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DRACO Illustrates the Poor Funding Situation for Radical Departures from the Existing Status Quo

DRACO, double-stranded RNA activated caspase oligomerizer, is a broadly applicable antiviral technology that has been under development at a slow pace for quite some time now. You might recall some publicity back in 2011, for example, but that marked the results of years of earlier work. DRACO attacks infected cells, not the viruses themselves, following the principle of finding a common vulnerability to target rather than trying to tailor therapies to every different variety of attacker. Despite technology demonstrations to show effectiveness against a broad range of very different types of virus, and the fact that this technology can in principle be applied to near any type of virus, there is next to no ongoing funding for DRACO. It stands as an example of the fact that you can build a better mousetrap and still have the world ignore you. In this case DRACO is languishing despite grave concerns regarding spreading viral resistance to existing drugs, and billions devoted to constructing new drugs that are just more of the same.

Advocacy and philanthropy are often the only ways forward for a new medical technology that is a radical departure from the present status quo. This is a lesson to keep in mind when we talk about the various branches of longevity science. It is hard to obtain funding in the life sciences in any meaningful fashion, and the organization of funding for any ongoing serious effort has become a baroque effort involving many players, all of whom are operating with perverse incentives that only serve to slow down progress and make funding less effective on a dollar for dollar basis. For example the large funding bodies are extremely risk-averse, and thus almost never fund the most important early-stage and high-risk projects, the science that is actually science, at the forefront and involving new discoveries. These funding bodies only ever put money into ongoing development wherein which the researchers can already demonstrate proof of concept and an understanding of the mechanisms involved. Getting to that point for any new line of research requires creative accounting and the help of philanthropic donations, and even so there is far too little actual science taking place in major laboratories.

I noticed a recent paper, one of the few for DRACO of late, in which the authors provide evidence to show that DRACO is a worthwhile avenue for antiviral therapies in pigs, targeting diseases for which there are no presently adequate therapies. Another of the draws here is that DRACO isn't just an approach for near all viruses but also an approach that should work for near all mammals as well.

DRACO inhibits porcine reproductive and respiratory syndrome virus replication in vitro

Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause substantial economic losses to the pig industry worldwide. Current vaccination strategies and antiviral drugs against PRRSV are still inadequate. Therefore, there is an urgent need for new antiviral strategies to control PRRSV.

Double-stranded RNA (dsRNA) Activated Caspase Oligomerizer (DRACO) is a synthetic construct consisting of a dsRNA detection domain, an apoptosis induction domain, and a transduction tag. It has been shown to have broad-spectrum antiviral activity, but there have been no reports regarding its effect on PRRSV. Here, we demonstrate that DRACO exhibits robust antiviral activity against PRRSV infection by suppressing virus RNA and protein synthesis in both Marc-145 cells and porcine alveolar macrophages (PAMs). In addition, DRACO still exhibited strong anti-PRRSV activity when viral replication was enhanced by knockdown of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in Marc-145 cells. Furthermore, in PAMs, DRACO was capable of inducing IL-6 expression and reducing Hsp70 expression, which might contribute to the inhibition of PRRSV infection.

Collectively, our results imply that DRACO holds promise as a novel anti-PRRSV therapeutic drug.

Yet there is insufficient funding for any meaningful ongoing development of DRACO. Some people have been trying to put together a foundation to raise philanthropic funds, and of late some of their advocacy efforts can be seen at Facebook, but so far there is little progress towards gathering broader support. It is most frustrating; yet another example of the way in which our world is far from ideal.

Comments

"can in principal"

C'mon, another principle/principal error?

Anyway, DRACO is currently being researched at the Draper Laboratory at MIT, which does a heck of a lot of basic research. No argument that it needs more funding, though.

Posted by: Slicer at July 31st, 2015 6:26 PM

@Slicer: The perils of a freewheeling editor-less lifestyle.

Posted by: Reason at July 31st, 2015 6:37 PM

Go to the Chinese or Koreans. They will finance the development of DRACO.

