When Will We See a COVID-19 Medicine?

Hi @swamidass, @AllenWitmerMiller and @nwrickert,

Can someone please help me out here? I keep reading these reports saying that even if scientists come up with a vaccine, it’ll be 12-18 months before it’s on the market. Then I read other reports saying that we already have drugs that have shown promise, or that a vaccine could be available in as little as 90 days. See, for instance, these reports here, here, here and here. (You’ll notice that I read stuff that’s on both sides of the political fence, but never mind that.) So my question is: what’s going on? Do we really have to wait a year, and if so, why?

Some of you might be wondering what’s happening in Japan, where I live. Let me fill you in. Life is proceeding pretty much as normal, but people have made a few lifestyle changes. Hand sanitizer dispensers are now ubiquitous. Most (but not all) people wear masks on trains, not to protect themselves but to reduce the risk of transmission to others. People are generally expected to wear masks at work. Mass gatherings have been canceled, but people still dine at restaurants (I’ve done so twice this week, but I kept a fairly safe distance from people at other tables). Stores tend to sell out of toilet paper fairly quickly, but it’s still available every morning. There’s plenty of food on supermarket shelves. Cram schools re-opened this week, but most schools haven’t opened yet, and aren’t expected to do so until early to mid-April or perhaps early May. Children have been told by their teachers not to play with other children during the spring term break, and I think most teenagers are complying with that directive, but I saw some young children playing in the park near where I live, today. Finally, most people are still going to work: nothing, it seems, can stop the Japanese from doing that. However, many people (including myself) are self-monitoring before heading off to work, by taking their body temperatures every morning when they wake up (I was astonished to find that mine is only 35.5 degrees Celsius at that time of day).

Officially, Japan now has 899 cases of COVID-19, and 29 deaths. The testing rate is low (76 per million people), but higher than that of the U.S. (26 per million). I have a sneaking suspicion that the government doesn’t want to encourage widespread testing, as it may sap public morale. (They’re probably right on that one.) In the town where I live (population 33,000, located 65 kilometers from Tokyo), 1 case has been recorded. If extrapolated nationwide, that would be about 4,000 people. For the most part, people are carrying on cheerfully and trying to stay positive, but TV coverage of the virus is quite extensive. That’s all the news from over here at the moment.

On a positive note: it’s hard to be sure, but looking at the graphs for Italy here, it seems that the country is at or near a point of inflection. Certainly, the curve isn’t rising exponentially anymore. If Italy can weather this pandemic with fewer than 10,000 deaths, then it’s a fair bet to say that the U.S. will have fewer than 50,000. But I could be wrong.

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They have to figure out if the vaccine is safe and if it is effective. That takes time. The fourth link in your post focuses on an Israeli group that was already developing a vaccine against a closely related coronavirus, so they already have evidence that the proteins they are using can illicit protective antibodies, at least in chickens and for the closely related strain.

As to potential anti-viral drugs, those have already passed FDA testing and are being used off label. The maximal dose and side effects are already known which makes them readily available for use in this situation.

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There are three issues here, vaccines, new drugs, and existing drugs.

Vaccines

Given the urgent global need for a human Coronavirus vaccine, we are doing everything we can to accelerate development. Our goal is to produce the vaccine during the next 8-10 weeks, and to achieve safety approval in 90 days.
Israelis moving quickly to get out a COVID-19 vaccine - American Thinker

That isn’t technical regulatory langauge, but I think the safety approval referred to is the initial approval that allows the company to conduct clinical trials using the vaccine. So it is just the crossing the bar to begin testing in humans.

Bringing it to market takes quite a bit more time. You have to put the vaccine in a large number of people and watch them for long enough period of time to ensure that (1) the vaccine works and (2) it is free of rare but serious side effects. It is hard to imagine how it could come to market without thousands (if not tens of thousands) of people in the study. That is a billion dollar study, and usually it will require smaller trials before the trigger is pulled on the big one.

However, this is a once in a century pandemic. The precise rules are going to change. What you can be certain of is that it will take 12-18 months for a vaccine to be on market, assuming everything goes perfectly and one of the vaccines currently being tested actually works. That is a huge bet.

