Running ahead of Pandemics: Achieving In-Advance Antiviral Drugs

From Jaspreet Pannu (an EV winner, by the way, Jassi Pannu), here is a new, short Mercatus policy brief.  Excerpt:

I propose adopting innovation prizes with awards large enough to justify investments in broad-spectrum antiviral drugs developed up to phase III clinical trials in the FDA drug approval process. I also emphasize the importance of starting this effort with pathogen families of known pandemic potential, such as respiratory viruses.

…the medical community needs—and currently lacks—a class of drugs designed for emerging viruses of pandemic potential. These broad-spectrum drugs that target entire viral families can be developed as individual drugs or platform technologies.

Just before the outbreak of COVID-19, researchers at the Johns Hopkins Center for Health Security stated that “broad-spectrum [antiviral] therapeutics should be pursued given their potential value.”

There is much more at the link.

Comments

Why would anyone want to be voluntarily constrained by the FDA? Wouldn't South Korea or Japan be much better places, considering their interest and recent experiences? And particularly in light of this - "Favipiravir, also a broad-spectrum antiviral, was successfully approved in Japan as a treatment for various influenza strains and is stockpiled there for flu pandemics. Clinical trials are underway to test favipiravir against COVID-19. If those tests are successful, it will be the clearest indication yet that in-advance therapeutics works."

CNTRL + F + "prize" = 1 hit, not bad, it's a start.

CNTRL + F + "patent" = 4 hits. Even better.

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

Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAb) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those cells. Alternatively, in radioimmunotherapy a radioactive dose localizes a target cell line, delivering lethal chemical doses.[1] More recently antibodies have been used to bind to molecules involved in T-cell regulation to remove inhibitory pathways that block T-cell responses. This is known as immune checkpoint therapy.[2]

It is possible to create a mAb that is specific to almost any extracellular/cell surface target. Research and development is underway to create antibodies for diseases (such as rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Ebola[3] and different types of cancers).

How long does it take to ramp mAb production up? We can presumably find antibodies that inactivate COVID-19 in the body, and an injection of those antibodies would probably be a very good treatment for SARS-CoV2, but I expect it will take quite awhile to find the right antibody, get the yeast cells to make it in large quantities, and ramp up production of the resulting drug. Anyone know what kind of timeframe would be there?

I'd assume years. While it's a good route to follow, this is going to be an expensive treatment (even the biosimilars are on the pricy side) and will have non-trivial risks involved (they can trigger nasty allergic reactions which might be difficult to manage in Covid patients).

Disclaimer: on a mab Treatment for an autoimmune disorder

In case it was not clear, this will neither be broad spectrum nor preventative.

"We can presumably find antibodies that inactivate COVID-19 in the body..."

Yeah, maybe next week, next year, next decade,...

A prize or automatic FDA approval and CMS payment of $10,000 a dose won't have much impact on when it happens. If it did, ebola treatments would have happened before the 21st century out of fear of ebola being used by saddam or muslim terrorists. The efforts to produce antivirals and vaccines began anew in the 90s for "national defense", along with defense against bacteria and chemical weapons.

Two mid-90s novels, The Hot Zone and Executive Orders, along with other events made virus epidemics by terrorists a threat like commies under our beds, a threat now gone due to the destruction of the evil empire, the USSR. Until it came time to hike taxes to fund it while attacking Clinton on deficits and trying to impeach him. Better a viral pandemic while Clinton was president than tax hikes.

Great points! This all sounds horrific!

So now we have "mulp" telling us that things are so bad that we need to postpone the November elections. Who's with him? Just the deniers, I suspect.

Very experimental, doesn't usually work with cancer, but it's promising. Of course if they had my ideal patent system in place we'd have a cure for cancer, for Covid-19, and flying cars by now. And backyard nuclear fusion (I wonder what happened to commentator Mark? He was working on this a few years ago).

Bonus trivia: is it tasteless to do April Fool's jokes this year? Probably.

