Before I launch into the topics of the day, I am going to share with you an opinion piece about the recent CDC guidelines. I find myself in complete concurrence with this piece, which was posted a few weeks ago on MedPage Today, a medical website that is a very helpful source of information for Doc Gumshoe. The author of this piece, Lawrence O. Gostin, is a University Professor at Georgetown University, where he is a professor of medicine and the founding chair of the O’Neil Institute for National and Global Health Law. He is also a professor of public health at Johns Hopkins, and the director of the WHO Center on National and Global Health Law.  I would have agreed with Professor Gostin’s views even if he had not had such sterling credentials.

What Was CDC Thinking With Its New Mask Guidance?

“This opinion piece will be sharply critical of the new CDC guidance on masking for individuals who have been fully vaccinated against COVID-19, so I want to begin by saying the agency has been, and remains, the envy of the world. There’s good reason why China, Korea, Europe, and Africa all named their public health agencies after the CDC.When CDC speaks, scientists fall behind in lockstep, and the public trusts and follows its advice.

But not this time. Its mask guidance has been greeted by scientists and the public alike as confusing, inconsistent, and frankly, unsupported by scientific evidence. I’ll explain why.

The CDC has lurched from over-caution to abandoning all caution. Just over 2 weeks ago, the CDC recommended universal masking in indoor spaces. The nation’s top health officials pleaded with the public to wear masks or face dire consequences. Now CDC states that the fully vaccinated “can resume activities that you did prior to the pandemic” without wearing a mask or distancing. In other words, CDC gave a bright green light to return to normal — indoor dining, shopping, and resumption of schools, colleges, and workplaces. It seems a bit premature to declare victory.

You might think there were new, important scientific findings justifying such a dramatic shift — there weren’t. Vaccines are almost flawless at preventing serious disease and death, and they do significantly reduce SARS-CoV-2 transmission. But we knew that weeks ago. The U.S. has vaccinated more people in the last several weeks, but we’ve been on track to do that for quite some time. And remember, CDC guidance doesn’t just apply to affluent zip codes with high vaccination rates. It applies equally to  areas that have very low coverage.  And in such a mobile society as ours, there will be lots of travel to all areas of the country.

My supposition is that CDC prematurely recommended “back to normal” because it wanted to give hesitant people an incentive to get vaccinated. But there is no behavioral evidence that giving more freedom to vaccinated people will encourage more to be vaccinated. Why? First of all, most Americans won’t even perceive CDC’s new advice as “vaccine” guidance, but rather as “mask” guidance. We see that in all the headlines, and many states are now dismantling, or considering removing, their mask mandates. But there’s more: Individuals opposed to vaccines are just as likely (maybe even more likely) to just take off their masks as they are to get a jab.

There is a galling disconnect in federal policy on COVID-19. CDC is telling states, the private sector, and the public that it is vital to differentiate between the vaccinated and the unvaccinated. But at the same time, the Biden administration has made that all but impossible. The administration stubbornly refuses to offer any way to demonstrate proof of vaccination. Other places like the European Union and Israel have successfully used digital health passes (so-called “vaccine passports”) as a way to ensure a safe return to normal. Will anyone have confidence being in a restaurant, mall, church, or gym if they’re not sure that all of the maskless people crowding around are fully vaccinated?

So, what will be the outcome of the CDC’s new guidance? It’s highly likely that both vaccinated and unvaccinated individuals will throw away their masks. < This poses a significant risk of a surge of cases and hospitalizations. Over 60% of Americansare still not fully vaccinated.

Many immunocompromised people are vulnerable eve>n if fully vaccinated because they can’t mount a full — or often any — immune response. Children under 12 years old aren’t eligible for vaccination. All these groups remain at risk. If even one unvaccinated person is in an indoor crowded space without a mask, it poses a risk of spread.

