COVID-19 Research, Drug trials and Pathophysiology

This is what's happening to the restaurant business according to the National Restaurant Association.

https://restaurant.org/downloads/pdfs/business/consumer-sentiment-mask-vaccine-requirements

New case numbers need to come way down or we develop more effective therapeutics if we're going to avoid a wrenching redeployment of capital as the economy writes off a lot of service sector jobs.

 

Unless people shift to different personal mitigation strategies, we could see a serious economic downturn when support payments to people and businesses end.

That would be my guess and hope. Our economy can't take another two years of covid without a truly wrenching write-off of service sector businesses.

Fingers crossed.

 

Very interesting. Particularly this: proof of vaccination requirement would make 32% of people less likely to go to a restaurant but 33% of people would be more likely to go. The rest said it wouldn't have an impact on their decision to go or not go.

So, for the industry, requiring proof of vaccination only gives them a 1% advantage in retaining customers.

This, however, relates to the current situation. If more people get vaccinated due to the mandate, maybe this will tilt the stats in a way that it will be more favorable for restaurants to require proof of vaccination.

 

The news on Pfizer's Paxlovid is even better than I thought. The trial showed it cutting the hospitalizations by 89%, but there were zero deaths in the active arm of the study, while the placebo arm had 10 deaths. Another part of the news is that the subjects in trial were high risk. Not healthy young adults.

So, for high risk patients, the trial showed 89% fewer hospitalizations and zero deaths!

This is pretty major. This can be a true game changer, including because like I said before, these antivirals (there are three of them being studied; one of the three, Merck's molnupiravir, has concluded phase 3, has been authorized in the UK already, and has applied for FDA authorization) hit all variants of the virus, because they do not target proteins that mutate, but rather, they target enzymes needed for the replication process, which is the same for all variants.

Pfizer executive Annaliesa Anderson said the "results are really beyond our wildest dreams."

I said within 3 days of diagnosis. It's actually within 3 days of the first symptom. So once this is authorized and available in pharmacies, people who develop symptoms need to get rapidly tested and rapidly get a prescription, to start the medication before the end of the 3rd day of symptoms, for maximum efficacy.

It's two pills a day for five days, to be taken at home.

Merck's pill will have its FDA review on November 30th.

Pfizer said they'll apply as soon as possible.

I think that at some point in February or March we may have two effective antivirals against the SARS-CoV-2 in pharmacies, which will be a huge game changer.

 

Three questions:
1. Since the antiviral targets an enzyme and the virus uses the host to replicate will that not mean that the enzyme is also needed for the host to carry out a function inside the host? ie what is the function of that enzyme in the human body.

2, Do you know what the cost of this antiviral? If not too costly would it not be beneficial to distribute the antiviral to everyone before they actually get symptoms with the crucial instruction that the drug is not to be used unless you test positive? In the UK we are given free flow test kits and many of us test ourselves regularly.

3. does the use of an antiviral mean that the body will not produce a sufficient number of antibodies to fight future infections resulting in repeated infection and repeated use of the antiviral which could lead to side-effect risk linked to question 1?

Please forgive me if these questions have been asked and answered elsewhere

 

I've found the answer to the first question and the question is now redundant

 

Excellent questions.

1. Not a concern. This antiviral acts by inhibiting the specific viral protease produced by the SARS-CoV-2. Proteases can be found in all members of the Animalia, Plantae, Fungi, Bacteria, Archaea, and Virus kingdoms, but they are different from each other, and there are several different classes with thousands of representatives. We group them on the basis of their catalytic residue. They are classified into seven groups, but each group has several specific ones. The groups (and their catalytic residue) are serine proteases (serine alcohol), cysteine proteases (cysteine thiol), threonine proteases (threonine secondary alcohol), aspartic proteases (aspartic carboxylic acid), glutamic proteases (glutamic carboxylic acid), metalloproteases (usually zinc), and asparagine peptide lyases (asparagine).

Function in humans: many; digestion, coagulation, immune system, metabolic control, etc. Human proteases such as renin, gastricsin, cathepsin D and E, pepsin, trypsin, chymotrypsin, thrombin, plasmin, Hageman factor, etc. are structurally dissimilar from viral proteases, which have high specificity and only cleave a very restricted set of substrate sequences; so we can make antivirals that inhibit viral proteases without bothering the various human proteases (there are more than 640 of them, that we know of).

