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The Latest Antibody Data From Lilly and From Regeneron

We have a new paper in the NEJM from the Eli Lilly effort on monoclonal antibodies against the coronavirus. And there’s no reason not to be up front about it: it’s disappointing.

This is the BLAZE-1 trial (mentioned in this recent post), which is studying non-hospitalized patients. It was another trial (ACTIV-3) where this antibody was found to be ineffective in hospitalized patients, but the numbers from this trial are not all that impressive, either. I’ll be adding my voice to the chorus – here’s Jason Mast at Endpoints with a roundup of the reactions so far. The trial (which is still continuing) is evaluating single infusions of 700mg, 2.8g, or 7g of the monoclonal in people with mild-to-moderate infection. The primary endpoint is change in viral load at Day 11 after dosing, and what we’re seeing here is the results from an interim analysis in early September.

Here’s the problem: only the middle dosed reached statistical significance on that endpoint. That’s not great from a dose-response standpoint – as usual, the easiest result to understand is seeing the effects increasing with increasing dose. There are most certainly “U-shaped” dose responses, with the U facing either up or down, but with three doses it’s hard to know what that U is like or why it’s shaped like it is. You can bet that Lilly would rather not have seen the results come out the way that they did. One problem was that by Day 11 even the placebo standard-of-care group had a trend towards viral clearance, but the bigger problem is that the antibody wasn’t able to distinguish itself very well from that.

And that’s especially true since the company has asked the FDA for an Emergency Use Authorization for the 700mg dose, arguing that the viral load data – which was the primary endpoint, remember – isn’t the most important thing to consider. But that immediately makes you want to ask them why they made it the focus of the study, and makes this argument sound (unavoidably) like ex post facto special pleading. You also have to wonder what dose the FDA might approve for an EUA, if the FDA is minded to give them one at all. The effective dose in the trial was obviously four times as large as what Lilly is asking for.

When you look at other outcomes, there are trends for symptoms clearing a bit faster, a trend for slightly fewer people to be hospitalized at Day 29, and so on. But the antibody therapy (at any dose) does not distinguish itself much. I really hoped for better, but (all together now) this is why we run the trials. Sometimes we find things that work better than we expected, and sometimes we find a perfectly reasonable idea doesn’t seem to do as much as anyone would have predicted. I think the best hope for a really compelling use for this antibody is in the ongoing prophylaxis trial, but after seeing these data I wonder how that one’s going to read out, too.

Regeneron has also released more data on their antibody cocktail (although in another press release and not in a journal manuscript). This is another non-hospitalized-patient study, in about 800 people. They’re not seeing much difference either in their two doses (2.4g and 8g), so they’re asking for an EUA for the lower one, naturally. The numbers overall look more interesting than the Lilly ones (although it has to be said that these are different trials with different enrollments, etc., so you can’t necessarily just line things up head-to-head). That said, the Regeneron therapy does show significant results for reducing viral load and for follow-ons like reducing medical visits. The best results were in the most at-risk patients, whether that’s defined as higher viral load, pre-existing risk factors, or weak antibody response. That last one was the group highlighted in Regeneron’s earlier look at their data, you may recall. But the Lilly data also look best in these cohorts – that, at least, is a result that’s what you’d have expected.

Does this mean that an EUA would feature a recommendation to use either of these therapies preferentially in high-risk patients? Or a call to get an antibody readout before starting therapy, prioritizing those people who aren’t mounting as good a response? Or is there going to be one at all?

My guess is that yes, we’ll see such a move. But how much difference it makes, that’s another question. As Matthew Herper details in this column at Stat, we have not prioritized production of these antibodies the way that we have vaccines, so there are (at the moment) only about 50,000 doses of the Regeneron cocktail available. A look at the map will suggest that the entire stockpile, even if given immediate authorization and Star Trek transporter-style distribution, would vanish into the national epidemic like a rock thrown into a pond. You’d have to look very hard to see its effects at all. We had around 80,000 new cases yesterday, and that number is going up. 50,000 doses of an antibody that seems to help cut down on hospital visits is not going to make much of a dent in that situation.

Update: and now Regeneron has halted dosing of their antibody cocktail in hospitalized patients with high oxygen requirements, which fits in with the general “dose early” ideas. This one seems to have been both a safety signal and lack of benefit. . .

145 comments on “The Latest Antibody Data From Lilly and From Regeneron”

  1. Marko says:

    Yes , the MAb “bridge to a vaccine” is looking kinda rickety.

    1. Barry says:

      mAbs mimic a part of the IgG response a good vaccine would elicit, but none of the T-cell response, none of the IgA response, and none of the innate response. We knew months ago that some patients without appreciate IgG response fended off covid just fine, and some with high titers got very sick or died.
      The primary site of covid infection is the respiratory mucosa. Pumping Abs into the plasma compartment isn’t relevant unless they can ride Secretory components to the job site.

      1. Wesley says:

        Have you looked into aviptadil at all? It seems like it’s primary action is directly in the lungs protecting the alveolar type 2 cells. Not sure why it hasn’t gotten more press.

  2. charlie says:

    80,000 cases is a lot, but I the CDC is estimating 2300 to 13,000 new hospitalization in a month.

    50,000 doses in the next month would definitely make a difference.

    Herper is claiming 300,000 doses of the Regeneron cocktail in months, and Lily is saying 100,000 right now and “millions” by end of year (two months). Granted that is with the lower Lily dosing which does appear not to work.

    1. Mike says:

      It looks like these antibodies need to be given early to have much of an effect on prognosis. The trials in hospitalized patients have ranged from meh to no result.

      50k doses in the next month– if you give them to a population that has a 5% hospitalization risk, and it cuts the hospitalizations in half– would reduce total hospitalizations by 1250. I think this number is optimistic, but even so– it’s nothing to sneeze at but also does not dramatically change the picture of where we are.

      1. Marko says:

        “…if you give them to a population that has a 5% hospitalization risk”

        ideally , you wouldn’t do that , particularly with a limited supply of drug. You can risk-stratify by age and comorbidities to define a group with a higher hospitalization risk , by a factor of 5 times or more , I’m sure.

        1. confused says:

          Yeah surely you’d want to give it to either the elderly or immunocompromised (if it’s best in those who are not producing a good immune response of their own).

          If it was given, say, specifically to people over 70… the hospitalization rate is a lot higher than 5% in that population.

          1. ScientistSailor says:

            Nope, you’d give it to front-line healthcare workers who need protection. Immunocompromised and very high risk groups need to stay home.

          2. Dark Day says:

            Well . . . if that means everyone over 60 or 65, as well as everyone with high blood pressure, diabetes, obesity, or a raft of other risk factors (as well as everyone who is a recovering cancer patient), we’re talking about over 30% of the population. Making all those folks stay home would probably result in a de facto shutdown of the economy, to say nothing of being psychologically and emotionally devastating for millions of people. I agree that front-line healthcare providers should have first priority, but the “other” high-risk groups should be included as soon as possible. (I would include poor and working-class people, and people of color, in this cohort, by the way. If I have to wait a few more months so the single mom in the housing project down the street from me can get vaccinated first, I’m more than willing to do so.)

          3. Ian Malone says:

            It’s also no good asking these people to “stay home”, they will be interacting with others regardless. Take for example the single mother working in a care home whose child is at school. How does that work? (It’s not a contrived example either, a relative is in a place where that is exactly the case.) Or people who live in multi-generational households? Or live alone but occasionally need assistance? Even in the perfect well-enough-off-to-live-alone-and-not-need-home-help case they still need things delivered, and you can only avoid shared spaces if you either live in a detached house or never step outside home. And that’s slightly assuming we’re talking about people past retirement age, there are at-risk groups still in work.

          4. confused says:

            This is all true, but “at risk” is a sliding scale. There are tons of people who are over-60 and/or obese and/or diabetic etc. But I think a smaller set of people at much higher risk can be identified.

            There’s a huge difference in risk between someone who’s 60-65 and relatively healthy, vs. someone who’s 80-85 and in a nursing home.

            These *most* vulnerable people may be a much smaller more identifiable set.

