Antiviral Molnupiravir Reduces Risk of Hospitalization/Death by ~50 Percent | Hacker News Reader

Antiviral Molnupiravir Reduces Risk of Hospitalization/Death by ~50 Percent

merck.com

206 points_Microft270 comments

I think it's disappointing that this thread has devolved into a political discussion that is hardly related to the topic. The scientific/medical achievement here seems significant.

As an MD, the difference between calling in a script for a pill and arranging for outpatient infusion therapies is vast.

Indeed. The opportunity for prophylaxis with an oral antiviral is also amazing.

I definitely would not want to be taking a mutagenic prophylactically.

I was talking about post exposure prophylaxis. This drug does have mutation concerns.

If I'm choosing between a taking the drug right now for 2-3 days in lower doses Vs a 50% chance of taking much higher doses for 2 weeks, id take the former.

The moment you have symptoms peak replication is already over for two da,s. It's to late by then.

That's not how PEP works. You'd be taking it after having had a contact, before symptoms.

Thank you for weighing in. I am hugely excited about this and immediately sent a message to all my family. I know people who died because they didn't know that antibody treatments were available and effective when given early enough. I very likely saved my own father's life by helping him to get an antibody treatment when he and his own doctor knew nothing about it at the time. When we're talking about pre-hospitalization, this knowledge is everything. This pill is hugely promising and I will be following it closely.

Would you mind to share which antibody treatment were you able to get for your father? I would be useful for the rest of us if we ever find ourselves in this situation again.

It was the Monoclonal antibody treatment that is part of the official NIH treatment recommendations. There are a few formulations with different brand names, but the recommendation is to take whatever is first available and there is not published evidence of one being better than the others. I don't even know which he was given and does not matter at this point. The infusion lasted several hours at our local hospital and required a positive Covid test and needed to be ordered by a doctor stating that there were enough comorbidities to justify the treatment, the went through a lottery weighed on risk factors, then an appointment was scheduled. It is free to the patient but very expensive to taxpayers. It needs to be given as soon as possible after symptom onset to have the greatest effect.

The odd thing is that you have to start pushing strongly on the paperwork to get this fairly invasive treatment when you still feel perfectly well in order to get it in time. You have to act quickly purely on your risk factors and not on how you are feeling.

That's why this pill has so much potential. It could be handed out immediately after a positive test and prescription and is easy enough that it becomes "why not" instead of "why". Of course this is a very new drug, but for certain high risk people it may make a ton of sense.

If only he got the free vaccine, could've saved the rest of us tens of thousands of hospital bills.

Though they appear to have been available a couple months before the vaccine so it's possible the situation was warranted.

> devolved into a political discussion

Welcome to the "intelligentsia" debating anti-Covid measures. On the topic, you usually see worse than this.

Be wary of commenting on the tone of a thread. Skimming it 39 minutes later and it seems a very reasonable, varied thread. Wait for voting to do it's thing.

Some interesting points on the nature of our pharmaceutical patent system... (and while the cohort in this study does seem a bit small, the conclusions appear to be fairly valid):

> "Molnupiravir was invented at Drug Innovations at Emory (DRIVE), LLC, a not-for-profit biotechnology company wholly owned by Emory University, and is being developed by Merck & Co., Inc. in collaboration with Ridgeback Biotherapeutics."

> "In fiscal year 2019, more than half of Emory's total $689.1 million in research funding came from the federal government, the university's largest sponsor."

Clearly, this patent should be assigned to the federal government, not to Merck, and anyone who wants to manufacture and distribute it should be able to do so under an non-exclusive federal licensing program. The transfer of intellectual property created by the public funds to private entities is simply a criminal ripoff of the taxpayer.

[edit] Wait, was this a three-week clinical phase III trial? Seems massively expedited relative to other phase III trials?

> "Phase 3: Just 33% of drugs make it past Phase 2 and into Phase 3, which tests the potential treatment in the largest number of people. This phase measures both safety and effectiveness with many volunteers, sometimes thousands. Phase 3 trials last from one to four years."

Trial began on Sept 2 2021 apparently?

1. https://www.clinicaltrialsarena.com/news/merck-ridgeback-mol...

We would need to examine the research proposals, and the data rights included in them, and if any other institutions providing matching funds, that resulted in this drug.

Having said that, I broadly concur that we need to examine to what extent the federal government, and all of us taxpayers, should own outright some, or all as a % of the IP.

Why do people here always want to reduce the equity and income of pharma and biotech scientists?

It must be because they have extensively modeled the optimal societal benefit of reducing the financial incentive to these entities.

I don't think investing money necessarily transfers the ownership of things bought with that money to the investor. The government could put in their contract "we get all your drugs that you invent" if they wanted that. But this would be like startup VCs getting 100% of your company, or your bank getting the appreciation on your house when you sell it, etc. They could ask for those things, and you could say no... and most people do say no.

The government wants to focus research into particular areas, not compete with the pharmaceutical companies. (At least the money isn't for making a new advertising platform, which is probably something a VC would fund in a heartbeat. Drug discovery is too risky for them.)

You may disagree with that, but that's their intent. If you want the government to be discovering drugs and testing them, definitely tell your elected representatives that that's what you want, and the system can change. (Or get rich from an advertising platform and do it yourself! ;)

Even the VCs get a better deal here, they end up with equity. If followed that model, then the taxpayer would own at least 50% of the patents generated (via shares the corporate entity that owned the patents).

Under the current model the taxpayer gets nothing, which hardly seems reasonable given the amount of capital they provide.

Don't we already own a portion of what gets created though? If Merck makes a boatload of money off of this, the taxpayers will indeed be taking a cut.

No we decided that corporate taxes should be low so the company can reinvest. The shareholders benefit.

>If Merck makes a boatload of money off of this, the taxpayers will indeed be taking a cut.

Merck's effective tax rate was 15% in 2019 and 20% in 2020[0]

They make boatloads of money by underpaying their taxes [1]:

  In 2004 Merck disclosed that it might owe the U.S. Internal Revenue Service (IRS) some $2 billion after the agency notified the company that it was disallowing deductions Merck had taken since 1993 relating to a partnership set up in 2003 as a vehicle for obtaining financing for the acquisition of Medco.
  
  In 2006 the Wall Street Journal reported that Merck had set up a subsidiary in Bermuda that, in partnership with a British bank, was given title to the patents for the company’s blockbuster cholesterol drugs Zocor and Mevacor, thus saving Merck an estimated $1.5 billion in federal taxes over ten years.
  
  Shortly thereafter, Merck disclosed that it was embroiled in four separate tax disputes in the United States and Canada with total potential liabilities of more than $5 billion. In 2007 the IRS announced that Merck had agreed to pay $2.3 billion to settle its federal tax disputes.

They also make additional boatloads of money overcharging Medicare/Medicaid:

  In 2008 Merck agreed to pay the federal government more than $650 million to settle charges that the company routinely overbilled Medicaid and other government programs and made illegal payments to healthcare professionals to induce them to prescribe its products.
  
  In December 2011 the Massachusetts attorney general announced that Merck would pay $24 million as its part of a $47 million settlement reached with 13 drugmakers to resolve allegations that they overcharged the state’s Medicaid program.
  
  In 2012 the Louisiana attorney general announced that Merck and four other companies would pay a total of $25.2 million to resolve allegations that they overcharged the state’s Medicaid program.

[0] https://www.stock-analysis-on.net/NYSE/Company/Merck-Co-Inc/... [1] https://www.corp-research.org/merck

That's 15%-20% we the taxpayers own then :)

By that logic, they would own a similar share of Papa John's, your corner grocery, and companies funded by VCs or banks instead of public funds.

Then is the investment return fair? Do people kind-of get health and Merck gets their fleece?

> Then is the investment return fair.

That's a totally different conversation, and it has to start with what we mean when we say 'fair'. My definition is very likely different than yours in the context of taxes.

> Merck's effective tax rate was 15% in 2019 and 20% in 2020

20% is not unreasonable. That's similar to the European OECD nation average of 21.7%.

> The government could put in their contract "we get all your drugs that you invent" if they wanted that.

"The government" isn't an entity that can unilaterally decide anything. I think it's incredibly revealing that very little of this process is understood or publicized.

There is a clear path for taking ip that is beneficial for national security

I think a better option is for the pharmaceutical corporations themselves to reduce both their advertising budget and their shareholder dividends and pour those funds into their own independently financed research institutes (see Bell Labs for the model followed in the past).

The best way to encourage them to do this is to eliminate exclusive licensing of inventions financed even in part by the taxpayer, i.e. NIH, NSF funding etc. Under this model, Merck would still be able to produce the drug but any other competitor could also produce the drug, and then you'd have a competitive production process (see steel production etc.) which would, I believe, create the highest quality products at the lowest cost to the consumer.

