May Miscellany – Some Covid-19, Some Otherwise

Doc Gumshoe looks at Herd Immunity, Vaccines and Treatments... plus some updates on Alzheimer's Disease, Dementia and more...

I’m happy to report that despite the huge quantity of COVID-related news items that flood my in-box (as well as all news media), the tsunami has not drowned other health and medicine-related releases. Now, with the pandemic retreating – and, yes, it really is retreating – let’s use this as an opportunity to bring a few other issues to your attention.

But first, some COVID-19 bits.

How many people in the US have been infected with SARS-CoV-2? And what does that tell us about getting to herd immunity?

As of today (May 6th, as I am writing this) the recognized number is 32,559,283. These are confirmed cases, generally by means of one of the tests for the coronavirus. The question is, how many people have been infected with the coronavirus without having developed severe symptoms and without having been tested? That question is particularly important from the perspective of attaining herd immunity. We can assume that the 32-plus million people who have had confirmed cases have at least a degree of immunity. But how many more people are there who can be added to the herd immunity cohort?

A study in May through July 2020, in 11,832 volunteers who had not previously been diagnosed with COVID-19 reported that 4.6% of these individuals had indeed been infected with SARS-CoV-2. There was considerable variability in the seropositivity rate, depending on location and individual characteristics. As one would expect, the higher positivity rates were in regions with early outbreaks, and also in specific populations, such as younger participants (5.9%), females (5.5%), African-Americans (14.2%), Hispanics (6.1%), and urban residents (5.3%). Adjusting the data from the study to reflect the entire US population indicated that for every diagnosed case of COVID-19 by mid-July of 2020, there were 4.8 undiagnosed cases, and a total of 16.8 million undiagnosed cases nationally.

If the same ratio of undiagnosed to diagnosed cases detected in that study persisted to the present day, that would imply that in the US as of today, instead of the 32 million currently confirmed cases, there would be about 150 million people who had been infected with SARS-CoV-2, and would consequently have at least partial immunity. That figure is absurd; since those data were collected, the rate of testing has soared. We can be confident that there have not been 4.8 undiagnosed cases for every diagnosed case in the period from July 2020 to the present. At the same time, we can be equally confident that many mild cases escaped diagnosis, and there is abundant evidence that even mild cases result in a degree of immunity.

The question is, how many undiagnosed cases should we (speculatively) add to the 32 million confirmed cases to arrive at a total number of individuals who now have some immunity due to having had COVID-19. Can we reasonably assume that the number is around 50 million or 75 million? Or even 100 million?

Add that number to the 130 million Americans who have received at least one dose of the vaccine, and we get an idea of where we are in getting to herd immunity. The proportion of the population that must have some degree of immunity in order to achieve herd immunity is generally put at about 70%. In the US, we’re not there yet, but we’re getting closer by the day. If the combined total of the vaccinated population plus the people who have had at least a mild case of COVID-19 is somewhere between 180 and 200 million, which seems possible, then the herd immunity threshold in adults – at least in some locales – may already have been reached. Is that overly optimistic?

Understandably, the authorities (Fauci et al) are not making any announcements to that effect, and Doc Gumshoe bets they won’t any time soon. The news media have been treating the concept of herd immunity as though it was an absolute – we either reach it or we don’t, end of story. But of course, there are lots of variables that have to be considered. One of them is this: which herd are we talking about? If the herd consists of the entire human population on Planet Earth, then we’re a long, long way from attaining herd immunity. If, on the other hand, the herd consists of the population of our town in Western Connecticut, we might be pretty close.

Also, the way herd immunity works is by depriving the pathogen – in this case the coronavirus, SARS-CoV-2 – of hosts in which it can multiply. Remember, viruses are unable to reproduce on their own – they must use the resources of the host to replicate. When the novel coronavirus first emerged from whichever animal it had come from, there was no shortage of human hosts anywhere in the world. But now, in many parts of the world, vaccinations and previous infections have already reduced the number of potential human hosts, and this number will continue to shrink.

Taking these factors into consideration, I will state my opinion: in some regions, both in the US and elsewhere, a degree of herd immunity is well within reach.