Posted by: Abelard Lindsey at July 31st, 2015 8:10 PM

China and Malaysia are both very interested in biotech especially gene therapy. They are far bolder than the US and EU and I think they will push forward first. Medical tourism is going to be the norm once some of this regenerative tech hits.

Posted by: Steve H at August 1st, 2015 4:34 AM

So asian countries have now substituted billionaires in wish fulfillment fantasies?

You'd think that a cheap agricultural antiviral would get developed, but I guess they still need that first in pig study to be paid for.

I wonder what a developed treatment would actually be worth in the marketplace?

Posted by: Jim at August 1st, 2015 7:26 PM

Where there is no free market, there is no big progress. In a free market, the scientists would develop a working DRACO drug with a few million dollars of funding. There would be no huge and costly trials. They may find alternative ways to test the safety and efficacy of the drug. They would offer the drug for a certain price. Consumers would then decide if they are willing to buy the drug for the respective price, considering the risk or lack of safety data that is connected to it.

Only severly ill patients would try the drug in the beginning because their risk aversion is lower compared to the average population. If the drug works, news will spread very fast and more people will use it. The company will be able to reinvest money into more research and improvement of DRACOs. Other companies will show up, competition will increase, prices will go down, innovation will go up. New ways to test drugs will appear. Doctors and patients will decide what drugs they take.

The current system is broken. 12 to 15 years and 1-3 billion dollars are needed to get a drug approved. This amount of money is something you will never get through funding, especially if the respective disease is rare. The only solution I see is medical tourism.

Gene therapy gets easier every day. Less and less people and less and less money will be needed to conduct it. Find a country with low to no regulation and patients finally can decide themselves what they try and what not. Alternatives would include offshore ships, where those procedures can be done without FDA intervention. The current way of approval effectively inhibits progress but will not disappear anytime soon.

Posted by: Waverunner at August 3rd, 2015 1:36 AM

Trials have nothing to do with freedom of market, they have to do with protecting patients from snake oil therapies. Patents DO have to do with freedom of market, and eliminating trials wont make them dissapear.

Posted by: Antonio at August 3rd, 2015 3:12 AM

Yes, you are right, trials have nothing to do with a free market and therefore they stifle innovation. Despite mandatory trials, snake oil therapies are still sold all over the world. I couldn't care less if you only want 12-15 year old, trial tested drugs which cost a fortune but that has nothing to to with other patients, who really don't care about FDA regulation and see it as the main problem for new cost-effective therapy. Why not let patients and doctors decide what they take?

Posted by: Waverunner at August 3rd, 2015 3:46 AM

Because patients don't know medicine and doctors sometimes have conflicts of interest for selling a drug, and anyway don't have the money nor the time to make a proper trial. Neither a patient nor a doctor can make a double-blind, statistically significant clinical trial. Whether you like them or not, clinical trials are the only way to know whether a drug works or not. That doesn't mean that all is ok with current clinical trials law, but that is no reason to throw the baby out with the bathwater.

Posted by: Antonio at August 3rd, 2015 4:06 AM

For example, here in Europe I would streghten trials law, not weaken it, forcing all the products and therapies sold at drugstores, clinics, etc. to pass clinical trials first. That would eradicate homeopathy, acupunture, naturopathy and all that shit from Europe.

Posted by: Antonio at August 3rd, 2015 4:18 AM

@Antonio - Thanks for that link, really cool Nature article. Thanks for also being the voice of reason. Clinical trials and patient protection are obviously necessary due to the fiduciary (information asymmetry) relationship between doctors and patients. As someone who has had a close relative suffer and die from cancer, and who has seen all the quackery marketed around that, I am grateful for clinical trials. On the other hand the FDA has too little incentive to minimize costs, and people respond to economic incentives. Drug approval does look like a bureaucratic nightmare.

Posted by: Jim at August 3rd, 2015 6:56 AM

The 'Phase 0 testing' in that article does look like a very good idea.