Where is the motivation for Merck to pour funds into a drug they don't get any return on?

And if the government is doing this R&D instead of pharma cos, what is their motivation to perform? If you're a government apparatchik making decisions about what drugs to invest into R&D for, what penalty and upside do you get for being wrong/right? Getting fired or getting a promotion? That's hardly motivating at all.

Your proposal has terrible incentives for everyone all around and would certainly reduce innovation in the long run.

I think you completely misunderstand my point. Merck would be inventing new drugs on its own dime with no government input so it would own that IP outright, yes?

This allows universities to concentrate more on the kind of fundamental basic research that underlies all applied research discoveries; this basic research may not produce IP but is utterly foundational for new applied discoveries.

But the entire reason Merck and co don't pour money into foundational and/or exploratory research is because it's unprofitable. Giving the money to universities to do the research instead of doing it themselves doesn't change that. This is why things like DARPA exist in the defense industry: to fund exploratory research that would otherwise be unprofitable.

Government is already "profiting" by getting novel lifesaving drugs for their money. That's why if your research doesn't deliver results you don't get more grants. They also get a return in the form of jobs for their citizens. I don't see why it's govt's job to make profits off every venture, since their goal should be to maximize wellbeing of their citizens instead. And even if you think they should profit, the tax dollars from even a single successful drug would easily pay for a full year's NSF grants to the entire scientific community.

Bell Labs was hardly unprofitable, was it? So Merck can fund its own Bell Labs, can it not? Just invert the current typical R&D : S&M budget at any pharma outfit, which is like 1 : 3 at present (research vs. marketing).

Yes, they may have to cut shareholder dividends, yes a more competitive market will mean lower profits. However we are talking about people's lives here, and I don't care about Merck's shareholder dividends at all in relation to that.

AT&T was a national monopoly. Merck has a monopoly on a few drugs. The difference is huge.

> lower profits... I don't care about Merck's shareholder dividends

Aaand we're back to terrible incentives. You can't force people to do things that don't have incentives. Even the Soviet Union had incentives. The more you mandate regulation, the more people will find ways around it, either by finding creative ways around your regulations or just moving to other nations with more friendly policies (e.g. China, Europe). The only regulations that work are the ones where peoples' incentives are aligned with what government wants to achieve.

Regarding your edit: there isn't any shortage of covid-exposed people right now.

Often, trials lag because not enough participants fulfilling the criteria can be recruited. This is especially pronounced in rarer diseases.

Plus, you will know outcomes of covid pretty quickly. Compared to diseases such as Alzheimer or multiple sclerosis, covid develops fast.

> Clearly, this patent should be assigned to the federal government, not to Merck

How about a proportional slice? That would seem fair. IP and products can have fractional ownership.

What does "fair" have to do with anything? Are you suggesting that your proposal maximizes the amount of health-improving interventions that society will receive in the future? Do you have any reason to conclude that what you're suggesting will be even a slight improvement?

As a taxpayer / healthcare consumer who is not employed in pharma -- yeah, it would be nice if we (the US) did a little less subsidizing of drug development for the rest of the world. Proportional ownership of sponsored drugs seems like a nicely aligned incentive. What am I missing?

I don't know how the pharma industry decides what to pursue, but it is at least plausible that part of the incentive for what they do depends on being able to price discriminate in sales to other countries. Before suggesting we tear down Chesterton's fence, it seems reasonable that you should have more justification than just that it seems fair to you.

I don't understand your concern -- how does proportional ownership eliminate pharma's ability to price discriminate? I just think the US government should receive some prorated portion of profits from drugs they subsidized development of, which can be reinvested into further development.

These are separate issues. You said that the US is subsidizing drug development for other countries and suggested that you would prefer that we didn't. That affects drug development incentives.

You're also saying that the US government should have some of the profits that the drug companies currently have. Presumably this would affect something that drug companies do. Shouldn't you be concerned that the thing it will affect is them developing new drugs?

Maybe the current situation isn't optimal but there's no reason to think that your suggestions would improve things.

You’re sounding rather aggressive.

It seems reasonable that if I finance X% of something, I get to enjoy X% of it. Or Y%, adjusted for non-monetary investment by someone else.

It seems strange that the state finances (drug development) research, the companies say “cheers” and proceed to keep all the profits.

Such profits could for example go towards universal health care improvements.

Maybe we want different things from the US government and its health care system. I'd like to optimize health outcomes. You have some proposals. Can you explain how they lead to something better than the status quo? What are the unintended consequences? Do drug companies invest in less drug development if they get X% less from developing drugs? Have you taken this into account in your advocacy for enjoying the X%?

Or maybe you have a different objective?

Ultimately the issue is the licensing of the patent (which is likely retained by Emory or its non-profit affiliate), and under Bayh-Dole universities can exclusively license it.

By introducing non-exclusive licensing, then you have a competitive situation in which the lower-cost manufacturer can provide the drug more cheaply but at the same quality and monopolistic pricing schedules cannot be introduced by the likes of Merck.

The taxpayer benefit is lower cost of drugs invented with taxpayer funds.

You can thank Bob Dole for that wrt patents from Federal research funds.

TIL.

I'm slowly learning that, when the government has a choice between and obvious, smart way of operating, and a clearly dumb way. They choose the dumb way because some chucklefucks in Congress made it illegal to operate the smart way.

Not sure it's dumb... it's just the way... Academic institutions should be able to patent basic research. One would argue that the govt gets a 30% tax cut.. now maybe that's excluded since mosts schools are nonprofit but idk.

This is a consequence of the Bayh-Dole Act (https://en.wikipedia.org/wiki/Bayh%E2%80%93Dole_Act).

The phase III trial was cut short at the recommendation of the independent monitoring board. Apparently the effect was so strong they recommended seeking Emergency Use Authorization earlier, rather than waiting for the trial to finish, presumably so that they could save more people’s lives who might get sick and die waiting for trials to finish.

> Clearly, this patent should be assigned to the federal government, not to Merck

Would Merck have done the research if they didn't get to own the patent?

Merck didn't do the research, Emory did the research. Now, maybe you're thinking, would Merck finance the clinical trial of like 1000 people if they didn't get exclusive licensing right to the Emory-owned patent?

Well, perhaps in a non-exclusive licensing situation, other pharma outfits, or a consortion, or how about the federal government? would pay for the clinical trials. I'd guess this situation - competitive manufacturing - would result in a massive drop in the price of the drug for people who needed it.

> or how about the federal government

This is the answer I was fishing for. If you want the government to own the patents, they should do the work.

If they outsource some of the work in exchange for the patents, perhaps the work that they are outsourcing is specialized and difficult for them to achieve.

Say you owned the patent, the research was solid, high likelihood it would work, but needed a 1000 patient phase 3 trial and whatever, that you can't and don't know how to do.

Would you "outsource"¹ the work for price of an exclusive right to make the drug? Would you ask for something in return?

Remember, it is we - the people - that have the right and resources, and in our name our representatives distribute them to researchers and make the deals with salesmen.

¹ more like sell the businness

* Personally not from US, wanted to show the framing. In any case, most research is an international effort, so maybe I shouldn't completely exclude myself.

The trial was stopped early because the results were overwhelmingly positive, and thus it was considered unethical to leave the placebo group untreated.

Phase 3 trial was stopped on a positive interim analysis by DSMB and in consultation with FDA

Interim analysis was performed on approximately half of the total enrolled patients (775 of the 1550).

Trial included many delta and other variant patients

—————

Efficacy

  • ~50% reduction in hospitalization (14.1% PBO vs 7.3% drug)

  • 100% reduction in deaths (8 PBO vs 0 drug)

—————

Safety

  • fewer adverse reactions in the drug arm vs PBO (40% PBO vs 35% drug)

—————

[Merck Ridgeback press release] https://www.businesswire.com/news/home/20211001005189/en/Mer...

[clinicaltrials.gov] https://clinicaltrials.gov/ct2/show/NCT04575597?term=molnupi...

Looks like the clinical trial was for age 18 and above so an EUA probably would not allow use in children.

I mean I think that's ok at this point. Kids are at greater risk of a lot of other things before Covid. We're going to have to figure out how to get our kids to become nose breathers again and fix their enlarged adenoids.

Is 40% adverse reaction to a placebo typical? Really makes me wonder how many "side effects" are in our heads..

Couldn’t the adverse events in the placebo arm actually be caused by Covid?

Probably. There was no uninfected control group.

Given that this is a drug that's only given to people who _have covid_, I'd say it's incredibly difficult to disambiguate from covid symptoms.

