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An Antibiotic Discovery Prize

Ezekiel Emanuel of the University of Pennsylvania has a proposal in the New York Times for a prize in antibiotic discovery:

Let’s use prize money. What if the United States government — maybe in cooperation with the European Union and Japan — offered a $2 billion prize to the first five companies or academic centers that develop and get regulatory approval for a new class of antibiotics? As the XPrize — a foundation that runs competitions to spur innovations for difficult problems that often aren’t being addressed — and others have demonstrated, prizes for lofty goals can catalyze the creation of hundreds of unexpected research teams with novel approaches to old challenges. The prestige, bragging rights and renewed sense of mission created by such a prize would alone make an investment in research worthwhile.

I think that’s a good idea, and I’d submit that this is about the minimum amount needed. (It’s certainly a lot more realistic than this proposal). Regulatory approval is certainly the appropriate endpoint. If someone wants to put more money into it, I’d tighten up the requirements a bit to say a new mechanism of action against gram-negative organisms, since hitting the gram-positive ones is (somewhat) easier and (somewhat) less critical. Knowing that payout is waiting would make a good case for a number of small companies to try a lot of unusual things, and unusual things are just what’s needed in this area. Let’s see if anyone expresses serious interest. . .

38 comments on “An Antibiotic Discovery Prize”

  1. biologist says:

    MRSA is gram positive, therefore I would not restrict this to gram negative in any case. If I had the money (unfortunately, I am not William, First Prince of Microsoft) I would create separate classes, 10e9 each for gram positive and gram negative, and maybe an additional 500 M for fungi. Then I would ask the other nobles for a matching contribution (Duke Berkshire would contribute I think).

  2. anchor says:

    OK, this will be a good enticement! But, there are just one too many stumbling blocks in academia. Starting from scratch as the medicinal chemists (lead discovery, optimizations) do in industry is next to impossible in academia and I am from academia. I am trying to keep my sanity in check dealing with individuals from the department(s), tech. support, patent etc. and the list is long!!

  3. watcher says:

    I find it typically appalling that an academic scientist tries to spend a lot of government money on his own idea. If he thinks it’s so important to present such an award, then he needs to go to private contributors to raise the money. Will Gates contribute? Buffet? How about Zuckerberg or Ellison or the Kochs (do something worthwhile with their money) or the Walton family?

  4. Farmhand says:

    I think this is a terrific idea. Of course there are a million issues that can and will come up, as anyone who has administered prizes will know, but nothing compared to the potential benefits. I would not add too many restrictions. If there are five new treatments for gram-positive and none for gram-negative, we declare victory and restart the prize focusing on gram-negative. Yes, it may be difficult for an academic group working alone to succeed at this, but I can imagine some weighty negotiations between industry and academia to fund research at a very high level over multiple years in return for a period of exclusive rights to early results or technology. Sounds like a win-win to me.
    …And in response to the “appalled” poster, personally, I could give a rats ass where the money comes from. People are dying or getting really, really sick. If it makes you feel better, how about we start a government-sponsored foundation to fund the prize so both governments and individuals could contribute according to their means. Maybe then we could up the anti to 5 Billion. Just get the damn money out there and address the issue.

  5. skatesailor says:

    Emanuel’s idea is terrific, as Farmhand points out (4.). But Emanuel overreaches when he seeks to award the prize for regulatory approval of “…a [whole] new class of antibiotics.” When was the last time that any regulatory agency granted simultaneous approval to all the members of a new class of drugs, whatever their mechanism of action? What’s the probability than any agency will do so in the future? If the prize is to be awarded for the however-unlikely approval of a new class of antibiotics, then the award seems uninspriringly small.