This is not new. It is for example how antivirals for HIV work.

2. Merck's molnupiravir is supposed to be free for the public. The US government has secured an advance-purchase order for 1.7 million complete courses of treatment contingent to FDA approval, and will purchase more. Just like the Covid-19 vaccines are free for the public, and so are monoclonal antibodies, this antiviral will be free too (I mean, there is no free lunch, so it's actually, tax payers money). I do not know if similar arrangement exists for the Pfizer drug. Pfizer's CEO today said they will need to price it right so that it is accessible to the population, in the middle of this grave pandemic. Big Pharma are not especially charitable but I guess they are growing some compassion for this terrible disease. We'll see. A price point hasn't been established yet. This drug hasn't even had the full analysis of its phase III done yet.

Distributing the antiviral in anticipation of the illness - that would be quite wasteful, and depending on the side effects (which I don't know yet), might be dangerous by leading to unsupervised use of the medication. I don't think this is necessary. If someone develops symptoms, the person can walk into the nearest urgent care center, see someone immediately, get tested, and if positive, collect then and there a prescription for the antiviral, and get it from the nearest pharmacy (just like it happens now for the flu and Tamiflu). Why invest millions/billions in doses that will be in people's drawers and won't be used and will pass expiration date if that person never catches Covid?

3. No, just think of it. When you get a vaccine, you get a tiny bit of mRNA that teaches a bunch of your muscle cells, where the vaccine is delivered, to make spike proteins that your immune system will learn to recognize. These amounts are tiny. But when you get the full natural infection, you get literally billions of viral copies into you and they circulate everywhere. In order for them to produce symptoms (so that you know you have it, get tested, and get the antiviral) they have already replicated by the billions so it's like a HUGE dose of the vaccine. Then you take the antiviral and it zaps the virus, but not before the immune system has already read those viral copies as foreign, and has initiated the process of making antibodies against it.

Once a medication is out of your system, taking it again doesn't give you accumulated side effects, unless they are of an auto-immune or allergic nature. You shouldn't expect worsened side effects if you take a second course of an antiviral months/years later if you catch the virus again.

This said, the studies have not been published yet. All that I know is from Pfizer's executives, so I do not know yet what side effects Paxlovid is causing, if any.

 

BBC is reporting a cost of £500 per course for the drug just approved for use.

 

Overkill in their entirety for most of us, but a handy list of measures that reduce risk of either catching covid or having a bad outcome. My main departure from your list is using a 3M P100 respirator (available on Amazon) ...



... and I mention it here because of my experience of wearing it in public has been uniformly positive with a few people asking me about it and no one expressing hostility.

 

Yes, sure, a P100 would be safer for an immunocompromised person, as would an N100 which is not as huge and as uncomfortable. I think actually P100s are easier to find than N100s. Ultimately a very immunocompromised person, let's say someone with severe leukopenia getting close to agranulocytosis, might wear a PAPR. Cost is a problem for a PAPR; they cost between $1,000 and $1,250. The replaceable filters are $40-$50. When the rechargeable battery is spent, a replacement costs $250. So a PAPR is an expensive device for a lot of Americans, but would be the safest device for seriously immunocompromised people. Some might get their health insurance to pay for it.

 

That would be my guess.

My takeaway from the survey is that significant numbers of people are mitigating risk by avoiding situations where they might catch covid. Restauranteurs are worried with good reason.

 

P100s have been consistently available on Amazon for more than a year.

Maybe I'm used to wearing the P100, but I don't find it uncomfortable. I can walk up several flights of stairs without feeling winded, although I have developed a habit of breathing more deeply when I anticipate needing more air.

As is often said, "It beats the alternative."

 

It sure does.