          5. kriggy says:

            @Ian Malone

            But its the best solution. My country handled the winter thing well by imposing 2week lockdown where you were only allowed to go to work, medical visits or grocery shoping (dont think you need to be that extreme but im not epidemiologist). Most of us were working from home or the companies did many kinds of measure to slow the spread. There are some that suffers (restaurant bussiness for example) but here comes the government to help those.

            You just need to limit the spread, limit the contats between people. It doesnt mean everyone stays home and does nothing. It means you limit the contacts to as low as possible. If necessary, you wear facemasks or whatever. You just have to deal with the fact that your birthdayparty is not happening or you will not visit your mum this weekend.

    2. Mammalian scale-up person says:

      *ahem* How many months are we talking?

      4-6 months for tech transfer, engineering runs, PPQ batches and PAI. I got 24-25 batches for 300,000 doses at 2.4 g/dose and 3g/L titer, at a takt time of 4 days / batch + 30 days ramp up from first thaw after PPQ + a few weeks for final batch release, looking at about 10 months assuming we have all raw materials and consumables on hand and there’s nothing weird or animal derived and all equipment is on hand. I literally checked in with one of our equipment suppliers today and was told there’s 40 weeks lead time on equipment that used to be 6 months for off the shelf standard design.

      Nope. Not happening. I don’t know where these people get their timelines but it’s not reality.

      1. Patrick says:

        You seem to be assuming A) they haven’t already done a lot of this (knowledge transfer, etc), and B) that these equipment shortages you’re seeing apply to these guys in the same way, rather than their being *the cause of it*. If the companies claim these timelines, I see no reason to doubt them more than at the margins. These aren’t startups.

        1. Mammalian scale-up person says:

          It’s true the Regeneron expansion in NY is *ongoing* but it is still not fully commissioned; they had a mud pit and cranes as of mid last year, probably have their shell space up and are receiving equipment now but they are not fully commissioned. In fact they announced in August they will use some of Roche’s capacity for this particular thing, which means they do still need to tech transfer.

          But let’s imagine that this is totally efficient and they are way ahead on tech transfer, they’ve done cleaning studies and engineering runs – OK, they still need to do PPQ and PAI, which is two months instead of 4-6. Let’s say they put it in the Vacaville site, where they can run a batch every 3-4 days, 20kL/batch, and whatever else they were making there is going to be shifted to CMOs. You’re still looking at 6 – 8 months till you make the 2.4g doses.

          Regardless of size (and I’m not a startup person, I enjoy my Big Pharma budget too much), generally we do try to keep our commercial manufacturing facilities pretty close to full occupancy with minimal downtime; that CAPEX costs a lot and needs to be paid down. If we need to make a lot of stuff in a hurry, either we have to do a lot of our own tech transfers to CMOs to create space or we have to build more capacity somehow. The only spare capacity we really have is in development facilities which are designed to have flexibility for the latest and greatest out of the pipeline.

      2. PharmaPharm says:

        PAI is typically waived for EUA

        1. Mammalian scale-up person says:

          Huh, you learn something new every day. I never had anything approved that way, working on boring regular things that actually had to meet standards. Brave new world we live in.

          That is…pretty terrifying, actually. I have seen the inside of consent decree sites where the FDA padlocked the doors because it was so disgusting. I would not want a drug made in an un-inspected facility unless I was sure that the other option was certain death. I definitely would not want it for such marginal benefits as this. Now, Regeneron is making it in Roche’s existing multi-product network: that’s not so bad, they get inspected for plenty of other things all the time, their last inspection will have been recent-ish. But I would not want, for example, startup company vaccines that had not gone through PAI. I will just keep working from home, getting my stuff delivered and wearing a mask to take the recycling out, until Merck, Janssen et al. come out with their version. If that means the local taco stand and gym close for lack of my business…oh well.

          1. Some idiot says:

            Agreed…! It is the sort of new information that (very literally) makes the hair rise on the back of my neck… I have seen some sites during inspections that I wouldn’t want to buy stuff from. I think most of us have…

        2. confused says:

          For those of us who are not in the industry, what’s PAI?

          1. Some idiot says:

            “Pre-Approval Inspection”.

            After you have filed an NDA (New Drug Application, i.e. you actually want to sell the stuff and get it approved), the authorities like to have a look around the place to see whether or not you know what you are talking about, and are doing things properly…! Sometimes they can be combined with another more random inspection, but this needs to be agreed upon beforehand.

            🙂

          2. Derek Lowe says:

            Pre-Approval Inspection (by the FDA)

          3. Some idiot says:

            More generally, also the EMA (European medicines agency). Obviously not for a product sold in the US, but…!

          4. confused says:

            OK, thanks.

            So if that’s not required for an EUA how quickly could production be scaled-up?

          5. Mammalian scale-up person says:

            Well, if tech transfer has already taken place – hypothetically you’re looking at 4-6 months.

            30 days from thawing the first vial out of the master cell bank, you’ll have your first harvest out of the production bioreactor. About 1 day to harvest, then say the usual three chromatography steps, viral filtration and UFDF into the formulation buffer takes another 5-6 days; if you run as semicontinuous, you can do a batch every 4 days or so, assuming batch fermentation times of about 15 days + 2 days to turn around the bioreactor (they need cleaned, pressure checked and steamed before re-use). Most big facilities have 4 – 6 production bioreactors, that’s how we get to 4 days takt. A typical yield in the bioreactor is 3 g/L but the purification process tends to eat a little less than half of that, so you get about 33 kg / batch in the end. If you need to make 300,000 doses of 2.4g each, and you assume 10-15% contingency (batches getting contaminated, failing quality checks or something) you’re looking at around 24-25 batches. My general feeling however is that if you choose to skip engineering runs, you will have enough failures and contaminations to make you wish you had done engineering runs after all.

            I can’t remember if Vacaville has their own fill/finish? Often we make the bulk material at one site but perform the final fill into vials, labeling and packaging somewhere else, and that’s another week or so. Then the batch needs release-tested and all the deviations sorted out to the Regulatory group’s satisfaction, which is another couple of weeks at least when carried out in a decent, clean facility by humans who have souls and I have no reason to believe that either Regeneron or Roche are staffed by monsters.

            So: 30 + 5 + 25 x 4 + 14 = 149 days.

          6. CM says:

            If I remember right Vacaville can do fill/finish but they’ll have to ship it out for label/pack so add six weeks to the timeline.

          7. confused says:

            Has any of that beginning part already been started, or is that 4-6 months *plus* however long we have to wait for FDA to issue an EUA?

            Is that a “minimum technically possible to physically produce the product” timeline, or could it be shortened if regulatory steps were expedited or skipped? (Not saying that would be a good idea — but is it even technically possible?)

            And after that 4-6 months, what kind of quantity would be available?

            Sorry – I am not very informed on this, but am very interested!

          8. Mammalian scale-up person says:

            Given their clinical trial stage at the moment, they’re probably just making and qualifying the master cell bank and putting the finishing touches on formulation chemistry now. They may have done information transfer and sent a few vials of working cell lines to Roche’s MSAT group to play with and get some scale-down runs. Those take a couple of months to do. They won’t thaw the first real vial until the EUA is signed, sealed delivered, that’s when the clock can start ticking. If they are indeed doing finish work elsewhere, it’ll be more like the 6 months to reach 300,000 doses and after about 3 months they would be producing 26,000 doses / week.

            Disclaimer: I work for neither, I just do a lot of this stuff and mAbs are completely standard things that don’t change a lot regardless of who is making them.

          9. Some idiot says:

            I’m not good on the mab side, but I can give you a bit of background from the small molecule side. Broadly speaking, when the timelines for things are done, people work out when the NDA can be filed (ok, we are talking EUA here, but the principle is the same, i.e. these companies will have been planning for different options, and I would guess that their plan would have been to file an EUA, but with a normal NDA being the backup plan). From that they work out when a decision from FDA (EMA/whatever) is expected, and (assuming positive) when they want to launch. Launching in this case is going to be a bit different, since instead of trying to create a demand (and then trying to guess how that demand is going to change with time, and trying to plan production so that it tallies pretty well with the forecasts, but on the safe side), you more or less know that stuff is going to bounce off the shelf as soon as it hits it.
            The point is that (generally, anyway) the planning sort of assumes that the PAI is going to go fine, and a positive result is coming from the NDA/EUA. Because otherwise they are going to be real, real slow off the blocks.