  6. Dr. Manhattan says:

    New classes are very hard to come by. The recent Teixobactin (Gram positives only) points to one new path for revisiting natural products, a very productive area for antibiotics. Work from Novobiotics & Kim Lewis’ group suggest that producers can be coaxed to make new molecules. Other work by Sean Brady in expressing “silent” NP pathways also holds promise. There are other initiatives also underway to stimulate antibiotic R&D, even as some pharmaceutical organizations continue to exit the area. So given the stakes, I welcome any and all efforts to replenish the antibiotic pipeline.
    One “new” class for Gram negatives is the avibactam/relebactam beta-lactamase inhibitors, with novel structures and the ability to inhibit a broad range of beta-lactamases when combined with existing beta-lactam compounds.
    @#1. True, MRSA is Gram positive, but at least for the present, there are several therapies such as the old standby vancomycin, Cubicin (lipopeptide), two oxazolidinones (Linezolid and Tedizolid) and Televancin (dual action glycopeptide). The real need for now is the dwindling effectiveness of Gram negative therapies. So I would also not restrict it to Gram negatives, but I might incentivize Gram negative efforts at a higher level.

  7. lynn says:

    Let’s say that it was lack of money that prevented novel antibiotic drug discovery over the last twenty-five years [it wasn’t, but that’s a different subject]. Who would be able to spend a billion dollars to bring a compound from discovery through development before claiming the prize except for Big Pharma? And $1B would be a drop in the bucket for them. Academics don’t have the wherewithal to discover something and then show it is even worthy of development – unless through grants. And while NIH funding levels are low, the number of creative applications in the area is dismally lower. Small pharma…maybe. But the money is needed at the early end – rather than as a reward.

  8. Farmhand says:

    Skatesailor
    I did not read this as an approval of the entire class, only that the prize winners had to be from a new class. Unclear if he was suggesting that each prize winner would themselves have to be a distinct class from each other or just distinct from ones existing now, but at this point it’s just a proposal.

  9. Anonymous says:

    This is one area that I think the field of glycobiology could tremendously help out in. The peptidoglycan layer, LPS, capsule, teichoic acids and some of the other most important structural features of bacteria are heavily comprised of carbohydrates. What’s really interesting is the fact that extremely rare sugars have been found on bacteria in some of these structures that are believed to be species specific. Maybe it is time we moved beyond killing bacteria with broad strokes in which we kill gram + or gram – bacteria, because after all, the microbiome is also supposed to promote human health and is supposed to take years to recover from treatment with antibiotics. What if one day we could target bacteria in a species specific manner and inhibit the metabolic pathways that utilize or synthesize extremely rare sugars? Or what if one day we could modify the extremely rare carbohydrates to start taking advantage of bioorthogonal chemistry to modify the way bacteria can adhere or use them to selectively delivery drugs?
    For a review on these ideas see
    Recent advances in synthesis of bacterial rare sugar building blocks and their applications.
    Nat Prod Rep. 2014 Jul;31(7):870-9.
    and
    Glycans in pathogenic bacteria–potential for targeted covalent therapeutics and imaging agents.
    Chem Commun (Camb). 2014 May 11;50(36):4659-73

  10. slcimmuno says:

    good commentary. have mentioned this company before, but Cellceutix, picking up where Polymedix left off, holds the most potential as to getting a truly novel class of ABX to market—host defensin mimetics. the original work was done by research at U Penn, namely, william de grado (genius chemist who is up for the Protein Society’s Stein and Moore Award), and michael klein, genius comp/quant whiz). teixobacting got lots of love when it was announced but is years from market and does not affect gram – bugs, whereas Brilacidin, does show gram – activity. addtl work is being done at Fox Chase Medical Center to advance gram-negative defensin mimetic compounds. the answer to developing better drugs might be via the type of supercomputing/biomimetics polymedix advanced more than a decade ago. lets hope so.

  11. anonomoujs says:

    I also think that this is a great concept but one that increases in complexity in its administration. Perhaps the simplest case is the prize awarded to a company, since there may be instances in which a single company carries the project from conception to registration/approval. But how often is that the case for an academic? And who gets the prize if one scientist identifies the target, another invents the compound itself, and a third (collection of) individual(s) conducts the development (both pre-clinically and clinically)? Dividing the credit is challenging, particularly when a prize of this magnitude is at stake. Again, I’ll repeat that I’m highly in favor of the concept and perhaps these are more solvable challenges (and worthy of solving) if they would lead to real and necessary breakthroughs.

  12. Anonymous says:

    I thought the search for antibiotics were mainly geared for the threat of super resistant strains rather than a new penicillin.
    This makes it more of a risk prevention than something that would have immediate impact. And as people are often very short-sighted, harder to get it approved than say- something regarding cancer, Alzheimer’s disease or such.