And just look at the CDC website. It actually contains joyful images of unmasked people happily living their lives. But the images are deeply troubling. One is a group of unmasked adults and children playing. But wait, the children can’t get a vaccine. Another is a gym class, but these have caused major super-spreader events. Yet another photo shows a person shopping without a mask, but what about the supermarket worker who may not be vaccinated or has undergone cancer therapy?

This is why a public health agency like the CDC has to take a population approach. The impact of their new guidance on the public is predictable. But what I foresee isn’t a surge in hesitant people now eager to get the jab. I see unvaccinated people feeling they have a license to throw away the masks they have always disliked. What behavioral scientists understand is that culture and peers have major influences on how we behave. If everyone around you is wearing a mask and distancing, it is likely you will. But if many, or even most people, are maskless, you will remove your mask as well. People won’t be making “nice” distinctions based on the CDC guidelines.

And speaking of confusing distinctions. Under the new guidance, vaccinated people must wear masks in an airport or bus station, and in a homeless shelter or prison. But they can remove their masks in a crowded restaurant or mall. And they can go to church and sing, or join a gym class with heavy breathing and shouting. How does the epidemiological evidence support all those distinctions?

I’ve worked with the CDC for decades, from the AIDS pandemic through to SARS, influenza, Ebola, and Zika. I know the staff are world class scientists and they work tirelessly for the public good. They are our modern-day heroes. It is therefore agonizing to see the erosion of public trust, first with the truly unconscionable undermining of the agency by the Trump administration. And now, feeling tugged in opposite directions by Congress and the public. We need an independent CDC with a steady hand. CDC must be guided by the science, but it also has to become a talented health communicator that gains public trust and shapes public behavior. The latter has been sadly absent during the COVID-19 pandemic.”
–Lawrence O. Gostin, JD

…and now to the questions and comments…

As I’ve said many times, Doc Gumshoe greatly values those questions or comments that point to topics that have not been explored. Mostly, I have never heard of them, as in the first one below. This came from a reader who reported that her husband is in a clinical trial of a treatment that “is showing promise for us in regards to Alzheimer’s. When he was on the “open label” he got his spark in life back. Now we are in the double blind segment and the spark has gone so I can only assume we are on the placebo. The drug is called Fasudil.”

I replied that I had never heard of Fasudil, but would check on it. How could I not? Anything showing promise in regards to Alzheimer’s is worth a look.

What do we know about Fasudil?

Fasudil has been approved in China and Japan since about 1995, where it has been used for the treatment of spasmodic constriction of cerebral arteries, a severe condition which frequently follows hemorrhage in the subarachnoid region of the brain. It is a potent inhibitor of a kinase called Rho-associated kinase isoform 2 (ROCK2), which is a potent vasoconstrictor. In other words, fasudil inhibits the agent that causes constriction of cerebral arteries. This mechanism may also improve the cognitive decline seen in stroke patients due to reduced arterial blood flow. Fasudil has also been found to be effective in the treatment of pulmonary hypertension. And there is some evidence that the drug improves memory in normal mice.

Fasudil was developed in Japan by Asahi Kasei Pharma and marketed under the name Eril. It was licensed in November 2019 to Woolsey Pharmaceuticals. At this time, fasudil has not been approved either by the FDA or by the European Medicines Association; however, the FDA has given its blessing to the clinical trial mentioned above by our reader.

The purpose of the Phase 2 clinical trial is to assess the effectiveness of oral fasudil in subjects with dementia in reducing wandering behavior and getting lost. Various other effects will be assessed, such as excess movement, cognition, memory, neuropsychiatric symptomatology, and safety and tolerability.

The potential effectiveness of fasudil in improving cognition / reversing cognitive decline is likely, at least in part, attributable to fasudil’s effectiveness in increasing blood flow in the brain by blocking the kinase that causes arterial constriction. Increased blood flow brings with it increased oxygen supply and increased neuronal activity.