I do own a P100 but I tend to only use it for painting jobs at home. I was waterproofing a wooden gazebo in my backyard and the fumes are very toxic. It was a job that lasted for several hours. So I had the P100. It worked perfectly (I couldn't even smell the fumes) but at the end of the day, the bridge of my nose was hurting, and I had these deep marks on my face, and was sick and tired of wearing the cumbersome thing. I don't think I'd be able to wear one all day long, every day. But filtration is the same for N100s and they are much more comfortable to wear. The N and P difference has to do with oily fumes, which are stopped by the Ps but not the Ns. However, in terms of virus filtration, they have the same filtering ability (99.97%) so for Covid-19 prevention, I don't see why one would want to wear the bulky P100s versus the smaller and more comfortable N100s. But like I said and you confirmed, P100s are actually easier to find than N100s, but if someone can find N100s, I think they are a better solution. And they won't attract as much attention on the streets, because they don't look very different from N95s (they are larger and bulkier but not too much). But yes, if an immunocompromised person can't find N100s, then P100s are a great solution.

 

Yes, after I posted my answer to @truth and justice I also found this information. Both the Merck and the Pfizer drug are being priced at about USD $700 per course of treatment, which is very expensive for a lot of people, so, the Pfizer CEO's words that they'd have to make the drug accessible price-wise, were BS. Like I said, Big Pharma companies are not charitable organizations.

Over here, the American people will have to rely on the government buying these medications and making them accessible for free to the infected individual (which will mean, we taxpayers will subsidize it, or money will be printed and inflation will increase).

Our wonderful [insert sarcasm here] politicians have always blocked every piece of legislation that would have allowed Medicare and Medicaid to negotiate drug prices directly with the companies or buy directly from the foreign market. Big Pharma lobbies have always managed to defeat such legislation, by giving campaign money to our politicians, who definitely value re-election much more than the interests of their constituents.

 

Free at the point of service here of course, God bless the NHS.
Mind you, at £500, if it saves you being hospitalised it's good value for money for the health service.

 

More details on the two antivirals being looked at, for Covid-19.

Merck's drug molnupiravir acts by introducing errors into the genetic replication of the virus, producing defective copies. The safety profile is very good. Side effects were comparable to the ones seen in the placebo group, were mild, including diarrhea, nausea, dizziness, and headaches, with a few cases of increased blood pressure. No effect in the genetic mechanisms of host cells, when studied at higher doses and longer courses in animals. The US government has contracted with Merck to purchase 1.7 million complete courses of treatment in case the drug gets authorized by the FDA when they meet on November 30th. However the drug will not be available in pharmacies, initially. These 1.7 million courses will be available only through medical providers who will receive an allocation, proportional for each state. Merck said they will produce 10 million courses worldwide by the end of this year, and 20 million by the end of next year. So this drug will be quite scarce at first.

Pfizer's drug Paxlovid, like I said, is a viral protease inhibitor, and I've already explained above how this works. They haven't finished phase III yet so they haven't applied for an FDA EUA authorization but plan to do it as soon as possible (probably just a few weeks away). The excellent results, superior to Merck's drug, still need to survive the end of phase III but the company believes there is no reason why the drug wouldn't. However, it will be even more scarce at first. Pfizer will only be able to make 180,000 courses of treatment by the end of the year, but they will be able to make 21 million courses by the end of June 2022. I do not know anything about side effects to the Pfizer drug except that they occurred in 20% of trial participants, a rate similar to the placebo group - but what side effects were those, the company did not specify (which, I'd say, doesn't bode well). Another detail is that when I initially said the placebo group had 10 deaths and the active drug group had zero, it's even more impressive than that, because the trial was divided in two durations of treatment, 3 days and 5 days, and the 0-10 result of the 5-day trial is to be added to the result of 0-7 of the 3-day trial. So in reality, the placebo group had 17 deaths while the active drug group had zero.

Both drugs can be also studied for post-exposure prophylaxis, and if approved for treatment of Covid-19, this indication can be added later, if trials are positive.

Both drugs are capsules taken twice a day at home. Given that they have different mechanism of action, it's not excluded that they might be synergistic, and ultimately when they are no longer scarce, people could take both simultaneously, to further disable the virus. There is another company studying still a third antiviral, with still a different mechanism of action, so if that one is also positive, we might potentially use 3 antivirals simultaneously like we do for HIV.

