned repeatedly. According to Cassava, simufilam binds to filamin, which is a common scaffolding protein. Scaffolding proteins regulate the interaction of many proteins and are responsible for many vital physiologic functions. Filamin in particular has been reported to regulate the interaction of amyloid beta 42 (Aβ42) and acetylcholine receptors, which supposedly triggers tau phosphorylation. Thus, distorted filamin molecules are thought to be crucial players in the development of Alzheimer’s disease, and if simufilam (as reported by Cassava) does indeed reverse the binding of Aβ42 and those crucial acetylcholine receptors, then its mechanism would characterize simufilam as a significant antagonist of the processes that lead to Alzheimer’s and a potential winning Alzheimer’s treatment.

Unfortunately, not only for Cassava, but for the multitudes with Alzheimer’s for whom treatment options are scarce, the basis for believing that simufilam is a potential Alzheimer’s treatment has been seriously eroded by statements from a range of highly reputable scientists asserting that Cassava’s studies were flawed and that the methods and results of those studies are highly improbable.

For example, in December of 2021 and March 2022 two well-respected journals – The Journal of Neuroscience and Neurobiology – published “expressions of concern” regarding brain studies published by Cassava’s chief scientific collaborator, Dr Hoau-Yan Wang, a professor at City University of NY. The editors of Neurobiology listed a number of methodological errors, and will wait to take further action pending an investigation of Dr Wang by CUNY.

Then, in March 2022 the journal PLoS One retracted five papers by Dr Wang after a five-month investigation into “serious concerns about the integrity and reliability of the results.”

In August of 2021, a citizen’s group filed a petition with the FDA asking the agency to stop all simufilam trials. And on July 27, 2022, the US Department of Justice started a criminal investigation to determine whether Cassava had manipulated data.

Cassava claimed that simufilam had the capacity to restore the shape of the filamin and prevent it from causing the damage that leads to Alzheimer’s. Evidence for this assertion was provided in the form of Western blot tests, viewed by many experts as lacking the sensitivity, reproducibility, or accuracy of new methods. But Elizabeth Bik, an expert in image manipulation, noting a pattern of irregularities in Western blot images in multiple papers, stated that it was highly likely that some manipulation was going on.

I hope you’re aware that I’m not putting Anavex and Cassava in the same boat. Anavex has a potentially valuable candidate drug and may just be getting in its own way by over-hyping it. Cassava’s candidate drug is a highly doubtful prospect to start with. My guess is that the insiders would like to boost the stock price to where it was, say a year-and-a-half ago, when it was triple the present price … and then get out! That’s just a guess, of course.

NervGen Pharma

I can’t say much about this outfit. It was founded in 2018 and so far has one candidate drug, NVG-291, which (according to NervGen) will help the nervous system repair itself.

The origin of NervGen came about in an interesting and affecting way. A young woman, Codi Darnell, experienced a fall and became a complete paraplegic. Her father-in-law, Dr Harold Punnett, made it his mission to find a cure for persons in Codi’s condition, and encountered Dr Jerry Silver at Case Western Reserve University, whose research was focused on the ability of the nervous system to repair itself after injury. Together, they founded NervGen Pharma in 2018.

The specific mechanism they describe is as follows: when there is an injury to a nerve, a scar is formed, and this scar contains chondroitin sulfate proteoglycans (CSPG), which bind to protein tyrosine phosphate sigma (PTPδ), a cellular receptor. This action interferes with nerve repair, and NVG-291 minimizes this action. According to NervGen, NVG-291 has brought about improved nervous system repair in lab animals, leading to improved bladder control, vision, memory, and movement.

NervGen intends to target Alzheimer’s disease, spinal cord injury, and multiple sclerosis. At this point, one Phase 1 clinical trial is under way, to evaluate the safety, tolerability, and metabolism of NVG-291 in human subjects.

That’s the total of what I’ve been able to learn about NervGen Pharma. What I can say about this outfit is that the material they’ve put out on the web seems to be sober and devoid of blarney. The mechanism of NVG-291 looks interesting and promising. I’ll keep an eye on them.

Could metformin prolong our lifespan?

Metformin is used by many millions of people with type 2 diabetes. Up until 1995, most persons with diabetes, whether type 1 or type 2, had to receive insulin by injection, sometimes as often as three times per day, but since the introduction of metformin in the US in 1995, most persons with type 2 diabetes (T2DM) no longer need to rely on insulin.

The history of metformin goes back to the 17th century, when extracts from the leaves of the French lilac plant were used as treatments for a number of ailments – bubonic plague, various fevers, snake bites – but not for the treatment of diabetes, which at that time was not well understood as a metabolic disease.

Diabetes has been recognized as a killer disease for at least two thousand years, and identified as a condition that caused the patient’s urine to taste sweet. But the root cause of diabetes as a failure to produce insulin was not fully understood until the end of the 19th century, and it was just about one hundred years ago that the first human patient with diabetes was successfully treated with insulin.

Metformin was first used to treat diabetes in 1957. It was marketed under the name Glucophage, but uptake in many parts of the world was slow owing to initial concerns over lactic acidosis, an increase of lactic acid in the bloodstream. But evidence that using metformin for control of blood sugar in persons with T2DM had far more benefits than adverse effects eventually led to its approval in the US in 1995.

With the widespread use of metformin came recognition of its numerous beneficial effects beyond controlling the elevated blood sugar levels produced by diabetes. Persons with diabetes treated with metformin demonstrate survival benefits beyond T2DM management, and their survival benefits are evident even when they are compared with non-diabetic controls. Metformin reduces the risk of cardiovascular disease in persons with T2DM, and also reduces cardiovascular risk as well as the risks associated with atherosclerosis in non-diabetic persons. Observational studies in humans suggest that metformin is beneficial in the prevention of aging-related decline and the incidence of some cancers, and metabolic analyses in persons in their 70s indicate that metformin produces effects that are consistent with a slowing of the aging process.