However, fasudil possesses another characteristic which may be particularly valuable in combating some of the mechanisms of Alzheimer’s disease. A recent review in a journal called Frontiers in Cellular Neuroscience points to ROCK2, which has been identified as the kinase that fasudil specifically targets. ROCK2 is an inhibitor of a physiologic activity called autophagy. Autophagy is a natural mechanism that removes unnecessary or dysfunctional components of cells. Autophagy could be a highly valuable function in removing both amyloid beta (Aβ) and tau, both of which are thought to be part of the pathology of Alzheimer’s disease. Thus, fasudil could function as an enabler of an activity that would tend to protect against Alzheimer’s. (Weber J. Front Cell Neurosci 3/15/2021 doi:10.3389/Incel 636019).

The review cited above also suggests that ROCK1 and ROCK2 may be therapeutic targets for a range of diseases and conditions, including cancer, asthma, insulin resistance, kidney failure, osteoporosis, and erectile dysfunction. Thus, acting by means of a combination of mechanisms, fasudil could be a valuable agent in the treatment of a range of diseases and conditions.

Fasudil is not the only ROCK2 inhibitor. Another one, belomusudil, is being investigated as treatment for idiopathic pulmonary fibrosis, graft versus host disease, and psoriasis. It is not entirely clear why the mechanisms of the two ROCK2 inhibitors would differ such that they target different diseases.

Woolsey Pharmaceuticals, the outfit to which fasudil has been licensed, is not a drug development company. Instead, Woolsey seeks to identify existing drugs and repurpose them for diseases for which there is a need. In particular, their focus is on neurodegenerative diseases, including Alzheimer’s, vascular dementia, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Huntington’s disease, multiple sclerosis, and others.

More about Anavex Life Sciences?

Back in February, in response to a query, Doc Gumshoe took a careful look at Anavex and its lead drug, blarcamesine. Here’s what I said at that point:

“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%).”   

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.”   

Rett syndrome is a very rare genetic disorder, affecting brain development mostly in girls, starting about the age of six months. Infants loose coordination, the capacity for speech, and use of the hands.

Anavex has another drug in the pipeline, this one designated as Anavex 3-71, which they describe as an orally-administered small molecule targeting sigma-1 and M1 muscarinic receptors that is designed to be beneficial for neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and others. The company announced the opening of a Phase 1 clinical trial with Anavex 3-71 back in July 2020 and expects to be releasing pre-clinical data in the first half of 2021, which means in the next month or two. So far, Anavex 3-71 has demonstrated effects which the company describes as “disease-modifying” in transgenic mice, including cognitive deficits and amyloid and tau pathologies.

Doc Gumshoe has just a couple of comments about Anavex. First, that it is really very early days to come to any sort of conclusion about the prospects for either of their agents.And, second, that the targets of their drugs are not very different from those of other drugs, most of which have failed to live up to expectations. Both muscarinic and sigma-1 receptors have been well-studied in relation to dementia and Alzheimer’s disease. I hope that Anavex 3-71 will surprise us!

Pritumumab enters Phase 1 clinical trial for brain cancers

A Gumshoe Irregular sent this to Travis, who then forwarded it to Yours Truly, who, in turn, found it highly interesting and did some sleuthing. Here, in part, is what that Irregular said:

“I believe he [Doc Gumshoe] would be interested in a small biotech company that has a patent on a monoclonal antibody that targets brain cancer. Full disclosure: I have been long this company for about 6 years now. What started out as “friends and family” investors has progressed to a small publicly traded company. Emphasis on small. But because of the small size, I feel very connected to the company and its mission to extend lives of those afflicted with one of the deadliest cancers out there. The five-year survival rate of brain cancer is abysmal. However, the company, Nascent Biotech NBIO, recently started a Phase 1 human trial and has begun injecting patients.

While this may seem premature for me to tell you and Doc Gumshoe about a Phase 1 company, what is generally not known (due to FDA rules) is that this monoclonal antibody made it to Phase 3 testing in Japan about 20 years ago and was very successful. In fact, my understanding is that the test results from 20 years ago are still significantly better than the current standard of treatment available for brain cancer patients today. However, the Japanese company owning the patent suffered the death of one of the founding scientists and shut down the studies. There were also issues about being able to replicate the drug on a large-scale basis, because the technology to do so was not available. But it is now. Nascent Biotech has been revitalized in the U.S. and began injecting patients with Pritumumab in the last week. Non-dilutive funding was recently secured that will get the company through Phase 1 and into Phase 2.”