Covid and at least one comorbidity. 14% of the control group died; it’s no surprise that 40% had some sort of bad reaction, since presumably they were in pretty bad shape overall.

Keep in mind that any negative effects, even those unlikely to be caused by the medication, need to be reported as adverse effects. It allows for making a clean comparison between the placebo, and also makes it possible to retroactively relate effects that have been overlooked previously. For example, you want 'patient was hit by a car' as possible side effect, because the medication could make people drowsy.

Please read the excellent popular science book "Cure: A Journey into the Science of Mind Over Body" by author/journalist Jo Marchant. It gives an excellent overview of all things placebo related.

ps. the answer to your question seems to be "quite a lot".

Came here to say that it's not necessarily in our head - you can knowingly get a placebo and still react to it. As far as I know it's a combination of head, genetics and other unknown factors. In my opinion an underappreciated and understudied field.

That depends. In the case of vaccines, the placebo is often all the ingredients of a vaccines minus the biological component, or in other cases, an already approved vaccine is used as the placebo.

So, it's probably a poorly controlled study, or garbage results, or both.

If you want to read a comment on this, try Derek Lowe's:

https://www.science.org/content/blog-post/molnupiravir-thor-...

Wikipedia has an article on the drug already if you would like to have a look at that instead:

https://en.wikipedia.org/wiki/Molnupiravir

> exerts its antiviral action through introduction of copying errors during viral RNA replication

How does this target only viral RNA, not the body's own?

Copying errors don't sound like something you want in your own RNA.

"However, there are inherent risks in this approach. NHC can be metabolized by the host cell to the 20-deoxyribonucleoside form by the ribonucleotide reductase and then incorporated into the host cell DNA. The mutagenic effect of NHC has been shown in animal cell cultures (10), raising concerns on the potential risk of molnupiravir-induced tumorigenesis and the emergence of detrimental mutations in sperm precursor cell generation and embryo development."

https://www.jbc.org/article/S0021-9258(21)00667-0/pdf

Yikes. I think, instead of quaffing carcinogens, it's wiser to get vaccinated.

100% agreed on getting vaccinated, but for the elderly or immunocompromised people vaccination isn't enough to necessarily prevent severe outcomes and it might be worth the risk. As a young person, I'd probably stay away, at least in the near term, given how effective vaccines are.

If you're elderly, I suppose it's down to how many years you have left under various outcome scenarios under various risks.

You're not going to reproduce, so reproductive harm isn't an issue.

I believe the reason the trial was in unvaccinated people, was so that it would have a big enough signal to detect quickly. If you did the same trial with vaccinated subjects, it might still be making a 50% reduction in hospitalization, but it would take a lot longer to detect that. I don't think the idea is to only give it to the unvaccinated.

I'd love to talk to someone who refused to get vaccinated but gave their informed consent to participate in this trial.

Kind of boosts my personal theory is that a lot of vaccine hesitancy is driven by the fact that it's an injection and if it were a pill instead people would be more willing to take it.

Your theory is entirely possible. But I’d also like to point out that the study population was entirely Covid positive people with one or more risk factors. Presumably if you’re overweight, over 60, and have Covid you probably are willing to take more risks than before to improve your odds of not dying. Even the vaccine hesitant might accept that risk.

I enjoyed this article explaining in more detail how the drug works, though much of it goes over my head: https://www.nature.com/articles/s41594-021-00657-8

Briefly, it causes the copying process of viral RNA to go wrong by increasing the number of G-to-A and C-to-U mutations. A potential worry is that such mutations will also increase in places where we don't want them, such as in host DNA, but apparently at least for mitochondrial RNA things look good.

> A potential worry is that such mutations will also increase in places where we don't want them

Can anyone speak to how the drug avoids this? I've tried reading the literature, such as the Nature link above, and have failed to see what makes the drug specific to the virus.

Nature link says the drug targets RdRp specifically which is a type of RNA copying mechanism (mostly?) confined to viruses. Wikipedia says about RdRp:

> RdRps can be used as drug targets for viral pathogens as their function is not necessary for eukaryotic survival. By inhibiting RNA-dependent RNA polymerase function, new RNAs cannot be replicated from an RNA template strand, however, DNA-dependent RNA polymerase will remain functional.

It's also known to be mutagenic in mammalian cells, see the link I posted in a reply to the parent.

Well one possibility is that, like chemotherapy or radiation vs. cancer, it's worth the risk. The body has DNA-repair mechanisms that could clean up the mess, if you're only taking the pill for a short time. The virus does not. Just a guess.

Seems like a lot of added potential risk for anyone at low odds of being hospitalized for Covid.

https://pesquisa.bvsalud.org/global-literature-on-novel-coro...

Curious why this is downvoted. Is this person wrong? It seems like an important detail if the drug is actually mutagenic in mammalian cells.

It is misleading but not directly wrong. Excessively high doses lead to mutations, but that's true for aspartame too. Nothing suggests that a therapeutic dose for a short time will give you cancer any more than X-rays from plane travel (i.e. there's a causal mechanism, but it's not statistically significant.)

See my reply to them for more details.

Judging from his comment history he seems to spread a lot of this kind of covid "doubting" information.

It clearly states that clinical use should be carefully considered, so don't worry they're aware of its side-effects.

Full text here it's not trivial to find [1].

This study doesn't show that molnupiravir (rNHC) is genotoxic at levels effective for treating covid. Dosage of 1µm reduced COVID+ cells by 15x, while 3µm removed the infection entirely. [2] 1µm and even 3µm dosing didn't lead to any statistically significant genotoxicity, only 10µm showed effects [3].

The authors know this, because their conclusion is that the risk of genotoxicity "might not be zero." They have not demonstrated that therapeutic doses cause any statistically significant increase in mutations.

1. https://academic.oup.com/jid/article/224/3/415/6272009?login...

2. https://academic.oup.com/view-large/figure/283696469/jiab247...

3. https://oup.silverchair-cdn.com/oup/backfile/Content_public/...

The wikipedia article on the drug mentions worry about it being a mutagen with some kind of controversy. Difficult for this layman to evaluate.

Disclaimer: I'm not promoting Ivermectin here, don't get me wrong. I just want to cover my bases as this announcement is definitely going to be used by people to support their conspiracy theory.

Earlier this year Merck the manufacturer of Ivermectin issued this [0] statement saying that Ivermectin isn't useful for preventing/treating Covid-19 and people shouldn't take it. Some people explained that with the fact that Ivermectin is cheap and they want to develop a more expensive option. I didn't take this seriously, just another conspiracy theory. But now they are coming out with a $1000 per dose solution. According to the FDA [1], the use of Ivermectin for Covid-19 is still being studied and they refer to ongoing trials. Now some people with actual subject matter expertise will know more than me but afaik we haven't completely ruled out Ivermectin for the treatment/prevention of Covid-19, have we? If not, could there be some truth to the allegations that Merck somehow is stalling the Ivermectin studies?

[0] https://www.merck.com/news/merck-statement-on-ivermectin-use...

[1] https://www.fda.gov/consumers/consumer-updates/why-you-shoul...

Is there any evidence they are?

Otherwise, that sounds like a conspiracy theory itself.

Not that I know if. I'm a layman I know pretty much nothing in that field so I'm just having a hard time dismissing the whole Ivermectin thing. Especially now that Merck will make a boatload of money with their new drug.

If I was Merck and I had a drug #1 that costs a few cents that might work and I can develop a new drug #2 that will cost $1000, then I'd probably not look into #1 much simply for financial reasons.

That might not be how it works but I simply don't know that.

Sure, but you're suggesting that they are doing that without any evidence.

This is classic conspiracy theorist rhetoric, whether that's your intention or not.

Sorry, I don't know how else to question the conspiracy theory itself without mentioning the conspiracy theory. I even called it a conspiracy theory.

I mean I think "some large entity (government, pharma company, facebook, etc) is screwing us over to make a ton of money or enact their agenda" is an idea that most people are pretty happy to subscribe to across the political spectrum, particularly in America.

Part of it is because we can see this shit happening in real time now - Epipen prices getting jacked up by the daughter of the currently-most-consequential senator (Manchin), who is basically refusing to enact even basic Democratic agenda items particularly in regards to healthcare, etc etc.

These theories just take on a different flavor depending where you are on the political spectrum. If you're on the right, Facebook is silencing right wing voices. if you're on the left, Facebook is silencing left wing voices, etc.

>A concerning lack of safety data in the majority of studies.

This is the part of Merck's statement that really rubs me the wrong way, and suggests to me that this communication was released with an agenda. The implication is that one of our safest, 60+ year old medications is suddenly potentially dangerous, and this press release is all too convenient when you consider that Merck was working on newer and more profitable alternatives.