            I guess that the short version is that they have just been pushing hard for the last 9-12 months to have systems that are ready to go. But the process development/process validation/process qualification/tech transfer (the latter is important whether or not you are moving over the road from your own pilot plant to your own manufacturing facility, or from someone else’s pilot plant to someone else again’s manufacturing facility, or any combination of the above) really takes time. Full stop. And it can’t start until you know what product you (probably) want to sell (ie when You get into the serious pre-clinical bits). The science of taking a synthesis of a small molecule and turning it into a robust, safe, practical and economic way of making a compound can be way complicated (and fascinating!!!), and even after you think you know how to do it, the painstaking job of mapping out all of the sweet spots (and even more importantly, the unexpected cliff edges and volcanos) for all of the process steps is just that: painstaking and time consuming. But it is this huge documentation package that you use to actually get something to work. Then you need to adjust it for the much bigger reactors that you are going to use for production. That is just one of the fun bits behind “tech transfer”.

            I seem to recall around 6 months ago that most of the big vaccine players said that they would be doing all of this work “at risk.” In a normal project, you have decision points at different places (typically when results from, eg, preclinical or clinical trials come out) where the organisation says “ok, this looks good, so we will now give the green light to another later stage of this process. That way, if something dies early you will not have wasted too much time and effort (=money) on something that didn’t work. Instead, working At Risk means just that: saying that well, we have no clinical data, but we will assume that it will work, because the cost of coming later balances up the risk of losing your money if it gurgles in the clinic. So this means that around 6 months ago they gave the green light for all of the scale up activities to get going.

            Note that many (but not all) of these activities are linear, which means that there are som time constraints that are doing to be real, real tough to compress.

            Now, like I said, that was from a small-molecule perspective, but would guess that the overall challenges would have a similar feel to them for mabs or vaccines, but I am damn sure that Mammalian Scaleup Person would be able to clarify that one!

          10. confused says:

            OK, thank you!

    3. myma says:

      Let us not forget to add that sterility testing takes a month.

      1. Mammalian scale-up person says:

        If you’re doing third party testing to confirm a rapid micro, sure. Most of the big dogs have fully qualified rapid micro – I am sure Roche does.

  3. Philip says:

    Not sure this is a WHAT (Worthless Hopeless Antiviral Trial). Subjects were those that presented with one or more mild or moderate symptoms. That is much better than the trials that only include hospitalized patients. Those trials using only hospitalized patients are WHATs.

    I still want to see antiviral therapies tried on presymptomatic patients, which was not done here. To do a trial on presymptomatic subjects is going to be hard and require a lot of testing to narrow down when a subject was infected.

    1. Ian Malone says:

      What use is that exactly though? You need a proactive enough testing regime to catch them even before they display symptoms, and then you have to treat thousands of people every day. And any study with criteria that makes it hard to run (catching pre-symptomatic infection for example) translates to a treatment that is even harder to run in practice. Factor in that we think actual infections are running quite a bit higher than reported infections in many countries, but since we’re talking pre-symptomatic treatment we have to aim for that higher number.

      Reference point, my own country is badly failing at infection contact tracing to get people to isolate. That’s the same process you need to go through to find people who need to be tested to give pre-symptomatic treatment.

      1. Philip says:

        The only way to pull off the trial or treatment is massive testing. That means using antigen surveillance testing, something the FDA does not seem to believe in.

    2. neo says:

      WHO is on first. WHAT’s on second. I Don’t Know is third, and I don’t give a darn.

      1. Some idiot says:

        Good to see that people still know the classics…!

        🙂

  4. Ezra Abrams says:

    Can we infer anything about how a vaccine might work from this data ?

    or is that just useless speculation ?

    1. Oudeis says:

      My only qualification is regularly reading this blog, but I think it would be useless speculation. These studies are only antibodies–there’s no T-Cell development like with vaccines. And these studies study people who are infected enough to know about it, and you’d hope a vaccine would have an effect before that point.

      We’ll see how the antibody prophylaxis trials turn out. Fingers crossed.

      1. passionlessDrone says:

        > My only qualification is regularly reading this blog, but I think it would be useless speculation.

        Pretty sure that makes you a PhD in the world of COVID blogging though.

    2. Charles H. says:

      IIUC, different of the in-trial vaccines have different activation profiles. Some of them, e.g., activate T-Cells, but that’s not replicated in monoclonal antibodies. OTOH, some of them only seem to affect antibodies.

      So this seems to indicate that some of the vaccines in process won’t be effective at all. This should show up in the phase 3 trials.

      Again, IIUC. Antibodies to COVID seem to be rather temporary. There’s some evidence that TCell responses are durable. (And there’s more than one kind of TCell, but ask someone else for that kind of detail.)

      So the current state of affairs is still “nobody knows, but we’ve got ideas of things to check out”.

  5. nobody says:

    To recap:

    We have a virus that has upwards of a 90% attack rate in enclosed spaces, spreads extensively through superspreading events, hospitalizes its victims for months (at best), and is so transmissible that a single outbreak can overwhelm any healthcare system within weeks.

    Monoclonal antibodies and convalescent plasma are almost entirely ineffective.

    Existing anti-viral drugs are completely ineffective.

    Sporadic reinfections are possible within six months of initial infection, meaning that widespread reinfections are a likely possibility over the longer term. Acquiring herd immunity though mass infection is not possible even if the death toll was acceptable.

    The best vaccines currently in testing are not expected to provide sterilizing immunity, meaning that herd immunity through vaccination will be impossible.

    The social will to impose short/medium term mandatory physical distancing strategies to protect health care systems, and minimize the mortality rate, either does not exist or has evaporated in much of the world.

    Most governments have been unwilling to ramp up production of respirators/masks of a high enough quality to allow uninfected people to protect themselves. Masks that the market generously allows ordinary people to buy are mostly only useful for source control.

    Most people are not psychologically able to cope with the kind of zero contact lifestyle that is required to keep the virus from spreading.

    Seems to me that anyone who expects ‘back to normal’ at any point in the future is being hopelessly optimistic.

    Seems to me that anyone who is completely confident that civilization won’t collapse within the next few years is also too optimistic. Europe did survive the black death, but society is a lot more fragile now than it was then.

    1. somebody says:

      I am worried too, nobody. But the situation cannot be nearly as dire as you put forth here. Discuss.

    2. CET says:

      Ok…I know I’m going to regret this, but:

      The data as a whole are inconsistent with the virus being both broadly lethal and very transmissible. Particularly in the current wave, where deaths don’t seem to be tracking infections anymore, it seems likely that COVID is rather less lethal than early models indicated.

      The disease does pose a serious risk to specific demographics, but in spite of the media’s charming insistence on hyping anomalous cases, the IFR for most of the population under 55 seems….less than apocalyptic. As in, COVID is probably less dangerous than eating McDonalds.

      1. Dark Day says:

        The lowering death rates, I think, are due primarily to the fact that most of the current surge in cases is occurring among relatively lower-risk populations, as well as the fact that we are a lot better at treating COVID in hospitals than we were months ago. That doesn’t mean, however, that deaths aren’t spiking as well, and it certainly doesn’t mean that this does not remain a terribly debilitating disease (sometimes, apparently, for at least months after “recovery”) for those who do contract it. And again, I’m troubled by this blithe assumption that “only” specific demographics are at “serious risk”. We cannot afford to minimize risk because it “only” affects “those people.” (Would we say the same thing about Tay-Sachs disease or sickle cell anemia?)

        That being said, I am more hopeful than Mr./Ms. Nobody that a decently effective vaccine, combined with improved therapeutics along with prudent public health measures and behaviors for as long as they’re necessary, can result in sufficient population immunity (and / or reduction in morbidities for the vast majority of people) that we can approach a level of population immunity that will allow us to lead relatively “normal” lives again at some point.

        In the meantime, though, I do agree entirely that “Most people are not psychologically able to cope with the kind of zero contact lifestyle that is required to keep the virus from spreading.” The question is — how long CAN we continue to live this way, and how long will it be required? That, I think, is [literally] the life-or-death question .