\Pritumumab is a natural human monoclonal antibody that works by binding to vimentin (sometimes referred to as ectodomain vimentin, or EDV), which is a protein expressed on the surface of epithelial cancers. Vimentin is a key structural protein present in many cell types that protects its nucleus against deformation, rupture and DNA damage. Because this protein is found in many cancers, clinical trials with Pritumumab could have important implications for a number of common cancers, such as breast, colon, and lung cancers. 

The story of how Pritumumab went from Phase 3 trials in Japan to Phase 1 trials in the US merits a few words.

Dr Mark Glassy, who was co-founder of Nascent Biologics, actually invented pritumumab in 1982, while he was a faculty member of the University of California San Diego (UCSD). Shortly after he invented the antibody, a visiting member of the faculty from Japan took it back to his country, had it licensed there and used the antibody to treat a relative with cancer.  Dr Glassy was told by the legal department at UCSD that there was no recourse available to retrieve the antibody since the Japanese party had already secured a license for the antibody from UCSD.

According to Japanese data, about 250 brain cancer patients have been treated with Pritumumab, with a response rate of approximately 30%. This is in contrast with the 5-year survival rate in persons with brain cancer, which is about 3%. In December 2008, Dr Glassy was able to retrieve the license for his own invention, and Nascent finalized the agreement with the Japanese scientist in July 2009.

For US clinical trials, Pritumumab was initially obtained from a B lymphocyte isolated from a regional draining lymph node of a patient with cervical carcinoma through traditional technology. As with many monoclonal antibodies, the drug is modeled on a naturally-occurring original and then duplicated in the laboratory.

On 31 March of this year, Nascent announced that patients have been enrolled and initial dosing has begun in the company’s Phase 1 trial to evaluate Pritumumab as a treatment option for brain cancer, including malignant primary brain tumors and adult brain metastases. Since Pritumumab’s target is a protein expressed on the surface of several other cancers, is can be used as a targeted immunotherapy that, unlike chemotherapy, targets only cancer cells without damaging healthy ones. Because of this dynamic, the current clinical study may have implications for future research on Pritumumab as a treatment option for a broad range of more common cancers, including breast, colon, and lung cancers.

And on 27 February of this year, Nascent heralded the publication of strong in vitro results from a collaboration with Syracuse University. The data from this study show that Pritumumab was able to block about 80% of SARS-CoV-2, the causative virus in COVID-19, from entering cells. Based on these results, Pritumumab will be advanced to animal studies. Once again, the mechanism by means of which Pritumumab is able to prevent the virus from entering cells is through its binding to vimentin, the cell surface protein found on the surface not only of many cancers but of many cells.

What has been learned about Pritumumab thus far points in many promising directions. Binding mechanisms are complex and need to be observed and understood at the molecular level, which may be beyond biology and often calls for a knowledge of physics. But understanding of this kind has led to major breakthroughs in the medical field, such as in the treatment of rheumatoid arthritis. As for Pritumumab itself, its usefulness may only beginning to be understood.

What will the next flu season look like?

Was there even a flu season this past year? Last fall, lots of folks in the health-care community were quite nervous about what would happen when the flu walloped us on top of the COVID-19 pandemic. But it turned out there was no cause to worry. There hardly was a flu season. According to the CDC, in recent years the flu season has averaged just over 200,000 cases. But this past year, from September through April, there were only about 2,000 cases. And that was not from lack of testing. In that same period, more than 1.3 million specimens have been tested for the influenza virus. There was almost no flu at all.

Comparing the death tolls from influenza with those from COVID-19 may cause some people to minimize flu as a danger, but it’s worth pointing out that the CDC estimates that flu killed from 12,000 to 61,000 people annually since 2010.