Posted by: Jim at August 3rd, 2015 6:57 AM

@Jim: You lost someone to cancer and you admit that despite the trials there is lots of quackery out there. Doesn't this fully contradict what you and Antonio are saying? The person you know died because he didn't get the drugs he needed. How do more trials or FDA regulation help to increase the number of drugs? How many people died because it is impossible for normal scientists to get a drug approved and therefore these drugs never become available?

How many people were killed because of FDA regulation and how many were saved? This is the question that should be asked. Again, forcing patients to only take approved drugs, even if these drugs don't work or are not avilable at all and even if the patient is willing to take any kind of risk to prevent certain death (e.g. in case of metastatic disease), is murder by omission, nothing else.

Posted by: Waverunner at August 3rd, 2015 7:46 AM

@waverunner - the clinical trials are what allowed me to separate the real evidence based medicine from the Quackery. They provide the information necessary for this vital process. What everyone chooses to do with evidence is up to them.

Posted by: Jim at August 3rd, 2015 8:32 AM

@Jim: Yes, I fully agree that clinical trials deliver great information regarding safety and efficacy. The big question is if would you prefer to have DRACOs available at unknown risk (companies will try to find alternative and cost-effective ways to determine and reduce risk, no company wants dead customers!) or if you would like DRACOs and other drugs not to become available at all. Who gives the FDA the right to withhold unapproved drugs from terminally ill patients?

Posted by: Waverunner at August 4th, 2015 12:51 AM

"(companies will try to find alternative and cost-effective ways to determine and reduce risk, no company wants dead customers!)"

I can't imagine any alternative way to evaluate risk apart from killing customers. And even that would be much less clear than a clinical trial, since there is much less control and monitoring.

Posted by: Antonio at August 4th, 2015 4:46 AM

"I can't imagine any alternative way to evaluate risk apart from killing customers. And even that would be much less clear than a clinical trial, since there is much less control and monitoring."

According to you phase I trials should be accompanied by a great number of dead people, since, you know, killing is the only way to evaluate risk. Fortunately, it's not like that. Pre-clinical development is key to avoiding these cases.

In summary, you would rather let a terminally ill patient die before letting him/her experiment with unapproved drugs. Suppose you were terminally ill, would you still make that argument?

Posted by: Waverunner at August 4th, 2015 5:28 AM

"According to you phase I trials should be accompanied by a great number of dead people, since, you know, killing is the only way to evaluate risk."

Nope, I didn't say anything like that. A phase I trial is very different from selling a drug. Doses are smaller, they are given to healthy people and they are closely monitored. Nothing at all in common to selling something and waiting for relatives to complain about their loved ones dying/worsening.

"Fortunately, it's not like that. Pre-clinical development is key to avoiding these cases."

... to avoid SOME of these cases. Many compounds fail later, in phase I, II or III due to risk or lack of efficacy. See my link above.

"In summary, you would rather let a terminally ill patient die before letting him/her experiment with unapproved drugs."

In summary, you would rather kill a terminally ill patient much more rapidly than he would otherwise, and also kill non-terminally ill patients, in order to let companies save some money.

Posted by: Antonio at August 4th, 2015 1:58 PM

Just to put a fine point on Antonio's comment about preclinical results: the Nature article's statement that "About 85% of therapies fail in early clinical trials" may tend to make people underestimate how often drugs fail in Phase I studies, before efficacy even enters the picture. Note that in its figure "The clinical-trial cliff," nearly 70% of drugs entering Phase I studies go no further, indicating either that the drug can't reach plasma levels high enough to plausibly have a therapeutic effect (a notorious problem with food phenolics, NB), or that it exhibited sufficiently gross toxicity as to make it not worth taking any further.

Now remember that for a drug to enter Phase I studies, it must already have been found seemingly safe and effective in rodent or other preclinical models, and sometimes more than one.

A Google on "reproducibility crisis" is also educational.

Think about this carefully the next time someone wants to sell you a supplement based exclusively on preclinical research.

Posted by: Michael at August 4th, 2015 4:49 PM

I think a big part of the problem is that mice are such a rubbish display technology. Hopefully organs/bodies on a chip can provide better pre-clinical information.

Posted by: Jim at August 4th, 2015 7:38 PM

"Nope, I didn't say anything like that."