The dosing regime purported to be most effective against covid is way higher than the antiparasitic therapeutic window, so the safety history is not as applicable.

Based on a single in vitro study. In isolation such a study is good indication that in vivo dosing is impractical (though a 35x dose is still far under the ld50 for ivermectin[0]), but given that there are dozens of studies suggesting positive effect and the complexity of human/viral biology, the effective dose in vivo may be far lower than the in vitro study indicated.

To be clear I'm not suggesting with certainty that ivermectin works, but I need a better explanation than "these 2 dozen+ studies are all low quality and/or use manipulated/fake data" before I'm willing to rule it out and jump on this bandwagon.

0. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835698/ [see section titled Toxicology]

How could Merck stall those studies? Ivermectin is widely available, you don't need to get Merck's permission to use it in a study.

That's a good point, thanks.

The FDA isn't immune to the same kind of corruption/conflicts of interest that impacts other federal agencies.

Scott Gottlieb worked at the FDA at a high level, before leaving for a stint in the private sector which included being a partner in a VC fund which invested in many medical startups. He left that to become the commissioner of the FDA under the previous administration. Gottlieb is currently on the board of Pfizer, and has relationships with several other companies in the pharma space.

It's not insane to think this person still has sway with people who are working within the FDA and are considering a move to the private sector.

> The FDA isn't immune to the same kind of corruption/conflicts of interest that impacts other federal agencies.

Do you think there's only one organization in the world that could possibly study these things?

Doesn't matter. The USA is the key market for pharmaceuticals because of the outrageous prices that can be charged there. Example: Mylan charges $600 for an EpiPen that's $100 in other parts of the world, for no other reason than they can.

If a company wanted to, they could certainly use the online social media polarisation to poison any discussion.

Any discussion of the validity of Ivermectin as a COVID treatment is now "political", in the sense that Team Red thinks that its a gift from god, and Team Blue thinks any consideration of it is anti-science stupidity.

And since there is a strong correlation between Team Blue and the vocal science community, in a sense someone could drive consensus about a drug to make and studies into Ivermectin political instead of evidence-based - because who wants their university peers to think they are Team Red instead of Team Blue.

Even though there are peer reviewed studies that show some correlation between Ivermectin and COVID viral loads - https://www.thelancet.com/journals/eclinm/article/PIIS2589-5...

I'm not saying they did, but its not unimaginable to do.

The problem is that if the in-vitro studies are correct on their dose curves, then the majority of the human trials are at ineffective doses. This doesn't mean they must be wrong, but it's not a good look. If the studies were showing unequivocal benefit, we could overlook the dose curves. But the studies are still quite equivocal.

On the other hand, molnupirivir is a nucleoside polymerase inhibitor, with a slam-dunk mechanism of action, evidence of efficacy against a broad range of viruses, and increasingly compelling human safety profile.

I don't know if Merck is stalling but the ivermectin case is certainly less compelling.

https://www.science.org/content/blog-post/ivermectin-covid-1...

Those in vitro studies were done with Vero cells, from the kidneys of a green monkey, which do not appear to be a good analogue for human lung cells with Covid. Even if you could give the Ivermectin doses recommended by the study without killing the patient, chances are it wouldn’t actually work.

There's an ongoing study: https://www.ox.ac.uk/news/2021-06-23-ivermectin-be-investiga... and I've also seen https://web.musc.edu/about/news-center/2021/09/17/trial-of-o...

I've read elsewhere that the problem with Ivermectin treatment for covid is that the dosages showing results have to be higher than for previously tested usages of the drug so side effects are also not explored enough

Drug companies have lots of products. Did J&J discontinue their baby powder because they secretly knew talc powder cures covid but they wanted to sell more vaccines?

Here is why this is a conspiracy theory and likely complete bull: there are 190 somthing countries in the world. Many of them have public health systems with socialized healthcare. Many of them are completely free of influence from Merck or the FDA. Ivermectin is cheap and widely available. There is no way Merck and the FDA could suppress a global consensus if the drug was strongly effective.

Conspiracy thinking often relies on a simplified model of the world, one in which other countries, other governments, and other healthcare systems simply do not exist. One where a single centralized entity could have ironclad control over a messy, complex and heterogeneous world.

If you are engaging in these patterns of thinking, I recommend you step back, get out of your bubble and your normal context, diversify your information diet and try to ask more pointed questions of the viewpoints you are taking in. And please stop wiggling your eyebrows at us.

> If you are engaging in these patterns of thinking, I recommend you step back, get out of your bubble and your normal context, diversify your information diet and try to ask more pointed questions of the viewpoints you are taking in. And please stop wiggling your eyebrows at us.

I am not. I clearly pointed out that I think this is a conspiracy theory. However I should still be allowed to ask questions that help me point people that believe in these conspiracy theories into the right direction. That doesn't make me a conspiracy theorist.

> If not, could there be some truth to the allegations that Merck somehow is stalling the Ivermectin studies?

You are holding this conspiracy theory up as something that should be discussed and considered as possible truth. You didn't say you believed it, only that it was worth our attention.

Almost a year ago, nih.gov wrote about a study, 'Ivermectin is an FDA-approved broad-spectrum antiparasitic agent with demonstrated antiviral activity against a number of DNA and RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).'

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539925/

Over one year ago, Nature said ivermectin has antiviral properties. 'It is highly effective against many microorganisms including some viruses.'

https://www.nature.com/articles/s41429-020-0336-z

Literature says Ivermectin has antiviral properties. It is cheap and has few side effects. It appears to be safe and useful enough to be used as a prophylactic for those who suspect they have been exposed to the virus.

The literature doesn't just say it has antiviral properties, The Lancet itself has published papers that show that "A concentration dependent antiviral effect of ivermectin in COVID-19 was identified, with significant reductions in SARS-CoV-2 viral load in respiratory secretions among patients"[^1].

The fact that you are being downvoted, even though the science is relatively sound shows how polarised this topic has become.

[^1]: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5...

I am not surprised that the medical establishment are focused on the high-priced drugs while ignoring a promising treatment which is cheap. The people who turn health issues into blue/red or left/right seem to have missed out on the joys of healthy living and being physically fit. While I understand the medical monopolies want more money, I don't understand how regular people actively resist taking charge of factors of their own health.

We wouldn't need to spend $1000/dose if people just got the free vaccine!

The vaccine is free to patients, but the US government negotiated a price of about $20 per dose of the Pfizer vaccine and insurers can be charged $150-$190 per dose.

Pfizer reported $10.6B in net income in the first half of 2021, up $3.6B from 2020 - largely due to the Covid vaccine.

I'm not complaining though. $60 (2 shots + booster) to drastically reduce the chance of dying from covid seems worth it. Hospitalization can also cost $10K+ per night.

Not to mention that high vaccination rates probably helped California move past the delta peak.

A potential bottleneck in the deployment of this is that only Heimdall is able to wield the Molnupiravir.

Thor! Or, perhaps, The Thing and the Hulk. Superman probably as well. So, still, a shortage of capable health-care workers to distribute, you're correct.

This is not my field. But if there is a pill that can reduce death by 50% from the virus, I would like to know more about it.

> Bright's concerns that similar drugs in its class have mutagenic properties

As a layperson, this instantly raises a red flag in my mind. Should I be concerned? Why, or why not? More importantly, where can I find research that elucidates this for me?

>That's the effect of NHC and of molnupiravir. What about the bad side? Well, auxh nucleosides can also be taken up by many other enzymes, including those that handle our own nucleic acids, so some of them are mutagenic. Indeed, that's how NHC was first characterized, as a mutagen in bacteria. They also tend to be cytotoxic, via a number of mechanisms, and nucleoside drug candidates are notorious for wiping out in human trials due to toxicity in the liver, kidneys, and other organs. That was a feature of the 2012 scramble in the hepatitis C area, where Bristol-Myers Squibb paid 2.5 billion for a nucleoside addition to its proposed therapeutic cocktail, only to see it all demolished within a few months when it turned out to have severe problems in human trials. From this story and others you can also conclude that you don't necessarily get a good reading on this stuff in animal trials - another feature of Fun With Nucleosides.[0](Derek Lowe)

[0] https://www.science.org/content/blog-post/molnupiravir-last-...

(edit: this is just a note I found, does not solve why/why not in my mind)

There are quite a few nucleoside analogues that have been used for HIV treatment: AZT, Zerit, FTC, Videx, Abacavir, 3TC, Hivid. There may be others I'm missing.

Of these, only Abacavir and FTC (as part of Truvada) are still used, the others have fallen out of use or are no longer even manufactured due to their bad side effect profiles and propensity for severe adverse reactions. 'Nuke-sparing' regimen planning specifically would combine other classes of drugs to avoid this class due to side effect issues.