  13. bacillus says:

    @9. One reason for the relative success of antibiotics is that you don’t have to wait for a definitive diagnosis of what ails the patient first. Although, I do agree that hitting the microbiome each time one takes an antibiotic is not good. Of course, if a gram positive or gram negative pathogen becomes a big enough threat, then a vaccine might be the best approach. I often wonder whether we’d already have good vaccines against e.g. Klebsiella, Staphylococcus if antibiotics didn’t exist.

  14. TGS says:

    Rather than distinguishing the prize in terms of Gram-positive and Gram-negative, perhaps just focus on the ESKAPE pathogens?

  15. MTK says:

    @4,
    Concur.
    I don’t find putting up public money to help solve a public health issue an issue at all.
    The whole point of putting up the public money, if that’s what the source would be, would be to stimulate private money investment.
    At the same time, it would be the public paying only for concrete results and a delivered product, which is a lot more than we can say how the government often spends money.

  16. Douglas Kell says:

    Excellent idea. Such prizes are well known stimulants of innovation. It needs to be staged; no academic will win if they have to get APPROVAL.

  17. Eric says:

    I like the suggestion, at least in theory. John LaMattina has some relevant comments on the practicality of the approach on Forbes.com
    I’m not certain if this approach would really work – but we do need to come up with alternative approaches to funding research of this type. This extends to many other therapeutic areas as well. Many people have clamored for ‘individualized’ medicine but this ultimately leads to a very fragmented market and who will be willing to pay for research into these numerous niches without some certainty of return on investment?

  18. Anonymous says:

    Why is a prize necessary? Is it because there are no market based incentives for such antibiotic drug discovery?
    Merck/Cubist?

  19. Farmhand says:

    @ 17
    I hurried on over to Forbes to read John LaMattina’s comments. I wish I hadn’t. What a crock, is all I can say. His closing comment sums it up:
    “unless payers and governments are willing to provide favorable pricing for such a drug, the big companies are going to focus their R&D investments in areas like cancer, depression, and heart disease where the return-on-investments are much higher.”
    What, $2B guaranteed upfront if your successful isn’t enough for a niche market? Sure, it’s a fraction of the potential profits for a block-buster oncology or antiviral, but it’s not like you’ll only have a few years of sales to make up your investment. That’s already taken care of. Yes, you will have manufacture and sales cost. I think they can handle that. Hell, you don’t even have to sell it. You can out-license it to someone else if it’s too much trouble to market it and invest the money in…oh to hell with it. This, in a nutshell, is precisely why a prize is such a good idea when the market isn’t huge but the medical need is so high. No excuses, no “but we can’t do this without concessions”, just go for a big payout that, if you are successful, will all but guarantee a decent return in dollars, prestige, and good will (something the industry could clearly use). It’s a crap shoot. That’s research. He of all people knows that, but some times you just have to do the right thing. If Big Pharma is unwilling to go for this, then by all means, sit this one out. I can imagine a consortium of smaller more entrepreneurial outfits and academic centers pooling their knowledge to make a try. Some will fail, but some will succeed. When they do, they will deserve every bit of money and every bit of praise we can heap on them.
    There, I feel a little better now.

  20. Why not just change the regulatory and reimbursement environment so that antibiotics are more attractive investments?
    Right now, antibiotics used in the in-patient setting are terrible investments. Hospitals receive bundled payments (via DRGs) and if a new, more expensive drug comes out, they are forced to take the loss. Right now a $5K drug raises eyebrows in hospitals. Carve out the drug costs so hospitals care less about expensive antibiotics.

  21. DJK says:

    Are potential rewards for developing a new class of antibiotics really not enough?
    I would think $2billion would be chump change compared to the patent royalties and associated monopolies the first inventors/applicants would have.

  22. jbosch says:

    @7 Lynn, “And while NIH funding levels are low, the number of creative applications in the area is dismally lower.”
    Are you surprised by that ? NIH is self-selecting for non-innovative research, true innovation is not understood by the reviewer panels and are triaged.