Both seem to be priced at about $700 per course of treatment. That's a lot. We'll see how health insurance companies will cover it (they should; if their insured don't take the drug and develop serious cases that require hospitalization, they'll spend a lot more on those patients than $700) and also, the government is planning to make the drug available to infected individuals at high risk, for free, like the vaccines and the monoclonal antibodies. This has been already contracted for the Merck drug, but not yet for the Pfizer drug.

The above is all that I know about this, so far.

It's certainly very exciting, but the downside is that they will both be quite scarce at first (and expensive), so this great tool to curb this pandemic may be months to one year away or more, before being widely available (and affordable) in a pharmacy near you like Tamiflu is for the flu.

 

Aren't we humans getting ever so clever.

 

I wonder if breakthrough cases do better than the unvaccinated.

 

Probably. Of course the breakthrough cases do have antibodies already, so the virus would be attacked in two ways, by antibodies and by the inhibition of their protease.
All trials for these antivirals were done with unvaccinated people, and the Pfizer one, only with high risk individuals. So 89% reduction of hospitalizations, no deaths, among high risk, unvaccinated people, is a simply outstanding result; like the Pfizer executive said, "beyond our wildest dreams." Too bad that it will take a good while for this medication to be widely available. Lots of avoidable deaths will occur until this medication starts preventing them.

 

Pfizer said they will complete their studies by the end of the year. They will apply for the Emergency Use Authorization likely in January 2022.

Another detail: their drug is given together with a low dose of ritonavir, which intends to keep the Covid-19 antiviral working for longer and at a higher level, I assume, through a drug-drug interaction.

Pfizer also said the side effects were "mostly mild."

I look forward to reading the real studies, without the executives from the company issuing vague terms. I want the real science behind these statements. But they haven't published that, yet, so I guess I'll have to be patient and wait.

 

I did some reading up on ritonavir a while back. It’s an old HIV protease inhibitor that was limited to use with other HIV protease inhibitors at low dose because of its side effects at higher doses. I believe it substantially increases the half life of other protease inhibitors but I’m not sure of the exact mechanism. It’s very low dose with this new Covid drug so side effects shouldn’t be an issue.

 

The P100 doesn't bother my face, but I'm not wearing it for hours.

Your fumes experience reminds me of last summer when the wildfire smoke was so bad we stayed in the house all day. I put on the P100 to do a few things outside and I couldn't smell the smoke.

The N100s may still be hard to come by in Canada, but I suppose I should make another effort to find a reliable source.

They're no doubt a better choice for most people if they csn get them.

 

Australia will negotiate a price per pill through the PBS - if not free I am sure we will see massive subsidisation

 

Again I feel we are talking at cross purposes. I am not suggesting we shouldn't have had emergency conditions in the middle of the pandemic.
I disagree with you that we are currently in the middle, we are at the end, trying to decide how we go forward and return to our new normal.
The numbers getting seriously ill and dying are (In the UK anyway) far below those at the peak and while they do vary they are pretty flat.
(My points address that current situation and the numbers going forward from there.)
Yet still many are calling for things that cost our economy and infringe our enjoyment of life. Generally I find those calling for restriction want restrictions that don't effect them particularly. Wearing masks does have an effect on spread but a far more effective method would be a ban on meeting inside each others homes. Yet this is not suggested as that would effect those lobbying for caution. Wearing masks is promoted as good because it only effects people like me in the leisure industry.
It is human nature to most call for change/improvement that has no personal cost.
Against that background what is the acceptable level of fatality and how long do we think it will take to get there.

 

Sure, but I remind you that several times now, people assumed we were at the end of the pandemic, then the virus mutated and restarted the whole thing. And while some countries are (maybe only apparently) in better shape, others are not. In the United States if we look at the number of cases, we had already 5 surges. At the end of each of the five, some people declared victory of the virus, just to see the next surge take place a while later. So, I'd hold back in calling the pandemic at the end, and I'd keep observing what happens next. I am optimistic, though, that the antivirals being developed, which hit every single variant because they target mechanisms that all variants have in common, will deal a decisive blow that will really cripple the pandemic. The companies don't have a dramatic capacity to make them yet, so it will be several months before they become common and readily available. Until then, we'll still need to remain vigilant.