        1. confused says:

          >>We cannot afford to minimize risk because it “only” affects “those people.”

          Sure, but I think we can say that this is very serious (the worst public health crisis in decades) without suggesting that it’s a threat to *civilization itself* as “nobody” suggested.

          And I do think the age distribution is relevant to that. A disease with ~0.65% IFR wouldn’t be civilization-collapsing anyway, but one that preferentially killed working-age people with dependents/”breadwinners” would have much more damaging “secondary” effects than COVID does (which I think is part of why HIV/AIDS is so destabilizing in some parts of Africa).

        2. Ian Malone says:

          We can’t entirely discount the effect on the working population. The numbers of deaths make the headlines, but people in their 30s and 40s are being put out of action for months, we still don’t know how long ‘long covid’ is (though people do seem to be starting to recover). There’s gathering evidence of cognitive impairment https://www.medrxiv.org/content/10.1101/2020.10.20.20215863v1 Additionally the load on health services will have knock on effects to other groups.

          It’s not the end of civilization, and coronavirus mitigation measures likely overshadow or overlap the direct economic effect it would have, but coronavirus would have its own economic effect even if we tried to carry on regardless.

          1. confused says:

            >>We can’t entirely discount the effect on the working population.

            Discount, absolutely not. It’s definitely much more significant than any other infectious disease in the US. But it’s just not end-of-civilization levels.

            And while some people in their 30s and 40s are “out of action for months”, I think that is *very much* not the usual case.

        3. CET says:

          “And again, I’m troubled by this blithe assumption that “only” specific demographics are at “serious risk”.”

          Sure – and I don’t mean to imply that this makes it a non-issue. Just that it is a risk to be evaluated and managed, and not the end of days. 200K deaths is a lot of people, and it will certainly continue to climb, but the point I wanted to make here (and was perhaps overly flippant about) is that COVID is killing far fewer Americans than cancer or heart disease (and fewer than accidental injuries for many age cohorts). That doesn’t mean policy and personal behavior aren’t important – just that a lot of the populace could really stand to take a couple of deep (safely distanced) breaths and get some perspective on this thing relative to risks that we already live with.

          “The question is — how long CAN we continue to live this way, and how long will it be required?”

          I agree. But, it seems likely (and supported by the evidence so far) that the severity of the outbreak as measured by deaths and hospitalizations is generally decreasing over time. That could change, but if it holds, it’ll be interesting to see if a vaccine is still relevant by the time it can be developed and distributed.

          1. Dark Day says:

            ” . . . it seems likely (and supported by the evidence so far) that the severity of the outbreak as measured by deaths and hospitalizations is generally decreasing over time. ”

            It doesn’t seem that way to me, either here or in Europe, but of course we’ll have to see how things progress over the next few weeks. This surge, though, does look pretty major, and (as usual) hospitaliztions are trailing new cases but rising steadily, and deaths will no doubt show the same pattern. There will be fewer deaths, no douobt, for reasons already discussed, but I’m guessing that to the extent we continue to see infections among the high-risk populations, the death rates will continue to be high. And, again, even with a vaccine, those populations will continue to be vulnerable.

          2. confused says:

            Well, death rates can be, and I think are, both increasing (in terms of deaths per day) and decreasing (in terms of deaths per thousand infections) in the US/Europe.

            >>And, again, even with a vaccine, those populations will continue to be vulnerable.

            Do we actually know this, given that we don’t know which vaccine(s) will be approved, and what other treatments will be available?

            It makes sense that a vaccine will be less effective in the most elderly population – but if monoclonal antibodies are specifically good in people with the weakest immune systems, and if they are widely available in say a year, that problem may vanish.

            Let’s not borrow trouble too early.

        4. Charles H. says:

          Actually, people are very compatible with the kind of lifestyle that is required to keep the virus from spreading. Divide the population into groups of 50 or so people and isolate those groups from each other. Impose a 2 week delay on any physical contact between those groups. (Simulating travel by caravan or caravel.) People are quite compatible with that situation, it’s modern civilization that isn’t compatible.

      2. confused says:

        Yeah – not to minimize it at all – 230,000 deaths so far is a whole lot! – but the comparison to the Black Death is simply absurd. That was well over 50% mortality; COVID now is probably something like 0.5% (CDC “best estimate” is 0.65%, but it seems to have dropped over the course of the pandemic, so is likely a bit lower now?) A 100x difference.

        Part of the issue with COVID is precisely that it’s quite deadly in elderly populations, but *not* in younger ones, and younger people often simply don’t take it seriously. And this applies to some older people too… it rather seems that the President has taken the fact that he survived COVID (and there were no deaths in the White House outbreak) as confirmation that it’s not as dangerous as thought.

        1. Dark Day says:

          Agreed. We cannot minimize the deleterious effects of mixed (and often downright false and irresponsible) messages from on high. On the other hand, to be fair, even in many countries where officials have conveyed good and consistent messages, and where robust preventive social policies were enacted early on (e.g., Germany), we’re seeing very disturbing resurgences which are already resulting in the re-introduction of partial lockdown measures. So, as appalled as I continue to be with the inept blundering of the Trump administration (virtually since the beginning), looking at what’s happening in Europe makes me realize that we can’t blame him 100%. This thing IS serious, it IS tenacious, and it’s going to be a long, hard struggle to get it under control.

          1. Michael says:

            The resurgence is, of course, disturbing, but is it surprising? At the start of the pandemic, the consensus expert prediction was that (a) the most significant wave of the pandemic would be the Northern Hemisphere second wave starting in the fall, and (b) it would take 12-18 months to develop and start to roll out a safe and effective vaccine.

            The second wave is occurring as predicted (maybe a few weeks ahead of schedule), and the vaccines are on (and hopefully a bit ahead of) schedule. And because these things — predicted 7-8 months ago — are happening, suddenly the end times are on the table? (I know you don’t think that, Dark Day, but you know what I mean.)

          2. confused says:

            Oh, I agree with all that… but that’s not really the point I was making. There are in fact places in the US right now where very uncontained COVID outbreaks are happening yet *not* producing society-collapsing results. It seems very implausible to me that society in, say, the Dakotas will collapse in the next month or so.

          3. Dark Day says:

            Good point, Michael — I think that one reason a lot of folks (and yes, myself included) have been rather haunted by “End Times” specters recently is that when those predictions were first made, it was at least hoped (if not assumed) that people would heed them and proceed to move slowly and prudently toward “opening up” their economies, personal lives, etc. over the course of the next several months. (Remember, one of the reasons prophets make dire predictions is to convince people to change their evil ways before it’s too late, to keep those predictions from coming true.) That didn’t happen, so the dire scenarios that were foretold are now coming true.

          4. confused says:

            I have to say that back in the first half of March I expected *nothing* to be done in the US outside of CA, WA, and possibly NY, so I thought the first wave was going to go to herd immunity in most of the nation by June or so. I was very surprised to see stay-at-home orders in most states.

          5. Dark Day says:

            It’s that “most states” that’s the problem. Our Federalist system of individual states with a lot of individual freedom is wonderful, but there are times when a coordinated nationwide effort to confront an emergency is necessary. We can hypothesize all day long as to exactly why that didn’t happen in this case, but it didn’t. And I will say that if something like it doesn’t happen after a vaccine is rolled out, we may well be in schitt almost as deep as that foretold by Mr. / Ms. Nobody above, at least as far as not being able to return to “normal” is concerned.

        2. Sleepy Joe says:

          Not to worry! This whole crisis will be solved starting on Jan 21. Federal mask mandate for everyone with the National Guard deployed to lock up & quarantine anyone who does not comply. Follow that by another 3 month stay at home order, with NG checking to see if you are on a Master List of approved “essential workers.” Master government lists of those who have received a vaccine and gotten a Vaccine ID card. Entry into any public building, airport or other space will require a valid VID.

          1. confused says:

            From what Biden said in the debates, it seems clear that he recognizes that things like mask mandates and stay-at-home orders are State powers, not Federal ones; he referred to getting governors to impose mask mandates, not doing it himself.

      3. theasdgamer says:

        Less lethal now than before…that’s kind of how it goes with novel, acute, infectious, viral diseases.