Very experimental? Well, the first one was approved in 1986...

No, but the flavor of the April Fools jokes has changed to become more fanciful:

https://www.solarquotes.com.au/blog/ancient-egypt-solar-power/

Also, April Fools has already been affected across the English speaking world over the past couple of years by the United States. We've had to cut back because the Trump Administration is consuming most of our tolerance for nonsense.

(This is not a joke. Google has actively discouraged April Fools stories for the past couple of years and, like it or not, it has a major effect on world communication.)

Track what Regeneron are doing. This research is already underway. Monoclonals can be produced at scale as the technology is well established.

Great idea, just do not use money extorted from the tax-payers. Try with Gates of Bezos, you might get what you need.

For the future, Jessi, If I were you, when I “suggest” something, I would also state where I am going to find the money. When it is not clearly spelled out, people tend to think that it is tax money that it is going to be used. For what is worth, this taxpayer does not like other people thinking about how to improve the world stealing his money.

In the US legal system, taxation is not theft or extortion as listed in the US criminal code. It’s taxation. Taxation is not in the US criminal code and can not prosecuted. Understandable that you might prefer not to be taxed, especially if you’re selfish & socially & politically immature, but calling it by the names you used implies an illegitimacy that does not exist in any functional, established or generally accepted sense. Hope that helps.

Oops, I irked one of the children of Oceania...

Where I live, these guys come to your shop and politely ask for your taxes. If you refuse, they bring you with force in a dungeon, and if you don’t pay you end up dead after some time. In exchange, they provide policing.

Of course, on top of the maras, in Honduras we also have the police of the State. They do exactly the same, the only difference is that their policing is useless and that they ask for more money.

Apparently it was Jonatan Swift that said there are people that count noses to distinguish between right and wrong. But what’s wrong is wrong, even if the majority of the owners of the noses say the contrary, it is still wrong.

You’d better go now, it is time for the two minutes of hate.

Novel antiviral class that couldn't get funding for development in the past: "As of December 2015, research related to DRACOs had ground to a halt due to a lack of funding."

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

I agree with the other comments and criticisms of the naivete (and maybe even stupidity, as Yancey Ward describes it) of the Mercatus policy brief.

Still, there are a couple of small things that can be said in its defense. One of them is this observation about DRACO, which I had not heard of before. Maybe prizes will resurrect the DRACO research program.

OTOH, maybe the reason that DRACO can't get funding is because it won't or can't work, and we might as well fund phrenology research. I don't know enough to judge what the real situation is.

The other critiques are basically spot on, it's not as if researchers and drug companies have been ignorant of the value of broad spectrum anti-viral treatments!

But though this is a cliche it's still valid: incentives matter. If the "market" for research has under-funded research into broad-spectrum anti-virals, then the government (or foundations as some commenters have suggested) should step in and increase the incentives.

Again the key question is what is the optimal amount of such research? Is it truly being undervalued? Maybe (citing Yancey Ward's other comment) we might as well ask researchers to put more effort into developing a time machine. That'd be a highly valuable technology too, but it's not something worth large amounts of research effort.

It’s seems as though owning a patent on a broad-spectrum drug for respiratory viruses would already be worth a bazillion dollars (dwarfing any specific prize)... did we not know that until 2020? It seems as though we haven’t. Given SARS and MERS among others, it’s amazing to observe that no one has already done this given its value.

Given there has been an outbreak of a respiratory virus every 5 years or so since at least 2002, can someone please explain the market failure here. The issue has to be technological, right?

Clearly, there was a lack of prizes

“what firm will invest millions developing a drug for a nonexistent pandemic market?“

There has been a respiratory virus epidemic every five years... how can we say there has been no market for this?

There are technical barriers due to the diversity of respiratory viruses and their different antigen targets. It's hard to have a universal therapy to hit all of them. Also, historically aside from flu and classic SARS they weren't that dangerous, just a few sniffles. We had a missed opportunity since classic SARS was ultimately contained that efforts to build a vaccine and treatment were abandoned midway.

