If you're been reading the headlines, you're aware that nearly every drug company that you have ever heard of (and many more that you haven't, if you don't work in the field) is trying to come up with a piece of the puzzle to combat Coronavirus. And, just recently, a group of financial heavyweights, lead by Tom Cahill, announced that they were forming a brain trust akin to the Manhattan Project to combat the disease.
Those kinds of announcements result in popular speculation that because we have our best and brightest on the case, along with nearly unlimited resources and money, a cure can only be around the corner. All of which sounds good. At a time like this, more than any time in a very long time, America and the world are looking to be saved by their superheroes. And this time, they are perceived to wear lab coats, not tights.
But all the wishes in the world don't make something a reality. And the reality is this: Drug discovery is very difficult. You can crudely break the necessary ingredients for successful drug discovery into four parts:
It's also why cookie-cutter business school graduates make really bad drug company CEOs. In business school, they teach you that nearly any problem can be solved by a combination of leadership, process, and resources. You want to build that car? Put enough ace designers in a room, and you can get a good design in short order. Need to build a bunch of those cars? Modify your assembly lines to make the necessary parts, make it financially attractive for your suppliers to get their assembly lines up and running quickly, and on it goes.
But the history of drug discovery run as a standard process-based business is dire. The biggest drug companies in the world have spent many billions of dollars over the years on internal R&D, with the assumption that more R&D will lead to more drugs. In many cases, that spending has provided little in return. Interesting disease targets can be identified and often the internal molecules that can regulate those diseases can also be found. But going from an interesting target to something a person can take to alleviate the disease is fraught with uncertainty. A short (though not complete) list of issues that can be encountered in trying to develop a drug to an identified disease target include:
Small molecules: It typically takes at least three years to identify and refine a small molecule drug, and that does not include the clinical trials. The only way to short circuit this timescale would be if you could "repurpose" an existing drug for use against Coronavirus, either a drug on the market, or one that has already gone through clinical trials for something else (and failed due to lack of efficacy, but not due to severe toxicity). The chances of success in this realm are small. But this is the allure of using drugs such as Hydroxychloroquine: It's relatively safe, it's cheap, and it has been studied for many years.
A full set of clinical trials for any vaccine would take a minimum of close to a year. You can't bypass the clinical trials because vaccines can have severe unexpected side effects, including death. Since we are talking about a virus with a mortality rate that appears to be less than 1%, any vaccine would need to be quite safe for general administration. There are already some proposed vaccines moving to clinical trial, but the chances that the first vaccine to the clinic will be "the one" is, based on history, not high. Probably many putative vaccines will need to be tested before is identified as efficacious and safe. A realistic "best case" estimate would be roughly 18 months. And that's the best case. There is plenty of history to suggest it might take a lot longer (maybe years) than that.
Those kinds of announcements result in popular speculation that because we have our best and brightest on the case, along with nearly unlimited resources and money, a cure can only be around the corner. All of which sounds good. At a time like this, more than any time in a very long time, America and the world are looking to be saved by their superheroes. And this time, they are perceived to wear lab coats, not tights.
But all the wishes in the world don't make something a reality. And the reality is this: Drug discovery is very difficult. You can crudely break the necessary ingredients for successful drug discovery into four parts:
- Hard work
- Inspiration
- Resources
- Luck
With the efforts of all the drug companies, the Cahill consortium, and billions from governments all around the world, you really have the first three locked up. But what you can't buy with money and intent is luck. And that's what separates drug discovery from standard process, like designing and manufacturing a new car.
It's also why cookie-cutter business school graduates make really bad drug company CEOs. In business school, they teach you that nearly any problem can be solved by a combination of leadership, process, and resources. You want to build that car? Put enough ace designers in a room, and you can get a good design in short order. Need to build a bunch of those cars? Modify your assembly lines to make the necessary parts, make it financially attractive for your suppliers to get their assembly lines up and running quickly, and on it goes. But the history of drug discovery run as a standard process-based business is dire. The biggest drug companies in the world have spent many billions of dollars over the years on internal R&D, with the assumption that more R&D will lead to more drugs. In many cases, that spending has provided little in return. Interesting disease targets can be identified and often the internal molecules that can regulate those diseases can also be found. But going from an interesting target to something a person can take to alleviate the disease is fraught with uncertainty. A short (though not complete) list of issues that can be encountered in trying to develop a drug to an identified disease target include:
- We don't fully understand the incredibly complex bodily systems that redundantly regulate relevant molecular targets associated with the disease and the drug won't do what we thought it would
- We can't identify a drug that can modify the identified target
- We can't figure out how to get a sufficient concentration of an identified drug to the target
- The identified drug is too toxic
- The identified drug has unacceptable side effects
- The identified drug just doesn't work when given to patients for reasons unknown
Any one of these issues can torpedo the chances of a putative drug, and fleetingly few compounds become drugs without having to deal with modifications to circumvent at least some of them.