The health-care and scientific community has not arrived at a consensus regarding the likeliest cause of this totally unprecedented near-disappearance of a common sickness. Was it the fact that, because of the pandemic, people were avoiding crowded indoor spaces such as bars and restaurants? Was the closing down of movie houses and theaters the major factor? What about the cessation of most travel? Could it be that the major factor was mask-wearing? Or frequent hand-washing? Or heeding the warning never to touch your face? What part did scrupulously sanitizing play – wiping down with bleach anything that another person might have touched, including the groceries we bought, the mail, doorknobs and light switches … in fact, just about everything? Nobody questions that the precautions that were commonplace had a great deal – nay, everything! – to do with the squelching of the 2020-2021 flu season. The question that remains is, of those precautions, are there some that we should routinely continue to prevent the return of the flu in the 2021-2022 season?

The experts aren’t saying … or at least, not yet.

However, they are concerned. They point to certain specific threatening factors. One, which I suspect most people would respond to with raised eyebrows, is that the mere fact that the flu was so much less prevalent last season means that many , many fewer people were exposed to the flu virus at all. And merely being exposed to the virus does confer a degree of immunity, so a smaller proportion of the population as a whole has that degree of immunity. And that decreased immunity in turn would likely lead to more people infected, more people with serious cases, and more deaths.

Dr Richard Webby, a virologist at the St Jude’s Children’s Research Hospital in Memphis, was quoted in the N Y Times as follows: “Every year, anywhere between 20% to 30% of the population gets its immunity sort of boosted and stimulated by being exposed to the virus. We’re not going to see that this year.”

However, beyond signaling that they are worried, the experts are being cautious with their predictions.

Dr Sonja Olsen, an epidemiologist at the CDC said, “Decreases in natural immunity are a concern, and lower immunity could lead to more infections and more severe disease. We are always concerned about influenza causing severe disease, particularly in persons at risk of complications. We know that school-age children are important drivers of influenza virus transmission. However, because influenza is difficult to predict, we cannot forecast the severity of next season.”

On the other hand, Dr Rachel Baker, an epidemiologist at Princeton, said, “Right now, because influenza isn’t circulating as much, it’s possible that the virus has not had as much opportunity to evolve, meaning our vaccines could be more effective than normal.”

Another concern is that deciding on this year’s flu vaccine will be much more difficult than in previous years. The experts look at the strains that are causing illness in the current season and use that information to predict which strains are most likely to infect people in the next flu season.

Dr Webby, referring to the WHO panel that assesses the flu vaccine, said, “We met at the end of February to make those recommendations. And it was tricky. The amount of data was orders of magnitude less than it typically is.” That will make it more difficult to choose which strains to include in the vaccine.

Doc Gumshoe trusts that it will not be necessary for him to urge all denizens of Planet Gumshoe, along with all other fellow mortals, to get the flu vaccine when it is available.

And one more note of concern, relatively tiny in comparison, is the emergence of a highly pathogenic H5N8 avian influenza virus, which has caused massive mortality in both wild and farmed birds in Eurasia and Africa. So far, this infection has been limited to birds, except for one event in Russia, where seven poultry farm workers tested positive for the H5N8 virus.

May this event not portend a similar catastrophic chain such as the one that started in Wuhan in late 2019.

…and a short upbeat finale …

A paper in Science Advances, looking at data from Europe, North America, and Asia, concluded that the decline in pollution and nitric oxide levels in the air, resulting from COVID-19-related lockdowns, has resulted in about 32,000 fewer premature mortalities (Chossière GP SciAdv 5/21/2021;7:#21)

* * * * * * *

As you can see from this installment, Doc Gumshoe has excellent reason for welcoming comments and questions. I keep an eye on what’s going on in the realm of medical science and health care, but I need to know what interests Nation Gumshoe. So, as I always say, keep those comments coming. Best to all, Michael Jorrin (aka Doc Gumshoe)