      4. EJ says:

        *Almost* dying of COVID in a hospital, and then going into massive debt from the bills, is a factor that doesn’t show up in the death rate statistic.

        I’m also worried about winter, where there’s a good chance hospital systems will be overwhelmend. If people can’t go to the ER, will death rates spike?

        Thats not really something I enjoy thinking about..

        1. confused says:

          True, but there are hospitalization statistics, too.

          Not sure what to think about hospital system capacity. In the summer surge there were lots of media claims that hospital systems in places like Houston and Phoenix would soon be overwhelmed – this didn’t happen, though hospitals/ICUs did go to surge capacity (it’s possible that care quality may have dropped some places, though).

          But some of the areas surging now (the Dakotas and Montana, for example) are pretty rural and may have more limited capacity than the big Sunbelt cities. Does anyone know what the potential to transfer patients to hospitals in other areas looks like?

          1. confused says:

            And — though it’s not really an “optimistic” factor — places like the Dakotas are not doing much of anything. At this rate, might their surges “burn out” before we even get to winter?

            (SD has confirmed cases almost 5% of the state population, and their positivity rate is currently above 20%, so they must be missing far more infections than they catch … so what’s their real % infected? If they’ve caught 1/5 of infections, they’d be at 24% now… given another month of exponential growth, where will they be?)

            So the current Midwest surge starting in September may not really overlap with a hypothetical severe (peaking ~January) seasonal effect.

        2. theasdgamer says:

          In my county, the hospitalizations are “spiking”, yet hospital beds are still only at 50% of capacity. ICU beds similarly.

          This is flu season. Hospitals are used to dealing with flu season.

          1. confused says:

            The question is rate of increase. If it’s at 50% and rapid exponential growth is occurring, that’s a big problem. If it’s at 50% and the rate of growth is slowing, that may be different.

            It’s not a flu, but it is true that some places had to go into surge capacity in 2017-18 flu season. The question will be whether flu adds to the burden this year… but I think signs are promising that what social distancing remains will mean not much flu?

          2. Some idiot says:

            I think that you are right in that if the northern hemisphere remains reasonably sensible as regards hygiene measures, then this (northern) flu season is probably going to be limited.

            I base that on two points:
            (a) then experience on average in Europe, where the 2019-2020 flu season ended far more abruptly than usual. This has been ascribed to the sudden (and very effective) hygiene measure that were introduced in order to reduce the impact of COVID-19.
            (b) an observation that in Europe there has been a very significant increase in the interest in being vaccinated against the 2020-2021 flu. My feeling is that this is due to people (particularly at-risk populations) being kinda interested to do what they can not to get flu and COVID-19 at the same time…

    3. confused says:

      This is absurdly pessimistic.

      >>hospitalizes its victims for months (at best)

      Not even close. “At best” is no symptoms. Most cases are mild and do not require hospitalization.

      >>and is so transmissible that a single outbreak can overwhelm any healthcare system within weeks.

      This is an extreme overstatement. It is clearly *possible* for COVID to overwhelm healthcare systems, because it happened in northern Italy, but there have been poorly contained outbreaks in the US which went on for months without overwhelming healthcare systems (Houston and Phoenix in June-August, for example).

      So far it seems like overwhelming systems is very much the exception rather than the rule… OTOH there have been *some* mitigation measures in most places. The current outbreak in places like South Dakota could be different.Sporadic reinfections are possible within six months of initial infection, meaning that widespread reinfections are a likely possibility over the longer term.

      Monoclonal antibodies and convalescent plasma are almost entirely ineffective.

      Existing anti-viral drugs are completely ineffective.

      >> Acquiring herd immunity though mass infection is not possible even if the death toll was acceptable.

      If by “herd immunity” you mean “zero infections”, maybe, but if you mean “end of pandemic”, absolutely not — sporadic reinfections really provide no evidence at all; zero reinfections wouldn’t be believable for a disease with tens of millions of known cases and hundreds of millions actually infected.

      >> meaning that herd immunity through vaccination will be impossible.

      Could be true, but not terribly important – if it reduces COVID to cold-level severity, no one will care that it’s still circulating.

      COVID simply isn’t dangerous enough to cause a social collapse; if people gave up on measures completely, there would be a *lot* more deaths, but not social-collapse-level deaths.

      1. Michael says:

        Confused made many of my points, but it is helpful to bear in mind that past pandemics have not required fourth-generation vaccines with sterilizing mucosal immunity to recede. The Black Death is just not an apposite comparison — it was many hundred times more lethal. It killed nearly half the population of Europe!

        Re-exposures to the virus over time are likely to boost and continue to train the immune system, not attack people as if their immune systems are once again completely naive. Like with other coronaviruses and influenza. Put differently, long after the ability to block infection wanes, the ability to reduce symptoms through immune memory will endure.

        And if the choice really does become ramping up N95s and the end of the world (which it won’t), I’m confident that even the most incompetent governments on the planet will fire up the assembly lines.

        1. confused says:

          >> it is helpful to bear in mind that past pandemics have not required fourth-generation vaccines with sterilizing mucosal immunity to recede.

          Yes Even the worst-case of this is not going to be as bad as 1918-19. Even if it does infect say 60% of the population where 1918-19 might only have been ~1/3 … that was more than twice as deadly. (Maybe much more, depending on whose estimates for 1918-19 you believe… CDC’s 50 million deaths out of 500 million infections would imply 10% IFR!)

      2. Zambo says:

        “hospitalizes its victims for months (at best)”

        I have to say I laughed out loud when I read this. I hope most of us (reading this blog anyway) can admit at this point that this is a serious disease, but the doomsdayism that I’ve been seeing about recently is just absurd.

      3. Charles H. says:

        It’s worth remembering that in at least a couple of the cases the second infection with COVID was more serious than the original one. How common this is I haven’t a clue, but one can’t assume that reinfections will be milder.

        1. confused says:

          I don’t think I said that it necessarily would be?

          A few cases of more-severe reinfections, or indeed a few cases of anything happening, doesn’t mean much useful about a disease that has tens of millions of *confirmed* cases (and almost certainly hundreds of millions of true infections).

          The question is whether it happens commonly enough to make a difference in the overall course of the pandemic.

        2. theasdgamer says:

          Yeah, those hoofbeats might be zebras coming.

          Gotta keep pushing the fear and panic to accomplish The Great Reset. Time Magazine exposed the whole thing.

    4. John Stamos says:

      >>hospitalizes its victims for months (at best)

      This is not even a little bit true.

      1. Zach says:

        It was hard to keep reading after that ridiculous line…

    5. Another Guy says:

      A bit doomsday-ish.

      “Existing anti-viral drugs are completely ineffective” : that argument holds for hydroxychloroquine and its kind, however remdesivir showed some reduction in viral load. Not enough to change outcomes, but it jumped over the “ineffective” hurdle.

      Like many other viral diseases, there probably won’t be any single wonder drug or antibody for treatment and likely will need combination therapy once enough partially-active agents are discovered.

    6. Luis says:

      I am very optimistic,don’t forget that this is a new virus and with the vast sums of money and research spent on covid19 we will get there,i think the vaccine will be more effective that what people think of and i agree with the deadline of the end of 2021 beggining of 2022 for things to get back to some level of normality

      1. Dark Day says:

        I will say, though, as far as “normality” goes — with all this ongoing news about wedding parties, birthday parties, and country club get-togethers becoming “superspreader” events, I do wonder if there will ever come a time where even moderately large groups of people will be able to gather together, even outside (e.g., athletic events, festivals, family reunions, etc.). Even with a vaccine, which will probably be roughly 70-75% effective if we’re lucky, and which a LOT of people (estp. younger people) will probbly refuse to take, will the statistical probability of running into an infected person ever be low enough that we can risk being in groups of – let’s say — a hundred or more, standing close together and talking face-to-face, without the fear that we’re kicking off a new “super”spread?

        1. confused says:

          A vaccine doesn’t have to stop the *spread* if it reduces the *severity* to flu-like levels or less.

          I really doubt COVID will be all that scary in a no-longer-immunologically-naive population. Often diseases, historically, have been *vastly* worse in a naive population than one where it is endemic (think Europe vs. Pacific Islands/Americas).