I think it's great to have this new treatment option but this class of medications is well known for its side effects. Avoiding vaccines as 'unproven' and then going for this in particular I would consider eye rollingly wrong headed.

I'm not sure if this is tightly related, but here is Bright's whistleblower complaint [1] because it seems that mutagenic concerns are a different issue?

[1] https://s3.documentcloud.org/documents/6882540/R-Bright-OSC-...

P13-14:

> During the meeting, Dr. Painter and Mr. Clerici presented a drug, EIDD-2801, as a “cure all” for influenza, Ebola, and nearly every other virus.

> They requested that BARDA urgently invest millions of dollars into their “miracle cure.” Emory’s presentation included limited data, and no data at all from human trials. Dr. Bright asked targeted questions to understand the science behind the drug and its potential to safely treat patients. Dr. Bright knew that similar experimental drugs in this class had been shown to cause reproductive toxicity in animals, and offspring from treated animals had been born without teeth and without parts of their skulls. Dr. Bright accordingly asked Dr. Painter and Mr. Clerici about clinical trials, including whether Emory had conducted a reproductive study for toxicity, which they had not.

Molnupiravir, being a polymerase inhibitor (in layman's terms it "jams up replication machinery"), has the potential for mutagenicity. In fact it was dropped by a Gilead subsidiary for this exact reason. [1]

> A company called Pharmasset Inc. (a hepatitis C drugmaker Gilead bought in 2011) investigated molnupiravir’s main ingredient around the turn of the century, but it abandoned development over concerns that it was mutagenic, meaning it could lead to birth defects.

Actually the article is slightly wrong, mutagenic is causing mutations in the host's germ or somatic DNA, teratogenic is causing birth defects. Most mutagens are teratogens too. From the Dr Bright complaint filing, Bright was concerned about reproductive toxicity (teratogenicity) so I'm not sure if the article meant to say teratogenic, or the concern is that the drug is both mutagenic and teratogenic (polymerase drugs tend to be both).

Subsequent tests seem to have shown a lack of mutagenic activity in hosts (eg Painter 2021), at least enough to get through safety trials, which is excellent. But looking at it from a structural activity point of view, molnupiravir is way, way more likely to have a DNA-affecting mechanism than mRNA. It has also shown mutagenic effect in vitro [2]. Nonetheless, a small increase in cancer risk years down the road (especially in the over-70 crowd) is likely worth the 50% (!) reduction in mortality.

It's probably fine, as long as you aren't pregnant. Like all drugs, it's about risk/benefit ratio. The covid vaccine has a much more favorable profile and should still be the preferred option. I doubt it'll be approved for pregnant women without a reproductive toxicity study.

1 - https://www.bloomberg.com/news/features/2021-03-25/merck-mrk...

2 - https://pesquisa.bvsalud.org/global-literature-on-novel-coro...

Search for 'β-D-N4-hydroxycytidine safety' if you wanna dig deep.

It reduces death by 100%. It’s hospitalisation that’s reduced by 50%.

Atea Pharmaceutical is finishing up phase 3 trial of a Covid anti-viral pill in November that might be more effective (based on phase 2 trial data) and doesn't mutate the virus: https://ateapharma.com/at-527/

https://www.nytimes.com/2021/10/01/us/merck-antiviral-pill-c...

The NYTimes article sort of came off as suggesting this is a cheaper, easier to administer alternative to monoclonal antibodies. So I wonder what the overall effect will be on the number of deaths going forward. It’s definitely phenomenal science though, and hopefully we can use this to keep people out of the hospital!

The mechanisms of action are different. I expect clinicians would want to use both, at least for high risk cases.

the interview i heard this morning indivcated that there's also a big unknown around whether it can induce genetic mutation (presumably in gametes). (male) participants were advised against (unprotected?) sex during the trials to prevent potential future problems with progeny.

Male and female participants were required to abstain from unprotected sex.

Hospitalization from COVID-19

Funny that we just assume that anyways these days.

The full article title is:

Merck and Ridgeback’s Investigational Oral Antiviral Molnupiravir Reduced the Risk of Hospitalization or Death by Approximately 50 Percent Compared to Placebo for Patients with Mild or Moderate COVID-19 in Positive Interim Analysis of Phase 3 Study

The HN one is somewhat arbidged.

I had to check the title to make sure it is not there. I totally read "from COVID-19" in my mind.

There's a joke in here about the conflation of the data all throughout the pandemic and how there's been a failure to differentiate between with Covid and from Covid.

https://www.theatlantic.com/health/archive/2021/09/covid-hos...

There’s maybe an amusing counter point from this study. Here they ran a trial with a highly at risk population (due to comorbidities) and reduced hospitalization by 50%. I guess it’s possible the drug is 100% effective and the hospitalization of the remainder were driven by other factors, but even in that case you’d be overestimating hospitalization by just a factor of two. And since none of the people who received the drug died, I guess it’s good indirect evidence that we’re counting covid deaths among the high risk, diagnosed population reasonably well?

Paragraph near the bottom of Reuters article on Molnupiravir states:

"Merck has said data shows molnupiravir is not capable of inducing genetic changes in human cells, but men enrolled in its trials had to abstain from heterosexual intercourse or agree to use contraception. Women of child-bearing age in the study could be pregnant and also had to use birth control."

Link to said Reuters article: https://www.reuters.com/business/healthcare-pharmaceuticals/...

What do you suppose would happen?

I believe that is standard for trials like these.

Read this comment (directly above this question at the time of reading): https://news.ycombinator.com/item?id=28722155

If I understand things correctly, this only helps _before_ hospitalization.

The trial was on non-hospitalized patients, because you can't test impact on hospitalization risk with patients that are already hospitalized. But given the supposed mechanism of action, I don't think there's any reason to believe it would not also be an effective therapy for hospitalized patients.

This drug is an antiviral and isn't the Covid viral load already on the decline by the time that most people are hospitalized? See Fig 2 from https://www.bmj.com/content/371/bmj.m3862 . Its the other issues like the inflammatory cytokine response, tissue damage, and secondary infections that cause the poor outcomes in most hospitalized patients.

So you'd need to take any antiviral early on. I think they said within 5 days in this study. Also of interest is that the 5 day marker is where the mild and severe cases diverge according to the article I linked to.

It makes one wonder why they administer remdesivir and other similar drugs to hospitalized patients.

Right. Other wise "reduces risk of hospitalization" wouldn't make sense...

Well, yeah -- tautologically, it only helps reduce risk of hospitalization before hospitalization. But it could still be a useful therapy post-hospitalization -- I don't know.

People need to be proactive and get tested if they feel a sickness coming on. It seems like there are a few good treatments if you catch it early. When you are hooked up to a ventilator it is too little too late.

Now we need a way to get these pills safely to someone’s door in less than 24 hours. If you call your doctor just when you’re developing Covid symptoms, he should be able to get a regimen of these pills delivered to you on the same day. Without that, they’re not only pointless but will seem ineffective.

My understanding as well. By the time people are hospitalized, the disease isn't necessarily still prolific in their body; the post-infection damage kills them.

It is possible that it could allow for more aggressive immune modulation and immune suppression in people where post-infection and immune damage is the main issue.

Will this affect mandate requirements, if as effective as it’s claimed? If so we don't need to reach hard to achieve 95% vaccination rates and we can get closer to a normal life.

If it halves hospitalizations, it'll have a pretty drastic effect on overwhelmed ICUs but there's probably still a ways to go before ICU levels return to normal and we can skip mandates.

Norway, Sweden, and the UK no longer have mandates, it's a political question not a medical question.

We, Sweden, lifted the mandate 2 days ago and after a clear trend of the small fourth wave not increasing.

Precisely. Also congrats on having sane politicians. Sweden has 10x the hospitalization rates of many countries that still have mandates, thus it is a political question, not a medical one.

What countries? Show me the data.

Edit: Deleting most of my post since Sweden does not track hospitalizations, only ICU admissions so I compared incorrectly. Here is the graph for ICU, judge for yoruselves if there are any with a 1/10 of Sweden's numbers.

https://ourworldindata.org/grapher/weekly-icu-admissions-cov...

I misspoke, it was deaths, not hospitalizations. Norway has 1/10th the deaths per capita of Sweden. Canada has 1/2 of what Sweden has, and we are still have mandates and restrictions.

> it's a political question not a medical question.

Not as much here in Norway as it is in the UK. Our death rate per unit population is one tenth of the UK and local authorities remain prepared to reinstate restrictions. Here we have been living pretty much normally for months already anyway.