New Drugs

There are a ton of specious articles being published referencing studies purporting to screen virtual or physical libraries to identify potential COVID inhibitors. Unless something truly stunning, approaching miraculous happens, that would not be useful for patients for at least 5 years, and that would be stunningly fast.

The quickest approval I know of a new drug I know of:

Trikafta’s approval also showcased how fast drug development can be when the conditions are just right. Vertex first synthesized elexacaftor in 2016, just 3.5 years before the drug was approved. And the FDA approved the combination 5 months ahead of its anticipated Prescription Drug User Fee Act (PDUFA) date. Vertex credits its speed with Trikafta to its deep understanding and experience with cystic fibrosis biology and biomarkers.
https://www.nature.com/articles/d41573-020-00001-7

With COVID, we are missing the key ingredient for a fast approval: “deep understanding and experience.” Once again, we are in a unique moment, so I could be wrong.

Old Drugs

Here is a place where there is grounds for optimism. There is good reason to believe that some existing drugs will be effective in inhibiting the virus. These drugs are already well understood. There are going to be two barriers here:

  1. Production at scale, which takes time.
  2. Trials to determine efficacy.

However, because these medicines are already used in a lot of patients, we may not need as much time or patients for this trials. They might conclude quickly. A repurposed drug is the best bet, in my opinion, for a quick advance that would change the situation dramatically.

The most likely way this could help is by changing COVID, from into a clinically severe disease that kills people, into a treatable disease that is unlikely to kill you. We would likely give the medication to affected patients, reducing severity to keep them off of ventilators, out of the ICU, and perhaps even out of the hospital. In that case, the mortality could drop to the point that COVID just becomes a medical expense and access issue, which may be easier to manage.

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There’s a big time difference from “seems to work in the lab” until “tested, shown to be safe, and produced in sufficient quantity to be useful as a vaccine.” I’m pretty sure that the 12-18 months is based on previous experience for other vaccines, and assumes that all goes reasonably well.

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Hi @swamidass, @T_aquaticus and @nwrickert,

Thank you very much for your helpful replies. Cheers, and stay safe.

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@vjtorley, this article is a good read: As Virus Spreads, Drugmakers Are On the Case - WSJ

Also did not mention mAB, which have high promise for a rapid entry to market:

“We are pleased that, using the same platform that was used to isolate mAb114 which has proven to be active against Ebola, we have quickly identified antibodies with potential biological activity against SARS-CoV-2,” said Herbert “Skip” Virgin, M.D., Ph.D., Chief Scientific Officer, Vir. “We are working as rapidly as possible and look forward to sharing more information as we have it.”

Of note, Skip Virgin was the guy who hired me at WUSTL, chair of Pathology here till a couple years ago. Small world…

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The first stage for human trials of a new drug or vaccine testing is for safety. Give low to increasing doses and monitor for possible adverse reactions. With a vaccine they may sample blood to get early information about whether to injection triggers an immune response they expect to see. Only after safety conditions are met do they expand the trials to more people. The next stage(s) will test the vaccine efficacy, while still monitoring for adverse effects. The more people in the trial, the better confidence you assign to measures of efficacy and adverse reactions. I’m not sure how they’d test a vaccine faster than by monitoring whether inoculated people who are ‘naturally’ exposed to the virus show immunity. Ethically, there would be some serious concerns about intentionally exposing test subjects to the virus, so that would increase the time to assess the response.

Next are deep, deep analyses of results. If all goes very well (not a typical experience, IMHO), there’s approval (probably fast-tracked in this case) along with production and dispensing approval.

If a vaccine looks particularly promising, they’ll probably gear up for production in parallel with testing to save time. I would hope they would engage several experienced production sites, even at different companies, to ensure quick distribution. With several candidate vaccines being developed, I suspect testing and production would be well co-ordinated, at least in perfect-world scenarios.