The Pfizer-BioNTech vaccine works against the South African variant…

This conclusion is based on a Phase 3 clinical trial in South Africa, where the B.1.351 variant is the predominant strain of the coronavirus. The trial enrolled 800 subjects, and nine of those in the placebo group became infected with the virus, versus none in the group that received the Pfizer-BioNTech vaccine. That would translate to a vaccine efficacy of 100%. The trial confirmed previous in vitro studies that also demonstrated broadly neutralizing antibody responses against the variant.

Also, on March 13, Pfizer-BioNTech released data from a larger Phase 3 trial enrolling 46,307 subjects showing 91.3% efficacy against symptomatic illness seven days after the second dose, 100% efficacy against CDC-defined severe illness, and 95.3% efficacy against severe illness as defined by the FDA. There were 32 cases of severe disease as defined by the CDC in the placebo group versus none in the vaccine group, and 21 severe cases as defined by the FDA in the placebo group versus one in the vaccine group. The multi-national trial took place after variant strains of the coronavirus were present in all the trial sites.

A general conclusion about the Pfizer/BioNTech vaccine is that, although it is not 100% effective in preventing infection from SARS-CoV-2, it is close to 100% effective in preventing severe disease. In all the literature about the Pfizer/BioNTech vaccine that I have read – and also about the Moderna vaccine – I have not found a single reported instance of death in any person vaccinated with either of those vaccines.

… and also in younger teens

Pfizer-BioNTech conducted a clinical trial in 2,260 adolescents 12 to 15 years of age, randomly assigned 1:1 to the vaccine or placebo. A total of 18 cases of COVID-19 were observed in the placebo group, versus none at all in the cohort that received the vaccine. Lab results in a subset of participants showed that the vaccine generated a strong immunogenic response 1 month following the second dose, which was similar to the immune response generated in subjects ages 16-25 in earlier studies with the vaccine. Pfizer-BioNTech will submit these data to the FDA as a proposed amendment to the vaccine’s current emergency use authorization. Their vaccine is currently authorized for use in individuals 16 years of age or older.

Pfizer-BioNTech also made a statement about a study, currently underway, in children 6 months to 11 years of age. They are testing two doses of the vaccine in three groups of children: one group 6 months to 2 years of age, a second group 2 to 5 years of age, and a third group 6 to 11 years of age.

Although there is no reason to suspect that the immune response to a vaccine would be diminished in younger people, it is of course necessary for the producers of the vaccine to submit clinical trial data to the regulatory authorities in order to secure approval for use. In other words, you can’t assume anything!

Molnupiravir, a broad-spectrum antiviral potentially effective versus COVID-19

Merck has entered into licensing agreements with five generic drug manufacturers in India to accelerate access to molnupiravir, which is currently being studied in a Phase 2/3 trial in outpatients with COVID-19.

Molnupiravir’s origin dates back to 2003, when researchers at Emory University partnering with Drug Innovation Ventures (DRIVE), a non-profit biotech, were studying a closely-related compound which, in animal and lab studies, had been found to be active against a range of RNA viruses including hepatitis C, flu viruses, and coronaviruses such as severe acute respiratory syndrome (SARS) and Middle-East respiratory syndrome (MERS). The original compound was not well absorbed orally and further research was set aside.

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However, work resumed about ten years later when effective treatment was needed for the equine encephalitis virus, and the precursor compound was found to have broad activity against RNA viruses. By changing the chemical structure they made it into an inactive drug that only becomes active after being absorbed – a so-called pro-drug, now named molnupiravir. The drug acts as an analog for an enzyme which the virus uses to replicate. Essentially, molnupiravir insinuates itself into the RNA of the virus, which increases the viral mutation rate to the point that the virus can no longer replicate and dies — a process called viral error catastrophe.

When the COVID-19 pandemic was just picking up momentum, DRIVE formed a partnership with Ridgeback BioTherapeutics for the development of the new drug. Ridgeback launched a Phase 1 study in molnupiravir in January of 2020. The study demonstrated that the drug had good oral bioavailability, was well tolerated, and had a good safety profile.

Now in partnership with Merck, Ridgeback next started a Phase 2 trial, results of which were presented in March 2021. The trial included 175 participants with confirmed COVID-19, including non-hospitalized individuals, who were randomized to twice daily molnupiravir or placebo.
At 5 days follow-up, no infectious virus could be grown from nose swabs taken from participants who received molnupiravir. In comparison, 24% of participants who received placebo still had infectious virus on nose swabs at day 5. These results were considered to be highly significant (P=0.001).
So far, animal studies seem to support the idea that molnupiravir could block transmission of the virus. A study in ferrets infected with SARS-CoV-2 has shown that treatment with molnupiravir stopped spread of the virus from infected animals to cage-mates.