And while the government has occasionally overreacted both the government and population have mostly followed the Norwegian Public Health Institute (FHI) advice.

> it's a political question not a medical question.

>> Our death rate per unit population is one tenth of the UK and local authorities

It's a fat question at the end of the day. Norway doesn't have many fat people.

It has a lot more now than it did when I arrived here in 1986. Dramatically more so.

given the UK's death rate, I wouldn't use it as a data point for success.

If we’re worried about hospital capacity why are we firing healthcare workers?

Because it helps reduce capacity which increases the political will for mandates.

We have vaccine mandates because infected healthcare workers spreading COVID reduce capacity even more. We haven't actually fired many workers, because the vast majority just get the vaccine (mostly before the mandates).

1. You need to account for the fact that some percentage (perhaps large) of healthcare workers already survived COVID and have natural immunity. Since the science is demonstrating that natural immunity is as durable and robust as vaccine immunity (if not more durable and robust), one would have to ask what the rationale is for firing workers who have natural immunity (as verified by a past COVID diagnosis or presence of antibodies) and do not want to be vaccinated.

2. The science is clear that vaccinated individuals can contract and spread the virus. While this doesn't mean that the vaccines aren't useful (they absolutely are), we need to be realistic about this in high-risk settings.

Healthcare workers have been on the front line, unvaccinated, for going on two years. To mandate it or risk being fired has absolutely pissed off quite a few that I know of... My wife has gotten it, and even she is offended.

The hyperbole around this very serious situation just makes all the policies seem even more like theater.

To your second point, there was just a new report I saw yesterday that there is no difference in viral load between asymptomatic vaccinated and unvaccinated individuals.

> do not want to be vaccinated What's the reason for this? The vaccine has been approved fully by the FDA and hundreds of millions of people have received it.

> 2. ... Sure, and people who have had covid and get it again as well. But why risk sick days, lost productivity, severe illness when there's an effective, safe alternative. The capital cost of caring people who get sick with covid is far higher on a per capita basis for those who are unvaccinated.

> do not want to be vaccinated What's the reason for this? The vaccine has been approved fully by the FDA and hundreds of millions of people have received it.

It's none of your business why they don't want to be vaccinated. If science demonstrates that COVID survivors have strong immunity, why should they be forced to be vaccinated as well? We do not force people who can show immunity to measles, mumps, and rubella to get the MMR vaccine.

From the CDC: https://www.cdc.gov/vaccines/vpd/mmr/public/index.html

> You do not need measles, mumps, and rubella (MMR) vaccine if you meet any of these criteria for presumptive evidence of immunity*:

> You have laboratory confirmation of past infection or had blood tests that show you are immune to measles, mumps, and rubella.

> Sure, and people who have had covid and get it again as well. But why risk sick days, lost productivity, severe illness when there's an effective, safe alternative. The capital cost of caring people who get sick with covid is far higher on a per capita basis for those who are unvaccinated.

You are distorting the science by trying to lump people who survived COVID in with the unvaccinated. They are not the same group.

From Israel: https://www.medrxiv.org/content/10.1101/2021.08.24.21262415v...

> SARS-CoV-2-naïve vaccinees had a 13.06-fold (95% CI, 8.08 to 21.11) increased risk for breakthrough infection with the Delta variant compared to those previously infected, when the first event (infection or vaccination) occurred during January and February of 2021. The increased risk was significant (P<0.001) for symptomatic disease as well. When allowing the infection to occur at any time before vaccination (from March 2020 to February 2021), evidence of waning natural immunity was demonstrated, though SARS-CoV-2 naïve vaccinees had a 5.96-fold (95% CI, 4.85 to 7.33) increased risk for breakthrough infection and a 7.13-fold (95% CI, 5.51 to 9.21) increased risk for symptomatic disease. SARS-CoV-2-naïve vaccinees were also at a greater risk for COVID-19-related-hospitalizations compared to those that were previously infected.

> This study demonstrated that natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced immunity. Individuals who were both previously infected with SARS-CoV-2 and given a single dose of the vaccine gained additional protection against the Delta variant.

I wonder if the answer to all of this changes if insurance companies decide that covering the cost of laboratory confirmation of covid 19 antibodies or the cost covering the expenses related to hospitalization exceed the cost of vaccination people who may not need it.

If Aetna decided to not cover hospitalization if you are not vaccinated (or I'll give you laboratory confirmed immune), then it would be an entirely different calculus for people.

The argument of "Oh well I'll just find a different insurance provider" doesn't track in the United States either because most people do not have that option. The mandate and the exchange has been almost entirely gutted, so you're left with the option your employer provides.

That's another good point too. The government really doesn't have a lot of say in terms of whether or not you're vaccinated, it's entirely your employer. At the end of the day it's not Aetna/Kaiser/Blue Cross/et al. covering your health care costs, it's your employer. They certainly do not want to cover any unnecessary expense. So requiring employees to be vaccinated is the simplest, scalable, and cost effective solution.

If we're going to point to organizations that have no tolerance for the unvaccinated for diseases other than covid, we need look no futher than the US military: https://www.hhs.gov/immunization/who-and-when/military-membe...

I find it interesting that you're talking about ways to coerce people to vaccinate when the discussion here is how you deal with people who are known to have survived a COVID infection and thus have natural immunity. You seem to be conflating the immunologically naive with vaccine naive. Why? What is your intention?

Over 43 million Americans have already tested positive for COVID. I don't believe there's an official count of the number of people who have tested positive for antibodies, but speaking to your comment about cost, an antibody test is under $50.

https://www.labcorp.com/coronavirus-disease-covid-19/individ...

> Labcorp will bill the cost of the COVID-19 antibody test directly to your health plan if you are insured, or if you are uninsured, Labcorp will bill the appropriate government program. The cost of the test is $42.13 and is based on rates established by the Centers for Medicare & Medicaid Services (CMS). In the event that your health plan, or applicable government program does not cover the cost of the test, you may receive an invoice from Labcorp for up to $42.13.

Nothing you wrote addresses the scientific evidence, which is that people with natural immunity have protection that is not inferior to that provided by vaccines. In fact, the evidence increasingly shows that their protection is far superior.

Why can't you just leave the tens of millions of Americans who already have a confirmed history of COVID recovery alone? Why do you feel they need to be coerced by the government and their employers to receive a vaccine when the science shows they have higher levels of protection?

The vaccine has been approved fully by the FDA and hundreds of millions of people have received it.

Not unlike Red Bull and Cap'n Crunch.

Why do we have vaccine mandates for people working from home?

You've made an amazing claim, that infected healthcare workers, who, were caring for Covid patients for almost 2 years now, have been spreading COVID further. This, despite the fact that they are most likely to have caught it early as they were caring for patients prior to vaccines, and hence to have obtained natural immunity.

Please provide evidence to support your amazing claim.

I'm no policy or health care expert, but maybe because front-line and hospital workers are exposed to extremely large viral loads which seem to be related to the severity of the disease, and taking one HCW off the front-lines and adding them to the sick in the ICUs is worse than one less HCW and the same ICU level?

This seems like you are trying to start a flamewar about vaccine mandates, BTW.

There's no reliable evidence that healthcare workers wearing proper PPE are exposed to extremely large viral loads. Nor is there evidence that symptom severity depends on initial viral load (beyond some minimum threshold for infection). It's a plausible hypothesis but the human challenge trials necessary to prove or disprove it haven't been done yet.

> Nor is there evidence that symptom severity depends on initial viral load (beyond some minimum threshold for infection).

https://www.nature.com/articles/s41467-020-19057-5

> It's a plausible hypothesis

It's extremely plausible, and been demonstrated before in influenza, poxviruses, and other viruses. The human challenge trials necessary to prove a dose-dependent relationship between fall height and lethality haven't been conducted, either, but we have sufficient evidence from longitudinal and natural experiments to draw firm conclusions.

That study you linked isn't relevant to my point. The question is whether the initial viral dose at the point of infection is correlated with symptom severity later in the disease course. That remains unknown. The study looked at the relation between current viral load and symptoms after infection, which is an entirely separate issue.

Something extremely frustrating about virtually all reporting to date is that I haven't seen any statistics as to infection and reinfection rates among front line workers. The implication is that immunity post exposure/infection doesn't exist, but I suspect that this data is being deliberately withheld because it would suggest that frontline workers don't need vaccines, or at the very least don't need a mandate.

> I suspect that this data is being deliberately withheld because it would suggest that frontline workers don't need vaccines, or at the very least don't need a mandate.

Of all the possible reasons you couldn't find this data, a vast conspiracy is the most likely cause? Come on.

Don't you think it would be a public service for news to report such information? Have it listed somewhere conveniently?