          I think any long-term social changes from this, except ones that were overdue anyway (thinking primarily about increased telecommuting), are extremely improbable.

          People are having major weddings and stuff *now*, *before* a vaccine. Abandoning them *after* a vaccine seems to be completely incompatible with the facts on the ground.

          1. Michael says:

            And re “athletic events,” there are many jurisdictions with fans in stands now as well, before a vaccine, before effective therapeutics and with utterly primitive testing strategies compared with what’s to come.

            If the first generation of vaccines don’t facilitate mass gatherings, then it’s onward to the second generation. No way the world gives up on the concept.

          2. Dark Day says:

            Not to harp on this, but here’s Fauci’s latest prediction (as reported in the Los Angeles Times, Oct. 29):

            “If the U.S. can get a substantial proportion of residents vaccinated by around mid-2021, I think it will be easily by the end of 2021 — and perhaps even into the next year — before we start having some semblance of normality,” Fauci said in candid comments during an online discussion hosted by an Australian university this week.

            As a result, it may not be possible to achieve some longed-for hallmarks of normalcy without risking a super-spreading event, one in which a large number of people are infected, Fauci told the University of Melbourne. Restaurants might not be able to return to full capacity, and professional sports venues may not be able to allow spectators, until late 2021 or early 2022, he said. Fauci said he could envision people, in masks, returning to theaters at a reduced capacity around mid-2021. But returning to maximum capacity in theaters without requiring masks likely won’t occur until ‘well over a year’ from now.

            Our sense of what’s normal may also change, Fauci said. He said he believed wearing masks would continue to be common, as it has been in many parts of Asia for decades preceding this COVID-19 pandemic.

          3. confused says:

            I have to say I don’t understand this. If most people are vaccinated by mid-2021, plus maybe a few weeks for the vaccine to “take effect” – what *isn’t* “in place” then to allow normalcy that *would be* “in place” to allow normalcy a few months later (end of 2021/beginning of 2022)?

            IE – what is expected to change between mid-2021 and end of 2021/beginning of 2022, if it’s not vaccination uptake levels?

            (The mask cultural shift thing seems very implausible to me, outside of *maybe* a few hard-hit coastal cities. Certainly not in the central US.)

          4. Dark Day says:

            I don’t fully understand the timeline either, but I think he’s assuming an efficacy rate of no more than 75%, and probably an uptake rate of roughly the same amount (75% of 75% = 56%). That would still leave a lot of people vulnerable. Also, remember — most likely two shots roughly a month apart, then an additional month for the vaccine to fully take effect. Get your first jab in June or July, you’re not really good to go until September or October at the earliest. And if you were first in line, others will still be getting their first or second injection, or waiting for theirs to take effect, by that time. I could easily see that spilling into at least November or December, if not later — we’re talking upwards of 300 million people here at an average of three months each!)

            . . . and I still think uptake will be a problem. At the very least, a lot of people are going to wait awhile to see how it’s going for the “phase one” recipients before they roll up their own sleeves (several people have told me they’re going to wait at least six months or a year). It will also take a long time to undo the damage that the Trump-era politicization of COVID, preventive measures, and the vaccine itself has done.

        2. Dark Day says:

          . . . and also — Yes, I admit it: If this year has taught me anything, it’s that optimism is usually a fool’s game. If wishes were horses, they’d all break a leg and have to be shot.

    7. wubbles says:

      Taiwan and New Zealand are normal now. There was nothing inevitable about the failure.

      1. Dark Day says:

        Interesting to compare cultural, political, and social differences. Taiwan, of course, is a much less individualistic culture than ours, where people are far more tolerant of governmental policies and actions that Americans would never accept — they used electronic surveilance (they called it an “electronic fence”) to track the movements of citizens during the “shelter in place” phase of their lockdown efforts, and unless I’m mistaken, people got fined upwards of $20,000 for violating curfew restrictions. New Zealand wasn’t as draconian, but I believe that even now if someone tests positive he or she is taken to a government run “quarantine camp” for fourteen days.

        Good ideas? Epidemiologically, no doubt. Democratic? Most Americans wouldn’t think so.

      2. confused says:

        Not ‘inevitable’ in a laws-of-physics sense, but given a) the much more individualistic nature of American culture from its beginning, b) the decreased trust in institutions over perhaps the last 50 years … arguably since the Vietnam War, and c) the extreme amplification of that by the current administration, I think it was ‘inevitable’ in the US in the sense of what is *socially and politically* possible.

        Also, both Taiwan and New Zealand are islands. They have natural advantages as well as cultural/governmental ones.

    8. milkshake says:

      Even when the masks are available – people just do not like to wear them (at least in the Western world) the minute they stopped being scared. Here is what happened in Czechia: In the spring covid wave, the country got few weeks of warning after things got out of hand in Italy, Spain, and the spread was getting close (Austria and Germany). So Czechia went into a long lockdown relatively early, people were disciplined about wearing masks, etc. In the summer, the government and the Czech PM (with a shaky voters support) wanted to capitalize on a great success of preventing covid spread, declared the battle was won and removed most of the preventive measures – and the population was only too eager to stop wearing masks, go to go to pubs, have a summer vacation, etc. There were only few new cases reported in Czechia, and the mortality was below 1% anyway – the people stopped being scared. And the first lockdown caused huge drop of the economy, so it was difficult for the government to repeat it after declaring such a great success, and it would be unpopular.

      So now the country has even more cases per million than US and is entering into second lockdown. A similar story with Israel – and even more cases.

      1. Dark Day says:

        In the U.S., even believing that COVID is a serious problem (let alone accepting protective behaviors as a defense against it) has become a stand-in signifier for political allegiance. At least based on the anecdotal evidence being reported, areas that are primarily Republican and/or Trump-leaning are also the areas where bars, restaurants, churches, and other public gathering spots have drawn a “line in the sand” and refuse to require masking, “distancing,” etc. among their patrons / attendees. It even boils down to the proprietorship of individual venues — Democratic-leaning restaurateurs and bar owners enforce the mandates; Republican-leaning ones, not so much: https://www.nytimes.com/2020/10/29/us/politics/wisconsin-trump-biden-coronavirus.html
        At risk of sounding vax-uptake-obsessed (again!), I fear that when a vaccine is rolled out, a significant proportion of the 40 – 45% of Americans who are Trump supporters will refuse to take it simply out of political loyalty, no matter who is President by then.

        1. confused says:

          I doubt that; I think the political loyalty is more about rejecting restrictions. Sure, the people who believe COVID is literally a hoax wouldn’t get a vaccine, but I don’t think they’re actually that numerous. And half of 40% shouldn’t be enough to matter anyway.

          (Also, given current trends in many rural parts of the US, how many of these people *won’t* be infected by the time a vaccine becomes available to non-high-risk individuals?)

    9. theasdgamer says:

      Funny how Dr. Brian Tyson in El Centro CA has been treating covid-19 for months with ineffective drugs…>2000 patients…ONE hospitalization…ZERO deaths.

      Maybe you wanted a different word than “ineffective.”

  6. sPh says:

    Clearly the monoclonal antibodies needed to be combined with thiotimoline and zinc so they could be administered 3 days _before_ the subject was infected.

    1. confused says:

      Yes, certainly. That resublimated thiotimoline would be really useful for so many things…

      1. JasonP says:

        For those non-chemists:

        Thiotimoline is a fictitious chemical compound conceived by American biochemist and science fiction author Isaac Asimov. It was first described in a spoof scientific paper titled “The Endochronic Properties of Resublimated Thiotimoline” in 1948

        1. Non-Chemist says:

          Thanks!!

  7. Duncan says:

    This seems to me to be the most important bit – ‘The best results were in the most at-risk patients, whether that’s defined as higher viral load, pre-existing risk factors, or weak antibody response.’

    Was this only tested on the highest risk patients?

  8. Norm says:

    One word. Sorrento!

  9. Some idiot says:

    This is way out of my area (I’m a process chemist), so these may be stupid questions, but I’m kinda curious…:

    1) The end point of viral load is, I presume, from a nasal swab or similar. In the short term, how will a mab affect this number? Ok, sure, if you nuke the bejeezus out of the virus in the body (where I presume the mabs are going to do most of the work), then at some time the viral load in the airways is going to drop. But I would guess that virus being produced more or less in the outer layer or so of tissue in the lung/nasal/whatever area is not going to be affected by mabs that much (ie compared to “circulating virus”). Or do I have the wrong end of the stick, in a pretty decisive way?