Merck’s decision to ramp up production of molnupiravir in India offers a glimmer of hope in that country where COVID-19 is spreading devastation. At this moment, about one out of three residents of India tests positive for SARS-CoV-2; whether this holds true for the entire Indian population of 1.4 billion is not known, but the situation is dire.

George Painter, the CEO of DRIVE, said “This isn’t just India’s problem. This is the world’s problem. We live in a very interconnected world, and we’re all in this together. We’re quite pleased with Merck’s announcement this morning. This certainly is in line with the mission that DRIVE was conceived to meet.”

… but there are risks in generic drugs, particularly from India

India is by far the biggest manufacturer of generic drugs in the world. And there is reasonably good evidence that these generic drug manufacturers fall considerably short of scrupulous quality control, particularly when they are churning out drugs for the less-developed parts of the planet, including their own country. These charges are laid out in considerable detail in Bottle of Lies: the Inside Story of the Generic Drug Boom, by Katherine Eban.

At the core of this book is its research into the shameful story of Ranbaxy, one of India’s premier drug manufacturers. In 2013, in a well-covered court case in America, the company pleaded guilty to seven charges of selling adulterated drugs and paid $500 million in fines. Eban concludes that Ranbaxy was treating data as an entirely fungible marketing tool. “It was an outright fraud that could mean the difference between life and death. The company manipulated almost every aspect of its manufacturing process to quickly produce impressive-looking data that would bolster its bottom-line.”

I do not know which drug manufacturers in India are being employed by Merck, and I only hope that Merck is overseeing the process and insisting on higher standards.

However, drug manufacturing issues are hardly limited to India. In the United States, for example, Emergent BioSolutions, a Maryland biotech that produces anthrax vaccines, was paid by the federal government to have a factory in Baltimore always at the ready to produce drugs or vaccines in the event of urgent need. Emergent then became the main US location for the manufacture of the COVID-19 vaccines developed by Johnson & Johnson and AstraZeneca.

According to the New York Times, not one single dose of either vaccine from Emergent has been usable because regulators have not been able to certify the factory to allow these vaccines to be distributed for public use. At the beginning of April, Emergent said it would destroy 15 million doses of the J & J vaccine because of possible contamination with the AZ vaccine, and before that, Emergent had had to discard five batches of the AZ vaccine, also amounting to about 15 million doses, because of possible contamination. That’s despite Emergent’s having received a $163 million federal grant to improve the facility and prepare it for high-volume production.

Those manufacturing issues are only a part of the problems with the AstraZeneca and Johnson & Johnson vaccines, both of which have been associated with the incidence of blood clots, which has delayed their widespread adoption. I hasten to add that the consensus is that these side effects are very rare, and the benefits conferred by the vaccines far outweigh these possible risks. As far as I have been able to learn, these problems have not affected either the Pfizer-BioNTech vaccine or the Moderna vaccine.

And now for some non-COVID-19 related news items.

How can we stave off dementia?

Solid evidence has been accumulating in the past 20 years or so that physical exercise helps prevent cognitive impairment and dementia. And lack of physical activity is one of the principal lifestyle factors associated with the likelihood of developing Alzheimer’s disease. It ranks right up there with heavy smoking, excessive alcohol use, obesity, and depression.

A big literature review in Mayo Clinic Proceedings reported the findings of 29 randomized controlled trials which documented significant cognitive benefits of exercise in adults without dementia (although three of the trials enrolled adults with mild cognitive impairment). The review noted that the trial subjects attained significantly improved scores in memory, attention, processing speed, and executive function, all within the 12-month duration of the study, except for a single study that ran 18 months. Because these improvements were observed over a relatively short period, the investigators concluded that the benefits were directly related to exercise, and not through a secondary pathway, such as the beneficial influence of exercise on cerebrovascular diseases such as strokes. (Ahiskog JE. Mayo Clin Proc 2011 86(9):876-884.)

The literature review also cited a study showing that regular physical exercise among seniors was significantly associated with less loss of grey matter and preservation of synapses in the brain, as measured by MRI.