It would literally be the most accurate look at worse case constant exposure.

I'm not implying any sort of conspiracy, just an emergent combination of social pressure and implicit taboo. Lots of powerful and not so powerful reputations are riding on the "danger" of this virus and the "safety and efficacy" of the vaccines. And if that's not enough for you, don't forget that fear gets clicks.

The immediate parent comment is correct. Because Covid precluded elective surgery which is a major money maker for hospitals, the bottom line was hit. Consequently many hospitals cut back, and lot go physicians, PAs, nurses, techs, etc. When you hear hospitals are full, it very often isn't because of lack equipment or beds, but rather insufficient staff, especially nurses due to legal regulations around staffing ratios. (Source wife is a healthcare worker on the frontlines)

Alberta has 173 normal ICU beds. As of this Monday, there were 312 Albertans in ICUs, 265 of whom for COVID [1]. The extra 139 beds were surge capacity, created by shutting down other services, postponing surgeries, and diverting resources to COVID ICU treatments.

Even if the number of COVID patients in ICUs halved, we would have 132 people in the ICU with COVID, or 179 patients in total for all causes. It would still be over capacity and need surge beds, but it would still be much better than the current state. What this tells me is that whether we can skip mandates depends a lot on healthcare capacity in your region. Maybe the US with its higher population-adjusted ICU beds can get back to normal sooner than Canada.

[1] https://www.cbc.ca/news/canada/edmonton/alberta-health-care-...

Alberta has 4.4 mln or so people.

Colorado, with 5.8 mln people, has over 1700 ICU beds.

Alberta's been 'running on fumes' re: ICU beds and they got caught out...

I don't think the two jurisdictions count ICU beds the same. Alberta (and Canada in general) have about half as many ICU beds per capita as the US, not 1/10th. If I had to guess, I would say the number for Colorado includes other types of ICU (neonatal, cardiac, etc.) that the Albertan number doesn't. Alberta has 8,513 acute care beds. How many of those would be counted as ICU beds per the Colorado definition, I don't know.

https://www.albertahealthservices.ca/about/about.aspx

Arguably, most of the world's industrial economies have been running on fumes increasingly over the last 30-40 years, as "fat has been trimmed", JIT supply chains have taken over, and "efficiency via merger-then-closure" have been common themes in national economies.

What are normal ICU levels and is this a goalpost that can ever be achieved?

Long before Covid, it was well-known that hospital ICUs were designed to run fairly close to 100% capacity because it wasn't profitable to pay for staff that weren't truly needed at any given time. Is there any hospital that is going to pay for far more staff than they need and somehow manufacture many ICU beds out of nowhere? I feel like this is a goalpost intentionally designed to never be achievable.

As further evidence, if the situation was actually so dire, would unvaccinated people (many of whom already had Covid) be on the chopping block in so many locations?

Not to mention standardised admission criteria and ICU eligibility criteria were chucked out the window in many countries when covid became a thing

Edit downvotes and no discussion. This place is getting worse

> and is this a goalpost that can ever be achieved?

It could absolutely be achieved. Literally the only thing keeping things from going back to more-or-less normal conditions right now is that there are many unvaccinated people getting extremely ill from COVID and filling up ICUs.

Again, what are normal ICU levels?

As far as I'm aware, ICU staffing is modified to achieve close to 100% capacity at all times with minimal spare beds, whether pre-Covid or post-Covid. If this is the case, then there's no scenario possible, regardless of what happens with Covid, where hospitals report anything but "few ICU beds are available".

The data collected in the US by the Department of Health has routinely shown ICU availability in my county (Santa Fe, NM). That data has generally indicated that roughly half the available ICU beds are filled, with 1 or 2 patients there due to COVID.

p.s. according to our local newspaper, this data is incorrect.

Normal ICU levels are levels lower than "every available nurse and doctor is busy with ICU patients".

It's really not that complicated. Under normal conditions capacity can usually scale to meet the needs of the local community. Under COVID conditions, all theoretical capacity is already taken by COVID patients.

Yet, healthcare systems are currently rushing to axe many thousands of unvaccinated healthcare workers. Don’t you think it sends mixed messages to be claiming that there’s such a dire shortage of ICU capacity on one hand, but to be letting so many fully capable healthcare workers go? (many of whom have already been exposed to Covid and have natural immunity anyway)

remember that in exponential growth, halving the people going to hospital buys you one extra doubling time. (ie, if numbers increase every two weeks, halving the growth buys you two extra weeks.) You need to make sure that the growth has stopped, not just halved.

Yup, and with an R value for delta between 5 and 8 on a two week infection cycle... well thats about 3 days... even with 100% of people vaccinated it will buy about a month, assuming the vaccine numbers hold and 1/35th of the vaxxed vs unvaxxed get hospitalized.

If it’s patented and they can make real money off it, maybe

No. You will never be able to get this to enough of the people who need it when they need it. By the time most people seek treatment it is too late for antivirals to be effective.

Even if that wasn't the case, there us too much political momentum behind mandates in the US for this to change the course.

Hopefully not. mandates are great and we need more forced Medical procedures. Maybe forced sterilization or lobotomies will finally return.

The Ridgeback founders were on CNBC this morning in a very encouraging interview. A few takeaways: 1. They are testing now as a prophylactic and anticipate positive results. 2. The mechanism of action is different from the upcoming Pfizer pill, so it’s reasonable to expect they can be taken together as a cocktail for even better outcomes. 3. It is showing positive results with other viruses in animals.

Cool stuff!

> The Ridgeback founders were on CNBC this morning in a very encouraging interview.

This just feels wrong and makes me uncomfortable for reasons I’m not quite able to articulate.

Why? It’s my understanding that this flows from work done years ago at Emory University. With the exciting news, why shouldn’t they take a bit of a victory lap? Good for them.

Here's a nice Twitter thread explaining how this works:

https://twitter.com/bert_hu_bert/status/1444018619059429377

I wonder, what could be the potential drawbacks of protease inhibitors taken for long periods for prophylaxis? Aren't some essential processes going to be negatively and unpredictably affected?

It's a program that incorporates itself into another program while at the same time corrupting the program, and after several iterations there is a catastrophic failure.

Reduced from 14% to 7% risk. Would be nice to see how it compares to other off-label treatments such as Ivermectin which has had great success in India.

Since it targets RNA replication, I wonder if it may have efficacy against other retroviruses.

SARS-CoV-2 is not a retrovirus. That said, it is likely effective against a wide range of RNA viruses, and its original testing and development was mostly done against influenza[1].

[1]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848974/

So next, if you don't agree to take this drug after getting COVID, you'll be excluded from getting ICU bed if needed?

So an abbreviated trial in 775 people is considered sufficient to move forward with drug approval now?

For a safety trial, likely not, but for an efficacy trial, this is pretty conclusive. In any case full approval will not be granted with even more in the way of trials.

> So an abbreviated trial in 775 people is considered sufficient to move forward with drug approval now?

No. They don't have full approval, and aren't likely to get it in the next few months.

From the article:

> Merck Plans to Seek Emergency Use Authorization in the U.S. as Soon as Possible

Emergency Use Authorization is not full approval, and obviously comes with oversight and data gathering. "as soon as Possible" is not now. But they might get that in the next few months.

Other than that, I don't know what to say about "sufficient to move forward" - any drug at any stage of trials is either abandoned or moving forward? A small trial that meets its goals is sufficient to move forward to the next trial so .. yes? But not to full approval, which they aren't getting anyway.

This is an existing (but fairly new) drug so there there is other data on safety etc, links seem to be about 2019 onwards, at https://en.wikipedia.org/wiki/Molnupiravir

Was using "approval" colloquially, I understand the distinction between that and "authorized." However I have seen many larger trials for other repurposed drugs being tried in early treatment dumped on as "underpowered" so it's just odd that that criticism is nowhere to be found in this case. There were 7 people hospitalized in the trial group and 14 in the placebo.

The criticism is not present because this one wasn't underpowered.

> p=0.0012

I guess you are wondering why this is better than Ivermectin. From the article:

> The MOVe-OUT trial (MK-4482-002) (NCT04575597) was a global Phase 3, randomized, placebo-controlled, double-blind, multi-site study [...]

If you go to https://ivmmeta.com/ you will see:

* Most of the studies have not placebo, they just compare a group of people with another unrelated group of people. It's very difficult to be sure there are no unexpected differences.

* If you filter only the RCT, most of them are not statistically significant. That is a problem because if the drug has no effect, the reporting/publishing/selection bias will cause barely significant studies to accumulate.

* There are only 6 that RCT that are statistically significant. Have you read them? Some have very weird things that are very big red flags.