Metformin has been demonstrated to extend the lifespans of laboratory animals, specifically roundworms and mice, but not in the fruitfly. And the benefit in female mice appears to be greater than that in male mice. The reasons for these differences are not clear; they may have something to do with disparities in the dosing.

The specific mechanisms of metformin’s effects on the aging process are not clear. In fact, the specific mechanisms of metformin’s effects in controlling T2DM are extremely complex and at this time not fully understood. The ultimate effect of metformin regarding T2DM is essentially that it reduces hepatic gluconeogenesis, a process in which the liver generates glucose (sugar) from non-carbohydrate sources – sources which do not normally result in the formation of sugar.

Metformin’s effects on human longevity are currently being studied in a double-blind placebo-controlled clinical trial with 14 human participants, the Metformin in Longevity Study (MILES) to determine whether taking metformin 1700 mg/day can restore more youthful gene expression in elderly people with impaired glucose tolerance. Pre-publication data from this study suggest that metformin does have an effect on gene expression linked to aging. A larger study, the Targeting Aging with Metformin (TAME) trial plans to enroll 3,000 persons to observe the effects of metformin on any aging-related morbidity including coronary heart disease, stroke, congestive heart failure, peripheral arterial disease, T2DM, cognitive impairment, and mortality. Trial subjects will be taking 1500 mg/day of metformin for six years, with a mean follow-up time of 3.5 years.

There are uncertainties regarding the long-term use of metformin, including an increased risk of lactic acidosis, which primarily affects persons with abnormal kidney function, and even then is extremely rare. Another possible uncertainty is the possibility that long-term use of metformin may result in vitamin B12 deficiency. Observed instances of B12 deficiency in metformin users have typically been less severe and not accompanied by neuropathy or anemia, which are sometimes consequences of B12 deficiency.

Fewer than 5% of long-term metformin users discontinue the drug due to GI side effects including diarrhea, nausea, flatulence, indigestion, vomiting and abdominal discomfort.

Currently, hundreds of millions of humans take metformin, and the overall safety record of this drug is outstanding. But before use of this drug to promote longevity becomes widespread, the mechanisms through which metformin achieves its effects need to be better understood. Research is underway, and interest in the results is, understandably, quite elevated. After all, who wouldn’t want to take a pill that adds a few years to one’s life?

The big news: lecanemab (now Leqembi) gets FDA approval as of January 6th.

Perhaps I shouldn’t call this “big news,” since it was generally anticipated that the FDA would give lecanemab the same form of approval that it – controversially! – bestowed on adalimumab/Aduhelm. This accelerated approval was based on preliminary evidence that lecanemab eliminates toxic amyloid beta (Aβ). However, in this case Eisai is expected very shortly to submit the data on improved cognition to the FDA, which will then consider the drug for full final approval.

As Doc Gumshoe has reported, a large clinical trial demonstrated that treatment with lecanemab slowed both cognitive and functional decline in patients with early-stage Alzheimer’s by 27% compared with placebo subjects.

An adverse effect of concern is brain bleeding, which has resulted in the deaths of two patients thus far. Those two patients were taking blood thinners, which considerably increases the risk of a brain bleed. In patients not on blood thinners the risk is very low and manageable.

The drug was developed by Eisai, the Japanese biotech, and will be co-marketed with Biogen. The expected cost is $26,500 per year for a person of average weight.

Lecanemab/Leqembi will be restricted to patients with early stage Alzheimer’s who also have deposits of Aβ in their brains. It is the first approved drug that shows any benefit in the treatment of persons with Alzheimer’s disease.

Add this little news item to what Doc Gumshoe said about some hospice care outfits

The following is reproduced in its entirety from an NBC news release in Dallas:

“The owner of a North Texas medical company regularly directed nurses to give hospice patients overdoses of drugs such as morphine to speed up their deaths and maximize profits, an FBI agent wrote in an affidavit for a search warrant obtained by NBC 5.

“Executive Brad Harris, 34, founded Novus Health Care Services, Inc., in July 2012, according to state records. The Novus office is located on Dallas Parkway in Frisco.

“Harris, an accountant, instructed a nurse to administer overdoses to three patients and directed another employee to increase a patient’s medication to four-times the maximum allowed, the FBI said. He allegedly sent text messages like, “You need to make this patient go bye-bye.”

“In the first case, the employee refused to follow Harris’ alleged instructions, according to the FBI affidavit. The document does not say whether the other three patients were actually harmed.
Harris also told other health-care executives over a lunch meeting that he wanted to “find patients who would die within 24 hours,” and made comments like, “if this f—– would just die,” an FBI agent wrote in the warrant.

“No charges have been filed against Novus or Harris, who did not return messages left with a receptionist and at his Frisco home.

“An FBI spokeswoman declined to comment on the investigation.”

Of course, many – and perhaps most – hospices do provide excellent and vitally needed patient care. It’s the exceptions that are in it purely for the money.

* * * * * * *

Sorry if I didn’t get back to you on every single question. If you’re still curious, ask me again. In my next missive, I’m going to take another look at osteoporosis, a condition that affects a lot of people and has the potential to cause a lot of harm. But the management of osteoporosis has changed a good deal. I’ll try to bring you up to date. Thanks to all, and keep those stimulating comments coming! Best, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers once or twice a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.]