Also, about a month ago, a study in Neurology reported that among Parkinson’s patients who carried the apolipoprotein Eε4 (APOE4) allele – which is associated with greater cognitive decline – higher levels of physical activity were very significantly related to slower cognitive decline (P=0.001). In that study of 173 recently diagnosed Parkinson’s patients, the APOE4 carriers demonstrated greater cognitive decline on the 30-point Montreal Cognitive Assessment scale than non-carriers. However, physical activity appeared to counter the effects of the APOE4 allele. The investigators did not hypothesize a mechanism through which physical activity slowed cognitive decline in that particular cohort, but the association of aerobic physical activity with greater oxygen saturation looks like a probable candidate. (Kim R. Neurology 3/31/2021 DOI https://doi.org/101212)

These studies help confirm the general conclusion that if we want to keep our wits about us, we need to keep using not only our minds, but our bodies. Sitting mesmerized in front of the television (or these days, keeping our eyes glued to our phones) is about the worst thing we can do.

A drug that targets amyloid plaque shows promise in Alzheimer’s disease

This is far from the kind of major breakthrough that we have all been hoping for, but it points to a way forward in the treatment of Alzheimer’s disease (AD). This is based on the results of a Phase 2 trial, TRAILBLAZER-ALZ, recently published in the New England Journal of Medicine and presented at the International Conferences on Alzheimer’s and Parkinson’s Diseases. (Mintun MA. NEngJMed 2021 DOI 10. 1056NEJMoa21007080)

The drug is donanemab, an investigational monoclonal antibody that targets a specific type of beta amyloid called pyroglutamate-3. In a study of 257 patients with early symptoms of AD, donanemab met the primary endpoint, which was a composite measure of cognition and daily function known as the Integrated Alzheimer’s Disease Rating Scale (iADRS), slowing decline relative to placebo. Baseline iADRS score was 106 in both groups. Change from baseline in the iADRS score at 76 weeks was −6.86 with donanemab and −10.06 with placebo, a difference of 3.20, which was considered clinically significant, but just barely. (P=0.04),

Several scientists who were not involved in the trial pointed out that donanemab had unique qualities that made it stand out as promising candidate for treating AD patients.

Cynthia Lemere, PhD, a basic and translational scientist at Brigham & Women’s Hospital and Harvard Medical School said, “What’s unique about donanemab is its target. The big difference is that this particular form of beta amyloid, called pyroglutamate-3 beta amyloid, is a pathogenic form. Pyroglutamate-3 beta amyloid is not really hugely abundant in the brain in Alzheimer’s; there’s relatively small amounts compared to regular beta amyloid. But the difference is that pyroglutamate-3 resists degradation. It’s been shown to be very toxic to neurons in vitro. It aggregates not just amongst itself, but it can actually help regular beta amyloid aggregate and form plaques. In my own hands, when we’ve looked at unfixed human brain sections from Alzheimer’s patients, we see pyroglutamate-3 in every single plaque, every single one. We think it’s an integral part of the plaque pathogenesis, the actual initial deposition and the continuous deposition of plaques in the brain.”

Ronald Petersen, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, also pointed out that donanemab dropped the amyloid levels quickly. In the study, once the amyloid levels dropped to a certain level, the study subjects were switched from donanemab to placebo, but the effect persisted. What this may mean is that, with certain drugs it might not be necessary to treat Alzheimer’s patients monthly for the rest of their lives. Petersen said, “If this finding is replicated in other studies, it may be possible that you could drop the amyloid level to a baseline, then stop treating them.”

That would indeed be a major breakthrough. Of course, further studies with donanemab are underway. We’ll keep an eye on them.

The huge decline in cancer screenings during COVID-19 will have consequences

It certainly was understandable that people would want to stay away from any kind of medical facilities when the COVID-19 pandemic was at its worst, and it’s also understandable that, by and large, the medical community’s attention was focused elsewhere. But the decline in cancer screenings was very significant, and it will surely have consequences in terms of cancer progressions, in many cases going from a stage where the cancers can be treated with likely good outcomes to a stage where treatment is much more difficult and outcomes much more doubtful.

National claims data from January to July 2020 showed that there were 9.4 million fewer screenings during that period than during the same period in 2019. Screening deficits in that period compared with the same period in 2019 totaled 3.9 million for breast cancer, 3.8 million for colorectal cancer, and 1.6 million for prostate cancer, representing declines of 28.1%, 37.3%, and 15.5%, respectively. The sharpest declines were seen in April of 2020 compare with April 2019 – a 90.8% drop for breast cancer screening, 79.3% for colorectal cancer screening, and 63.4% for prostate cancer screening.