If Ivermectin has no effect, I expect like 2 of the RCT that are statistically significant to be caused by flukes. Can you pick your favorite 3?

I think we/they have to.

I'll don my tinfoil hat for a moment. A combination of initial vaccine effectiveness estimates having to be downgraded, and variants reducing effectiveness further, along with the infectiousness data of vaccinated carriers putting the herd immunity targets at risk have public health authorities scrambling for the next potential solution.

The data out of Israel and other places is damning. Not in the sense that anti-vaxxers would like, but in the sense that we are still nowhere near containing this thing.

We either need better vaccines, or drugs. So yes, epidemiological standards will relax in the face of a worldwide pandemic, to some extent.

Genuinely curios, and the time will tell, if the vaccine sceptics will be more open to the pill, or if they will be equally/more sceptic of the pill also.

I'm excited to hear why the EUA for this drug is good when anti-vaxers have said they didn't trust the EUA for the vaccines.

This drug helps the anti-tax after infection, but the vaccine helps others and only preventatively.

Also was this medication developed using "mRNA"? That "messing with your RNA" angle is hammered repeatedly in conservative circles - enough that some of my not-right-wing neighbors are worried about it (like, go ahead and vax, but not for the children!!).

But is it patented, expensive and in limited supply?

This is great news, but I worry that many people are going to take it as a continued excuse to actively avoid vaccination. Halving hospitalization rates would still leave ICUs everywhere filled with COVID patients taking beds away from people with other life-threatening conditions.

I'm sure this won't be patented and instead will be given away for free.

Right?

Considering vaccines are widely available and cheap or free, there's no reason this should be given away for free.

Uhm, no they're not. Many countries are struggling to acquire vaccines even today as they waste away in the US.

Trying to improve my skills in recognizing denialism, I would say that this was the “Nefarious Intent” technique, wrapped in a layer of sarcasm?

https://doctorow.medium.com/a-denialism-taxonomy-eeb1a276684...

This is phenomenal news - I'm also curious how the various tribalist memes evolve. Will the vaccine maximalists who ridiculed "horse paste" when the data was still weak in part because a pill-based regime would undermine the message that vaccines ought to be mandatory embrace this much needed second tier therapeutic? Will the anti-vaxxers who will inevitably see this as the goal of a big pharma conspiracy covering up the efficacy of their drug of choice demonize this treatment despite the fact it conflicts with their fears of a vaccine conspiracy and will undermine the justification of mandates? Get the popcorn.

edit: Maybe this should be marketed as Ivermectin 2? I bet that would get more unvaccinated people to take it.

The vaccine maximalists ridicule "horse paste" because many people are literally buying and ingesting products intended for livestock.

In his Nobel-prize lecture, the Merck scientist William Campbell, talks about how Ivermectin was always intended to be used in humans.

Two relevant quotes from his speech are, "I had always insisted that our written departmental objectives would include the development of new drugs for control of parasites in humans" and "The end of ivermectin is nowhere in sight."

Check it out: https://www.nobelprize.org/prizes/medicine/2015/campbell/lec...

I'm not talking about ivermectin itself. I'm talking about how people are literally going to livestock supply stores, buying products that contain ivermectin but come in forms and dosages intended for livestock, and ingesting those (even when intended for topical usage), based entirely on internet advice and without any kind of doctor oversight.

That's where "horse paste" mockery comes from.

Maybe they couldn't get a doctor to prescribe them the human pill because of all the politicization so they took the "horse paste" version.

You seem to have first hand knowledge of all these people's situations, are you following people to the livestock supply stores or talking out of your ass from stories you read on Reddit?

Most people that I know have that have took Ivermectin were taking the human pill. Only on the internet and news media have I seen people talking about horse paste.

Also, some vet meds are okay for humans (as long as you dose correctly), yeah you shouldn't take them, but that doesn't stop some of my liberal friends I know from taking horse tranqs (ketamine).

The only reason that they want an ineffective pill that doctors rightly won't prescribe, but not a safe and effective vaccine, is as you say, "politicization".

It's still a bad idea, on multiple levels: taking Ivermectin for COVID in the first place, taking the horse paste version, self-administering, and guessing the dose.

No, your first sentence shows you're lacking an understanding. They genuinely fear the vaccine and believe Ivermectin works. If it was exclusively about politics they'd embrace the vaccine since both Trump and Biden are pro-vaccine.

Taking Ivermectin for COVID from a doctor as an objectively "bad idea" is ridiculous, because it has been widely prescribed around the world for COVID. At best, it is a "marginally pointless idea."

It's been well-documented in the news, including people being hospitalized after overdosing on the stuff:

https://www.mississippifreepress.org/15002/person-hospitaliz...

https://www.usatoday.com/story/news/health/2021/08/25/iverme...

https://www.fda.gov/consumers/consumer-updates/why-you-shoul...

Since you cited the hilarious poison control story, you might enjoy this analysis: https://astralcodexten.substack.com/p/too-good-to-check-a-pl...

At least one of those was debunked, but yeah the same news that said that someone was convinced to drink fish bowl cleaner because T recommended hydroxychloroquine when it turned out she was trying to poison her husband. It's a smear campaign and if people are taking it, it's because they can't get the human form. It's perfectly safe to take the human form and people take it preventively.

You'd think the HN crowd would be for elective controlled drug consumption and against pushing people into black/grey markets.

Kinda rich coming from the people who try to use ketamine (omg horse tranqs!) for everything.

Ivermectin is useful for control of parasites in humans (1) and other animals such as horses, but the grandparent is also correct, people are "literally buying and ingesting products intended for livestock" - from the veterinary aisle (2), and self-administering random doses not safe for humans, with bad consequences (3). It's sheer lunacy to do that. If it was effective for COVID-19 (a virus, not parasite), then medical staff would be administering correct doses.

1) https://www.who.int/tdr/news/2018/moxidectin-approved-as-tre...

2) https://www.iflscience.com/health-and-medicine/store-only-le...

3) https://www.npr.org/sections/coronavirus-live-updates/2021/0...

Ivermectin is not just for control of parasites, the anti-viral properties it has is because it's a protease inhibitor. It prevents certain viruses from binding to cells.

How effective it is at inhibiting binding is the question. This pill in the article and Pfizer's prophylactic are most likely more effective since it's not a by product but the intent. Also more profitable because of patents.

Nah, not many are, it's being prescribed by doctors on the hope that maybe it kinda sorta works. (It probably doesn't.) It's a safe and widely used drug so on net it isn't a terrible idea if you have an extremely high risk person. Though my understanding is the evidence in favor has gotten weaker over time.

I probably fall into the "vaccine maximalist" category, having family who fall into high-risk categories (age, immune-compromised).

This doesn't change my feelings. The existence of a treatment doesn't negate the importance of vaccination. It does make me hopeful that a return to normal may come sooner than later, as any new treatments reduce the risk of my family dying should they, despite their best efforts, become infected.

People who are vaccine maximalists are those who hear news like this pill and primarily are concerned about its effect on vaccinations, as opposed to being happy we now have multiple effective defensive and offensive measures against the virus, which was always going to be necessary for us to return to normal.

The existence of a treatment doesn't negate the importance of vaccination.

I never would have thought that statement was controversial in any way. I'd say the same thing for measles too.

But here we are. Humans are weird.

Not exactly going to be the same thing.

Merck is applying for EUA use of this medication for Covid-19, something that Ivermectin never had. In addition, further studies didn't show Ivermectin to be useful for Covid. The study that first looked at Ivermectin has been proven to be not useful.

If another study came out opposing the Merck data, then we'd have to dig in as well to find out why, and see if either study was faulty, and if more studies are required or not.

This is how science and medicine works.

There is a large group of people that see disproving studies/claims to mean that some higher power is holding back the miracle cure. That's what happened with Ivermectin, Hydroxychloroquine, etc. This is not how science and medicine should be viewed.

My guess is that:

- anti-vaxxers will eagerly take the pill, but believe that Merck covered up Ivermectin's efficacy to get this drug to market. the claim the vaccine's EUA was held up by lack of evidence of such pills will be memory holed

- the pro-mandate authoritarians will swallow the pill (figuratively, pun intended) when the powers that be celebrate this as a success and it begins being widely deployed.

in other words, we all win. the failure mode is if a divisive political figure takes a strong position on the pill being safe or not safe. fortunately I don't see this happening.

I don't think it's a win that a significant portion of the population will only take a medication if it's wrapped in a conspiracy theory.

Well that ship already sailed. My point about the win is that the memetics of a safe, effective pill imply to me that it will actually be widely adopted by unvaccinated and will also calm a lot of people down who currently are having a bit of a mental crisis over the existence of said unvaccinated people. So we should be happy for several reasons of this news.

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