The most important thing to take home is that nothing in that list above will cede itself to sheer force of process or sheer magnitude of resources.
Well, what does this mean in the real world as regards treatment for COVID-19? There are essentially three types of potential treatments for a virus
- Non-biologics "small molecule" drugs, which target protein(s) required for the virus to function and/or replicate
- Monoclonal antibodies to the virus that block its function/replication
- Vaccines, which trigger an antibody immune response in the vaccinated person to protect against the virus.
Scientists are pursuing all three avenues right now, but there are two parts to any drug discovery process: Identification of potential drug matter, and human testing of that potential drug (clinical trials). Taking these one at a time:
Small molecules: It typically takes at least three years to identify and refine a small molecule drug, and that does not include the clinical trials. The only way to short circuit this timescale would be if you could "repurpose" an existing drug for use against Coronavirus, either a drug on the market, or one that has already gone through clinical trials for something else (and failed due to lack of efficacy, but not due to severe toxicity). The chances of success in this realm are small. But this is the allure of using drugs such as Hydroxychloroquine: It's relatively safe, it's cheap, and it has been studied for many years.
Monoclonal Antibodies: Antibodies are like magnets in your body, which are highly attracted to their target. Each antibody type is attracted to a different target. When a foreign molecule is identified by your immune system, your body will create novel antibodies that will seek out that foreign target, deactivate it, and mark it for disposal. This is why we don't die from every virus we come in contact with. You can expose a human or an animal to a known pathogen (like Coronavirus) and that animal will manufacture the necessary antibodies to shut it down. Once the specifics of antibodies specific to Coronavirus are known, you can create them in massive quantities using modern biochemical techniques. However, these antibodies will need to go through clinical trials and antibody therapies are also subject to a variety of liabilities that can render them useless as drugs, including a propensity to aggregate, insolubility, viscosity, unexpected off-target toxicity, and others.
Vaccines: Historically, a vaccine is a foreign substance injected into a human that alarms that person's immune system and causes it to develop antibodies to defend against the foreign (antigenic) substance. Typically, a low or non-functioning molecular construct that is similar to the virus of interest is injected. The flu shot you get every year is such an approach. A variant of this approach is being pursued by companies like Moderna, which propose to inject a special kind of RNA nucleic acid that will cause the subject's body to produce a relevant antigenic protein, rather than having to inject the protein itself.
As you can infer, none of these approaches is a "chip shot" and none is guaranteed to work at all for a specific target. For example, nearly three decades after the beginning of the AIDS viral epidemic, we still don't have a suitable vaccine, nor an antibody-drug. On the other hand, a vaccine for the 2016 outbreak of the Zika virus was developed by a company (Inovio) in roughly seven months. And that is a world record. (Though that drug never went into clinical testing for SARS, because the infection died out before it could be tested.)
A full set of clinical trials for any vaccine would take a minimum of close to a year. You can't bypass the clinical trials because vaccines can have severe unexpected side effects, including death. Since we are talking about a virus with a mortality rate that appears to be less than 1%, any vaccine would need to be quite safe for general administration. There are already some proposed vaccines moving to clinical trial, but the chances that the first vaccine to the clinic will be "the one" is, based on history, not high. Probably many putative vaccines will need to be tested before is identified as efficacious and safe. A realistic "best case" estimate would be roughly 18 months. And that's the best case. There is plenty of history to suggest it might take a lot longer (maybe years) than that.
By the time a treatment is identified, clinically tested, and ready to roll out, we will almost certainly be into 2021, and by then the virus will have had a chance to mutate (as all viruses do). Whether the tools being developed now will be highly efficacious against Coronavirus in 2021, or whether, like the flu vaccine, they'll be only partially useful, or like AIDS there will be no vaccine at all in that time frame remains to be seen.
But what is assured is this: Drug discovery is neither easy nor simple, no matter how smart or rich the team you assemble, and we're going to need some luck to have a good treatment by this time next year. For now? Stories of the Manhattan Project for viruses may make you sleep better at night, but the reality is that we're still an unpredictable ways away from a cure.
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