    2) The U-shaped dose response curve sounds kinda weird… If it is real (and not just simply a statistical bloop due to insufficient S/N), are there any known (or at least reasonable) mechanisms that would provide such a curve? I could imagine the incremental improvement with a larger dose tailing off pretty quickly, but I can’t really see why the total effect should be worse…

    Thanks in advance!

    1. Barry says:

      You have it right. The primary site if covid infection is the respiratory mucosa. Pumping Abs into the plasma compartment does nothing useful unless they can ride Secretory components to the job-site. I.e. they need to be IgA

    2. theasdgamer says:

      Covid will infect any cells with ACE2 or TMPRSS OR NPILIN receptors, iirc.

      ACE2 are in endothelial cells, like capillaries.

      Covid does most of its damage via microemboli which can occur anywhere because capillaries are everywhere. It shows up early in the lungs because so many capillaries are needed to aid in respiration. Lung scans show ground glass opacities. Damage also occurs in the CNS, heart, kidneys, and liver.

  10. Anon2 says:

    Derek, curious on your thoughts of the drug pricing proposals from Trump/Biden and if this will impact innovation? This being more important if we are facing a prospect of treatments/vaccines with little/no efficacy.
    Also in the background of Amazon being valued more than the top 10 drug companies combined. or Apple being valued at more than the top 10 drug makers. Facebook, etc.
    From an economic perspective, we have large amounts of global unemployment due to a this and the treatments still are still valued less than a cellphone or a social media account.

  11. David says:

    Meanwhile on the remdesivir front, Science mag just published an editorial “The ‘very, very bad look’ of remdesivir, the first FDA-approved COVID-19 drug”. The hard content there has already been discussed on Derek’s blog, but putting it all in one place makes for a very sad story.

    1. Marko says:

      I’ll be interested to see if the EMA is willing to flush their reputation down the tubes like the FDA by granting full approval without more data . Here’s the Science link , for others :

      https://www.sciencemag.org/news/2020/10/very-very-bad-look-remdesivir-first-fda-approved-covid-19-drug

  12. OC says:

    Sorry but this commentary is again FAR too pessimistic.

    The Regeneron data looks about as good as can be expected from an anti-viral agent. 72% reduction in medical visits in higher (by no means HIGHEST) risk population is a MEANINGFUL reduction in the burden of this disease assuming it flows through to hospitalisation, ICU admission and death (the study being too small to generate a statistical significant read-out on this).

    As other posters have commented 50,000 doses is only the first batch. Production is very rapidly ramping up.

    IF we triage patients into the highest risk cohorts (i.e. one or more of interferfon auto antibody positive, > 75 years of age, hypertension, diabetes, kidney disease, heart disease etc.) and treat them as soon as a positive PCR test is received (or even pre if strongly suspected) then a material reduction in morbidity is possible.

    This all assumes that the FDA will grant an EUA some time this decade though. Given how thoroughly underwhelming Remdesivir is it seems bizarre they are dragging their feet in allowing these treatments to get out to patients in the highest risk cohorts (remembering that mortality risk is literally several orders of magnitude different as you work through age cohorts)!

    1. confused says:

      >>Given how thoroughly underwhelming Remdesivir is it seems bizarre they are dragging their feet

      Wait, when was the EUA application submitted? I thought it was this week…

      1. OC says:

        The EUA was applied over 3 weeks ago:

        https://www.biospace.com/article/regeneron-requests-emergency-use-authorization-for-covid-19-antibody-cocktail/

        Given they gave EUAs to Remdesivir, Hydroxychloroquine and convalescent plasma with FAR flimsier data it makes little sense why they are taking so long to release these treatments (at least to VERY high risk groups).

        1. confused says:

          Huh, ok, I thought it was at the same time as the press release. Yeah, that is odd.

          Does anyone know why it might take so long?

          1. confused says:

            Hmm, one thing does occur to me… given that President Trump made bold (and implausible) statements about making Regeneron antibodies available to everyone who needs them shortly after he was treated, I wonder if someone at FDA is concerned that an EUA immediately-before the election would look partisan?

  13. JJ Walker says:

    I am too lazy to look it up but did Lilly look at infectious viral particles or only Ct values? If the primary endpoint of the trial was decreased viral loads Ct values are a crude and not entirely accurate way to measure that. Regeneron appears to have looked at viral particles

  14. Doc says:

    All mAbs are administered intravenously so the drug toxicity is high and only a small amount can reach the lungs.

    Next week a new trial starts in Brazil whereby mAbs will be inhaled directly in to the lungs. Most mAbs are humanised (developed in animals) so are fought off by a persons immune system also reducing efficacy. The drug being used in São Paulo is a fully human mAb called Foralumab, and because it’s inhaled, it can be given in small quantities in a topical approach. Toxicity will be a lot lower.

    Initial results should be known in a couple of weeks

  15. MadMabScientist says:

    So pure science question rather than social/policy or commentary.

    Assume the Lilly dose response is real and not a statistical fluke (which it very much could be). Might it be explained by antibody avidity (and Goldilocks) . Too high a dose and all mabs bind with one arm, too low and there’s not enough to make a difference. Needs to be just right… mid dose binds typical serum viral load with two arms. Avid binding allows for slower off rate and more effective blockade.

    1. Marko says:

      A good theory , but it does require Goldilocks’ intervention.

      There must be examples in the literature demonstrating this effect in vivo. I’d guess that the concentration differences between the effective dose and the too-high , non-effective dose are usually greater than the 2.5x difference between the medium and high dose Lilly used. Of course , maybe the real optimum for the medium dose was lower , say 1.4 g. That would make the spread 5x instead of 2.5x , making the theory a bit more plausible , on one hand , and less so on the other , since you’d be more inclined to expect the .7 g dose to show efficacy.

      Still , if I were on the Lilly PR team , I’d be pushing this explanation , at least until more and better data comes in.

  16. blogreader09 says:

    A lot of quite-elderly and/or really unhealthy people have been killed off by Covid19. These were not, typically, productive individuals and having them taken “off the books” so to speak has been a poignant but not totally disadvantageous facet of this pandemic.

    1. Marko says:

      Is that you , Mr. Atlas ?

      1. Dark Day says:

        No, I think it’s Mr. Malthus, or maybe Herren Hoche und Binding (look them up).

      2. theasdgamer says:

        That is extremely unfair and wrong. P Dr. Atlas recommends protecting our vulnerable population.

        1. Zambo says:

          Which is of course an absurd proposition, seeing that it’s not possible to just keep all vulnerable people in a Covid-free environment while letting it run wild in the general population.

          1. theasdgamer says:

            Of course, people over 60 can be instructed to mask and minimize contact for a month while the virus spreads among those least at risk.

            This isn’t rocket science.

    2. Bill says:

      A lot of meat-heads may think that way, but they wouldn’t put it so succinctly into writing.

      So I’m guessing a false-flag troll here.

    3. Barry says:

      “if they be like to die, they had better do it then, and decrease the surplus population”
      Ebeneezer Scrooge

      Exactly whom would you count among these disposable people? FDR? Stephen Hawking? Your own grandmother?

        1. WST says:

          Lazlo Toth (Don Novelle) is back, greater then ever.

      1. Irene says:

        I also meant to quote Ebenezer Scrooge, but I see Barry is ahead of me.

  17. I wonder why Regeneron didn’t disclose any differential fatality rate in the placebo vs experimental arms. Based on the endpoints they did report it seems like any such data would be in their favor. Too statistically insignificant for the trial population size?