A study in Spain confirmed that the decline in screening contributed to worse outcomes. During the first six months of 2020, there was a 38% decrease in new lung cancer diagnoses compared with the same period in 2019. However, that decrease in diagnoses was accompanied by a doubling in 30-day mortality, and median overall survival declined by almost a month.

It has been observed that declines in screening have led to more advanced cases in several cancers. For example, since the prostate cancer screenings via the PSA test have declined, due to the recommendations of the US Preventive Services Task Force, although there has been a decrease in the diagnoses of prostate cancers, there have been significant increases in cases of more advanced and metastatic cancers.

Larry Norton, MD, medical director of the Evelyn H. Lauder Breast Center at Memorial Sloan Kettering Cancer Center observed, “One of the great advances we’ve made in modern oncology is the ability to diagnose and intervene early, which often improves prognosis and certainly minimizes the therapy to achieve that good prognosis. So any slippage in our ability to diagnose early, which is through screening, is of great concern. It’s also a matter of what therapy is required to achieve a good prognosis. If we see later-stage cases, it is still possible we’re going to cure these people, but with much more aggressive treatments.

“That’s a part of the story the public may not be sensitive to. My fear is that people will think that when this pandemic is all over they can get diagnosed and get the same kind of therapy and the same kind of cure rate they could have got before. I don’t know if they realize that time works against you when you have a growing cancer.”

An over-the-counter placebo works as well as the trial drug in the treatment of erectile dysfunction

In this case, the trial drug was a topical gel compounded with nitroglycerine, which, applied to the head of the penis, would produce an erection within a few minutes. The placebo was an over-the-counter gel called DermaSys formulated with “volatile solvent components that are specifically tailored for the treatment of ED.” The specific DermaSys formulation, MED3000, is made by Futura Medical, as is the nitroglycerin formulation, which was called MED2005. Futura, a pharmaceutical company in the UK, conducted the trial comparing the two gels.

Employing nitroglycerin as an agent in the treatment of ED would seem to be a natural. Nitroglycerin is used as a quick oral treatment for angina, which is mostly caused by constriction of coronary arteries causing reduced blood flow to the heart. Nitroglycerin increases blood flow to the heart, and would be expected to do the same for the penis.

However, the placebo gel from Futura performed just as well as the version containing nitroglycerine. The randomized, double-blind, placebo-controlled clinical trial, dubbed FM57, enrolled about 1,000 subjects from nine Central and Eastern European nations. At baseline, about 62% of participants said they could insert their penis into their partner’s vagina. At a 12-week analysis, that proportion increased to 86% among those who applied the placebo and 83%-86% among those who applied the nitroglycerin gel. Also at baseline, 22% reported having an erection long enough to complete intercourse. At 12 weeks, this increased to 59% among those who applied the placebo and 58%-61% among those who applied the active treatment.

Futura Medical has disclosed that the European Union has recommended that MED3000 be certified as an approved medical device. It will be the first topical treatment for ED available without a physician’s prescription.

Futura also reported that it has reached an agreement with the FDA on a small clinical study to be conducted before the treatment is considered as an over-the-counter medical device in the US. The Phase 3 open-label trial, expected to start in the second half of this year, will include about 100 participants with ED. The trial will be led by Johns Hopkins University urologist Arthur Burnett, MD, and will compare the gel with tadalafil (Cialis) in terms of safety, speed of onset, and efficacy.

Comments on this topic have been mixed. On the one hand there are those who point out that the so-called placebo response in several clinical trials of treatments for ED have been quite elevated. They question whether the response to MED3000 might be something other than the response to the so-called “volatile solvent components that are specifically tailored for the treatment of ED,” such as the sensation of evaporation of the gel and its volatile ingredients, or the stimulation during the application of the gel. But on the other hand, there are those who welcome an addition to the ED treatment toolkit, which, as they point out, mostly consists of those same old PDE5 inhibitors – sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra).

According to Aritzon Advisory & Intelligence, the global market for ED treatment is projected to reach $4.7 billion in the next five years.

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Gumshoe Central has received requests for illumination on a couple of subjects. One – what are the prospects for pritumumab, from Nascent Biotech? Doc Gumshoe has only