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New drugs: Yeah, I don’t expect those to be quick. There’s a lot more ‘scientific distance’ between potential compounds and approved drugs. A lot of causal links that have to be established at each step. Considering current technology, anyone invoking virtual screening just makes me laugh. It has its place in drug discovery, just not a very big one at this time. There’s still a lot of brute force and iterative work that includes biological assays, toxicology and DMPK, and it’s not easy to move fast through those stages, even before getting to human tests.

Repurposed drugs: That can be the fastest route as Joshua notes. Not great odds, but worth investigating. With so many bioscientists stuck at home, a large number are undoubtedly keeping up with the reports and puzzling about connections & solutions.

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Happy news: Someone in from the virus testing group at UCSF put out a tweet asking for help in finding a particular PCR machine and a specific liquid handling system. With more instruments they could increase testing capacity. They got quick responses from biotech scientists around the Bay area.

Apparently chloroquine & hydroxychloroquine hold promise as a treatment for COVID-19:

https://www.nature.com/articles/s41421-020-0156-0

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Actually, the odds are better than you might think. There is very good reason to think think that several existing drugs will have efficacy with coronavirus. From a mechanistic point of view, there are several well motivated targets already hit by existing drugs. From an experimental point of view, there are several drugs that are well motivated that have shown efficacy in vitro similar to how they show efficacy on their original target. None of that guarantees clinical efficacy, but at this point we can be nearly certain someone somewhere will test them in patients if it is safe, and that is hurdle that the vast majority of candidates can’t clear. In fact, several of them are already begin tested in humans.

Once the trial is published, it will be published, and doctors can start prescribing it off label even before FDA approval. Some of these drugs are generic too, so scaling up will take work, but might also happen very quickly.

So, this is not as much a long shot as you might think!

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I happened to run across a Youtube video from an Italian doctor, and they are using the HIV protease inhibitor and chloroquine cocktail that has gained a lot of attention lately. I’m hoping they can get some extra help from researchers so that they can get the type of data they need. The medical staff is living at the hospital, so I can’t imagine they are focused on running a proper clinical trial.

I’m sure it is a proper clinical trial. The way this works, it is unethical to conduct a trial that deviates from protocol or uses a protocol that produces ambiguous results. Right now, I’m sure, the government is giving them every resource they need to make sure it runs properly.

The hard part about approved and funded trials is usually enrollment. In Italy, however, that is not a problem. There are a ton of cases, so that won’t be a problem. Because the disease course is just 14 days or so, it is likely that we will have clarity on that specific dosing within a couple months, at least for the subpopulation they are targeting (most likely severe?).

I think it helps that re-purposing avoids most of the issues regarding safety and the like. We know how to use these drugs safely, we just need to figure out how effective they are against the new virus.

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I got the impression the Italian doctor was using these drugs at his own discretion and without a formal clinical trial. Please correct me if I am wrong, but off label use is legal (within certain guidelines) in the US and presumably in other Western countries.

It is possible he used it off-label and filed a case report. What I’m nearly certain of is that there are also clinical studies testing that precise cocktail.

Yep.

There are some ethics and design issues that have to be addressed in every proposed test. Which stage / sub-population of patient is also critical to successful testing of a treatment. For example, while targeting the most severely affected patients might seem a good idea and maybe easier to justify experimental treatments from an ethical standpoint, it’s possible that those patients could be too far along to it to do much good. You might get stronger results in early or less critical cases. I’m not expecting a magic bullet drug, but anything that significantly improves outcomes or provides quicker recovery will be fantastic. I suspect money and red tape will not be a huge impediment. In a way it’s like the HIV work, just with a lot more people working to a much tighter timeline… and with a lot better tools.

Meanwhile, we’ve to get better at testing & containment. Old skool stuff.

And it looks like one drugs is about to be approved by the FDA already:

At this point, regardless of the FDA, doctors will start using it off-label. If it improves outcomes substantially, well that could be a game changer. This drug is a generic, and should have several suppliers that can ramp up production, hopefully quickly.

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Assuming it works, I wonder if the mode of action is similar to quinine, in which case my love of a good gin & tonic would be truly requited.

Both chloroquine and hydroxychloroquine are already being used. According to the article, there’s one manufacturer of chloroquine in the US.

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