  18. MTK says:

    SIAP, but Regeneron announced a complete halt on their mAb study for severe patients citing a safety issue and unfavorable risk/benefit profile for that patient group. Studies for early COVID patients and less severe cases still continuing.

    https://endpts.com/in-a-second-big-setback-for-covid-19-antibody-treatment-hopes-regeneron-halts-enrollment-for-more-severe-patients/

    1. Erik Dienemann says:

      It’s not a complete halt to the trial. The Regeneron antibody cocktail trial in hospitalized patients was put on hold for those patients on ventilators or high flow oxygen, by the data safety monitoring board, due to a potential “safety signal.” The trial has been modified to exclude those patients while the data on those patients is further evaluated (no word as to what the signal was), but will go on for the remainder of the hospitalized patients. This does not impact the ongoing trials in mild/moderately ill COVID patients (not in hospitalized) or those not infected, evaluating the possible prophylactic effect.

      This is why trials have DSMBs – to ensure patient safety. Certainly a setback, but it’s not clear if it’s a permanent setback or not, plus, almost any antiviral is likely to work best before patients become seriously ill, so this is not a complete surprise.

      https://investor.regeneron.com/news-releases/news-release-details/regn-cov2-independent-data-monitoring-committee-recommends

      1. confused says:

        Would this affect the EUA application already submitted? That one I guess is based on data in much less severe patients?

        But yeah if the really severe/late-stage stuff is due to immune overreaction rather than the virus itself, it would seem adding more antibodies wouldn’t be expected to be useful…

  19. wc says:

    Regeneron today announced they are stopping trials on hospitalized patients.

    Is there reason to believe that nano antibodies such as UCSF’s AeroNabs or tiny antibody such as Univ. of Pittsburgh’s Ab8 would have better results?

    Both can be administered by inhalation so it might be able to clear the virus in the upper respiratory tract?

    But when inhaled, would these nano or tiny antibodies reach the rest of the body and reach the lungs or heart or wherever the virus may have spread to?

  20. Paramus says:

    Having worked for Lilly in the days when it was a great company and I worked on things that made a difference (Zyprexa). The new Ricks Lilly is only in making a money-making machine, no science necessary. Just make sure the bonus continues.

  21. Marko says:

    CDC report on an outbreak at a summer school retreat for teens showed good evidence that previous infection ( documented as positive serology before attending the camp ) is protective against reinfection. Zero of 24 such students were infected , while the attack rate was very high among the other students :

    https://www.cdc.gov/mmwr/volumes/69/wr/mm6943a4.htm?s_cid=mm6943a4_w#T2_down

    I wonder if the current vaccine candidates will do the same…..

    1. Dark Day says:

      For teens, either previous infection or vaccine may well be very protective. For older people and/or people with other risk factors, we cannot know. ALso, will enough teens and 20-ish/30-ish people consent to get vaxx’d (thus, we hope, increasing widespread immunity as much as possible) if they don’t feel themselves to be at risk? Judging from what we’ve seen so far (e.g., college parties, crowded bars, etc.), that kind of altruistic thinking doesn’t seem like a strong possibility.

      1. Marko says:

        To me , the encouraging thing about this data is that it helps confirm positive COV2-specific serology as a correlate of protection. This is the second example I know of where those with positive serology were protected against infection ( i.e. becoming PCR-positive ) in a setting with very high attack rates. The other example was the fishing boat , with a smaller sample of only 3 serology-positive fisherman who were protected.

        Age will not be an impediment as long as we have a reliable serological marker. Non-responders can be boosted until they seroconvert. Those who fail in spite of that , most likely those who are severely immunodeficient , will at least know their standing , and can take proper precautions , or perhaps get periodic MAb infusions until the pandemic peters out.

        1. Hopeful Layman says:

          Marko — I have recently read that it’s possible for an adjuvant to be administered along with the vaccine when it’s given. I hadn’t known that; I thought the adjuvant had to be included in the vaccine itself (e.g., Novavax). Does this mean that a vaccine that showed only moderate efficacy in older people (or, perhaps, other at-risk recipients) could be “goosed up,” so to speak, and made more effective upon injection? I’m guessing this might be logistically infeasible, if the adjuvant along with double vaccine doses had to be manufactured, safely stored, and distributed to tens of millions of Americans. But I am wondering about the potential of this.

          1. Marko says:

            I don’t know of any examples where the adjuvant is given as a separate shot from the vaccine , but in theory it could work , as in general it simply stimulates a robust innate immune response , setting the stage for the adaptive response to follow.. My guess is we’ll see second-generation vaccines that are tailored to meet the needs of the elderly and other non-responders , just as for the flu vaccine we have a turbocharged version for the over–65 age group.

            I think the early strategy will be to try boosters of the first-gen vaccines , and monitor for serological response. It may be up to elderly patients and other likely nonresponders to order their own serology followups if they want to be sure , as I don’t think serology is considered a standard for all patients as yet.

          2. Barry says:

            Levy’s CpG “cancer vaccine” is basically a potent adjuvant delivered right into a solid tumor w/o an exogenous antigen. It seems he can goad the murine host immune system to attack a tumor that it had not attacked before.

            https://med.stanford.edu/news/all-news/2018/01/cancer-vaccine-eliminates-tumors-in-mice.html

        2. Hopeful Layman says:

          Sorry, another “Layman’s” question, RE: ” Non-responders can be boosted until they seroconvert.” Does this mean that someone could take repeated additional injections until evidence of seroconversion? I’ve never heard of this being done, but of course that doesn’t mean there’s no precedent for it. Aside from the ethical implications of a few high-risk individuals “bogarting” vaccine doses that will probably be in short supply for a while, what are the health risks of being vaccinated additional times?

          (And I guess I’ll add another question that has been bothering me. Given the election chaos in the U.S. – regardless of who wins – how chaotic will vaccine approval, distribution and uptake be (especially if Trump wins the election and makes good on his promise to “fire” Dr. Fauci)? What are the implications for this as we move into 2021 — still staggering under the burden of a massive nationwide COVID spike — hoping to start getting a handle on this as the early part of the year progresses?)

  22. Daren Austin says:

    RGN controlled for baseline viral load – patients who had started an antibody response of their own (10^4 cp/mL) saw little improvement. Patients with high viral load saw a good separation. Lilly did not. RGN used an earlier (7d) time point with strong separation. Lilly went for a later timepoint. None of them have a dose response because the dose is already off the scale too high based on their potencies. High doses do, however, get neutralising concentrations to the lung faster.

    Antibodies clearly have to be given vert early in the course of infection. That hopefully will lower the need for hospitalisations (about 1-3% of infections) and then reduce the overall IFR.

    1. Some idiot says:

      Sorry, I am a chemist, not a biochemist, but I there is something I really don’t understand here. You say that the reason that there is not a dose-response relationship is because the doses are so high that they are already off the chart re potency (more or less). However (from what I saw of the NEJM results from Lilly, at any rate), placebo was more or less in the middle of the doses. How does that work? What is it I am misunderstanding?

      For completeness, my first (and unqualified) take on the results was that the lack of a more or less expected dose-response curve was that the results aren’t far removed from noise. But I am happy to be educated on this point!

  23. theasdgamer says:

    Maybe Derek will comment on Dr. Brian Tyson’s results in El Centro. He treats with Zelenko’s triple-drug cocktail. Over 2,000 patients (he reported this in McCullough’s webinar), with ZERO deaths and ONE hospitalization.

  24. Alain says:

    Why aren’t we testing some of these antivirals and monoclonal antibodies in nursing homes and assisted living facilities? Advantages would include:

    –Patients are likely to be diagnosed earlier than patients in the community, so medications can be administered early when they are most likely to be effective
    –Nursing staff available to provide infusions
    –Very high risk patient populations, thus trials could more easily achieve statistical power for a wider range of endpoints (hospitalizations, ICU admissions, mortality) even though the intervention is started before disease becomes serious
    –Cost/benefit ratio is much better since this is such a high-risk population (and likely risk/benefit ratio as well)

    I have not seen this idea discussed, much less tried (that I know of). What am I missing here?

    1. Zee B says:

      Lilly is running a 2,400 patient prophylaxis study in nursing homes.

      1. Alain says:

        Thanks – I was not aware of that. I’ll look into it.

        I’d still also love to see an early treatment study. The logistics would be challenging, as it would obviously have to enroll quite a few sites and then wait for outbreaks to occur in some percentage of them. But I think the rewards would be worth it. If we learned that a drug administered early significantly reduced hospitalizations/ICU admissions/mortality in our highest risk populations, then we could dramatically reduce the hardship of this epidemic.

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