I think preventing the ARDS component of illness is a more useful therapy to prevent the worst case scenarios.

How would the patent payout? As soon as there was a large outbreak similar to COVID-19 the outcry to revoke the patent for the public good would be deafening.

Similarly, all other countries in the world would violate the patent in short order.

Yes. No private firm could ever profitably fund such efforts. As mentioned if a crisis occurs most countries would ignore patents on such drugs. Plus the money spent on them would be diverted from other drugs for other diseases. Different diseases have their lobbies and preventing diseases that occur on a regular cycle is easier to sell then treating diseases that pop up from time to time.

I remember a politician, a mayor, once saying that so many of the requests that he gets for funding are worthy, but he can't fund all of them. Resources can be gathered for diseases like polio or smallpox because the victims are constant reminders. Pandemics, like are current troubles, are harder to turn into easy slogans. "This may never happen, but we need to spend millions maybe billions."

I imagine such funding will be easier now. However, the urge to turn much of the funding into wasteful spending through the political rewards system is a real danger.

Treatments to reduce the dangers of pneumonia should be easy to sell. Emergency stores of PPE should be easy to fund (The private sector will have millions of homes wanting a case for the basement.) Hospitals could receive incentives to build nearby hotels that can be converted to hospital beds in emergencies.

The desire to close military bases could be met with a desire to turn them into emergency hospital complexes or regional staging areas for response teams. Sports stadiums of the future may not receive funding unless a contingency play for rapid conversion in the event of a crisis is demonstrated. Who knows how future disasters will unfold and if we will be able to plan ahead. But you can bet that every pet political project will be sold, in part, for how it will help some group in the pandemic.

This tragic event will be exploited by some in the near future. Will we be smart and thoughtful or revert to competing interests trying to get part of the pie? History tells us the latter is most likely.

According to investors in medicine tech, the rewards for making investments must be in the tens of billions of dollars, and Congress has already done a great deal to provide rewards of tens of billions, including:

Patent protection for decades after discovery by government funding on how nature works leading to a consensus on promising product innovation

Massive public and private tax funding of product sales, ie, Congress directs the executive branch to define buying patent protected products as medically neccessary so bot public insurers supported by public tzxes must pay high reward rents to patent holders, and private insurers must also pay high reward rents by hiking private taxes, aka premiums or mandated payments by big employers who pay for the majority of medical products.

The problem is the odds of getting the desired reward is less than 10% which venture capital expects from high risk investment when it comes to medical products. Eg, the investments in "personalized" medicine triggered by the Humane Genome project which provided both data plus a lot of Keynes capital, all the factories making gene sequencing machines, not the Wall Street capital of inflated priced durable goods, goods priced at ten times the labor cost to build them. No one has earned the tens of billions in rewards expected from the promises of the Human Genome project, with probably a hundred ventures funded.

And that is in the context of medical problems that exist today and will exist in 20 years, like cancer, diabetes, ALS, CF, malaria, dengue, common cold and flu.

The only reason vaccines exist is the public, either March of Dimes, et al, or government, pays for the work at every stage in advance. And that has been consistent only for as long as enough fear can be created to fund the work at 10% the level of commie dominoes taking over fear funded building a hundred thousand nuclear bombs, and then fear funded dismantling and storing away the radioactive bomb ingredients as waste in high security.

This proposal is like calling for a reward for a way to stop an incoming wave of commie, or muslim nukes so we can cut defend budgets by half, with a second reward for a product to eliminate scary people globally without paying soldiers, or police and judges.

So... the correct way to incentivize more government funded life science research is to have an adversary ramp up spending on bioterrorism weapons?

Blecchhhh. Honestly, Tyler's call to postpone the November election makes more sense than that.

While one cannot dispute the value of broad-spectrum antiviral drugs, one also cannot dispute that finding them is astonishingly difficult, even if you limit the scope to a particular class of viruses. Finding a safe and effective antiviral for only a single virus can take a very long time. Asking for broad-spectrum activity multiplies the difficulty.