Yes, actually you did. Please read your comment again: "I can't imagine any alternative way to evaluate risk apart from killing customers." If trials are the only way to evaluate risk than why do we have so few dead people from phase 1 trials? Moreover I didn't know that death was the main outcome for a phase 1 trial because as you said, there are no alternative ways to test for risk.

"Nothing at all in common to selling something and waiting for relatives to complain about their loved ones dying/worsening."

Your arguments are flawed on so many levels:

1) What incentive does a company have to kill its customers?
2) Is the patient forced to take the experimental drug or does he purposely take the risk in order to avoid certain death by illness?
3) Why wouldn't companies monitor patients and find alternative ways to avoid adverse effects?

"In summary, you would rather kill a terminally ill patient much more rapidly than he would otherwise, and also kill non-terminally ill patients, in order to let companies save some money."

First of all, it's not your business to decide for a terminally ill patient on how he has to die. You are saying that he has to die from his illness, which in many cases is accompanied by a slow and painful death. Focusing on these patients alone it becomes clear that what you say is disgusting and evil since you deny these people any alternatives and force them to die. Your assumption that companies would only sell new cyanide capsules is not based on any facts as well, because as I said, what are the benefits? You could easily introduce a marketing ban on new experimental drugs, so companies are forced to conduct respective research in order to make evidence based claims for their drugs.

"much more rapidly than he would otherwise"

Pure speculation and very low likelihood of being true. What is the incentive to kill customers unless you sell body parts like planned parenthood?

"and also kill non-terminally ill patients" Why would these people take unapproved drugs as well as the connected risk when a marketing ban is implemented? Why would companies want to kill their customers?

"in order to let companies save some money."

The argument was never about saving money, the argument was always about how drugs will never reach the market because they are not developed at all because costs are too high.

@Michael: Why do you think do so many drugs fail?

1) Because nothing replaces human testing.
2) Because the human body is more complicated than we can control for.
3) Because patient/disease heterogeneity is high.
4) Because if a drug only works for a small number of patients in a big sample it will never get approved. Take trastuzumab, if we didn't stratify patients for HER2-status this MAB would have never reached the market, despite the fact that it is a wonderful and effective drug with much less side effects than chemotherapy. Stratification of patients is only possible when we know what to stratify for, however, this is often not the case. Therefore many drugs, despite working perfectly in a subgroup of patients, will never be approved.

Posted by: Waverunner at August 5th, 2015 1:35 AM

Waverunner, your argument falls apart when you realize how many companies are trying to sell supplements right now and claiming that they do damn near everything, all the while saying that "These statements have not been approved by the Food and Drug Administration. This product is not meant to..." yadda yadda. Billions upon billions of dollars are spent every year on this crap. Would pharma companies save money by letting customers die, not really caring one way or another whether or not their products actually work? Of course they would- a lot of people already are!

"But terminally ill patients should have the right to try something that might save their lives" - Yes! They should! But it ought to be paid for by the drug developer as part of an extensive trial rather than by the patient, because otherwise the patient is buying something that may or may not actually work. Selling sick people drugs that don't work is completely unconscionable. Now, you can argue that this kind of thing needs money that smaller drug developers may not have, and I wholly agree- but the funding ought to come from investors or the federal government (which already spends hundreds of billions of drawing out sick people's deaths) rather than from dying people taking a chance on something that's likely to be totally worthless.

"Stratification of patients is only possible when we know what to stratify for, however, this is often not the case. Therefore many drugs, despite working perfectly in a subgroup of patients, will never be approved." What? Are you really arguing that companies should be able to sell a drug to everybody that only works in some people, even if they don't know who those people are? You need to find out who it works on, then sell it- not the other way around!

Posted by: Slicer at August 5th, 2015 2:22 PM

Rather than looking toward human trials, why not begin with agricultural animals and pets? There conceivably is a market for treating infected animals, and the hurdles are much lower. Funds derived from a company set up to do that could then be put forward for human trials.

Posted by: Carl White at July 12th, 2016 12:30 AM

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