Indeed, this seems entirely wishful.

This is the answer. As Student noted above, there is already plenty of incentive.

I cringe when I read things like this...cross-disciplinary work is important, but if you don't have a solid grasp of the other field...you are hurting and not helping. Does the author understand why vaccines for viral conditions can be made? Does the author understand why are hundreds of antibiotics that successfully work while only a handful of antivirals? Does the author understand why the two most well known antivirals (Tamiflu/acyclovir and derivatives) don't even work that well? Does the author understand why, despite potential billions in profits, we aren't even close to curing the common cold? Why are no real 'broad spectrum antivirals'? Let's not have bad ideas get the funding.

I am not the author and I do not know answers to these questions. Could you recommend a good read?

You may as well offer a prize for time machine.

You could actually hear Napoleon say ask me for anything but time.

I finished reading the paper and the naivete is stunning. One cannot design a broad spectrum antiviral in the absence of appropriate targets. There is a marked difference between drug therapy for viruses versus bacteria. In the latter case, there are broad spectrum therapies that have been developed (resistance is still an issue to address). There are lots of talented medicinal chemists who know this truth.

There are two areas where money and ideas can make a difference. First, the ability to do cross platform observational studies needs to be markedly improved. It's hampered by a lack of consistency across medical records system. The second is to completely rewrite guidelines for clinical trials during pandemic times. All trials should be multi-center with centralized data collection and analysis. A central IRB and DSMB should be used to set up the informed consent and oversee the trial data for emerging safety and efficacy. None of this is rocket science for those of us who spent our careers in the pharma industry.

Thank you for the discussion.

It is worth noting, and my own oversight for not explicitly re-stating, that advance market commitments are thought (by their inventor, Nobel laureate Michael Kremer) to be more useful for technologically distant goals (i.e. drugs that are hard to create, such as broad-spectrum antivirals) versus technologically close goals.

The question is not whether we have figured out exactly how to create great broad-spectrum antivirals (we have not). The question is whether it is worthwhile to do so, and if this should be incentivized more than it currently is. I think that it should. This could change (in either direction) based on how the rest of this pandemic plays out, including the success and speed of vaccine development.

The suggestion is also not to have a single drug for all viruses (impossible) but many drugs, more than we currently have. Patents on these drugs would not be worth a 'bazillion dollars', because the majority will never be used and will thus be 'worthless' in the normal market. Most respiratory viruses, as mentioned above, are not that dangerous - there is just the risk that they might become so. Influenza is an example where there is plenty of market interest (hence Tamiflu) because of a known pathogen, with known risk, and plenty of in-advance buyers. I expect any antivirals against SARS-CoV-1 or SARS-CoV-2 to be well-funded after this. But the next pandemic may not be influenza or a coronavirus.

Resistance is an issue primarily for antivirals used for chronic infections (HIV, HCV) which are precisely the infections that generate market interest. Resistance may certainly develop, but may be less of a concern in the 1-2 week treatment timeframes of acute respiratory viral illnesses.

Viruses are very divergent - thus the difficulty in creating broad-spectrum drugs. Perhaps my next paper should focus on all the new work currently occurring in the field on shared viral mechanisms, but the marginal utility may be low - I expect this to be a hot topic after the current pandemic.

Thank you for sharing re: DRACOs - I will look into this more.

You aren't even understanding the basic science of cellular biology, bacteriology, and virology. You are contributing to disinformation when you are making suggestions in a field that you barely understand.

What, really, I can't call an idea stupid? Would ignorant have passed muster?

Great idea! Let's just throw a bunch of s&!t at the wall and see what sticks.

We're at the point where Esteemed Economists want the November election postponed, because everything is so horrible.

Honestly, what is off the table at this point?

Because as Trump has pointed out, the Republicans need voter suppression to win an election.

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