  23. Some idiot says:

    #4, 19: Agree completely. With everything you said. Which is a bit unusual for me….! (-:
    This is an area which is a problem, and the problem is only going to get bigger. We have all heard about the risk of a “post antibiotic era”, and my personal opinion is that this is a real risk if something is not done about it.
    This is not my field, but as I understand it yes, commercial incentives as by the free market are minimal. Reason is a bit like this. When someone finds the next super-duper antibiotic, it will neither be the first nor second drug of choice. Why? Because the medical profession has (largely) learnt their lesson, and will only go for the newer, higher-potency antibiotics in bad cases, where the other ones have largely failed (to reduce the speed of resistance generation).
    Therefore, even if it is the best antibiotic known to mankind,it is unlikely to sell volumes in the first 5-10 years, so therefore market forces dictate that it ain’t gonna happen.
    So please, bring in the prize (with the right details in place) as soon as possible. I don’t want our children or grandchildren to risk growing up in a post-antibiotic age.
    There. I feel a little bit better now too….! (-:

  24. johnnyboy says:

    I’d like to know more about the kind of revenue that new antibiotics bring on, but I have a feeling that 2B$ is probably not a big enough incentive to be game-changing for antibiotics. Sure it would be a nice bonus to a company’s revenue (and we are talking about big pharma here, no academic lab could bring a new drug to approval by itself, and a small pharma would necessarily need to make a deal with a large one for clin trials and marketing, which would significantly dilute the 2B$), but when you factor in the expense needed to bring the drug to market, and the kind of ROI that the company could get in other fields, I doubt that the bean-counters in the finance dept would get very excited about it. I certainly don’t think it would sway a company that decides to divest from antibiotics, or would convince a company to get back into the game. At best it would be a nice potential bonus for a company that is already determined to stay in the field – so not something that would really bring a bunch of new antibiotics to patients, which is the stated goal here.

  25. Wile E. Coyote, Genius says:

    It’s not clear to me in his proposal when he says $2B to the first 5 companies what he means. Is that $2B each (probably not) or $2B split 5 ways? $400 million isn’t enough.

  26. Cato the Elder says:

    Right now I think there is a 0% chance of this happening, which I think is very sad. I really don’t get why more people are not as alarmed by the state of antibiotics (outside the few scientists in the know). What is it going to take for people to realize? A senator’s kid dying from an infection?

  27. bradpalm1 says:

    Lynn and jbosch….reminds me of the cartoon I keep near my desk where the examiner tells the researcher: “This really is an innovative approach, but I’m afraid we can’t consider it. It’s never been done before”. My small and cash-strapped biotech company has reached out to many groups over the years to elicit any degree of monetary support for our simple, yet very innovative approach to enhance the delivery and spectrum of existing antibiotics without success.
    Despite early success in other therapeutic areas with our novel technology, from my perspective new drug discovery sometimes seems to be matter of luck and providence as much as anything else. Very ironically, we’ve shelved this novel antibiotic project hoping a window of opportunity for some pre-grant funding opens in the future.

  28. DTX says:

    To Johnnyboy and others: The WSJ had a good article on market incentives. Ceftaroline fosamil, an antibiotic approved in the U.S. in 2010, costs around $600 for a 7-day course, whereas Yervoy for melanoma costs $120,000 for a 12-week course. It’s pretty easy to see why cancer is a hot area for research, not antibiotics.
    And on top of this, as “some idiot” notes, if used appropriately (i.e., only for resistant strains), the market for the new antibiotic is very small.
    So new antibiotics garner very little money for a very small market.
    See: H. Plumridge, Drug Makers Tiptoe Back Into Antibiotic R&D As Superbugs Spread, Regulators Begin to Remove Roadblocks for New Treatments. Wall Street Journal Jan 23, 2013.
    A prize is definitely needed to spur research into new ones.

  29. johnnyboy says:

    @DTX: Apples and oranges. Antibiotics are going to be used on a lot more people than a specific cancer drug. When I was at Pfizer in the 2000’s, Zithromax was under patent and was one of their top 5 revenue generators. So not necessarily such a tiny market.

  30. Barry says:

    We knew about his brother, Rahm. The other Emanuel is also a weasel. When he writes: “Because it
    costs at least $1 billion to develop a new drug, the prize money could
    provide a 100 percent return — even before sales”, note the “could”
    and the “at least”. He knows that the latest estimate published puts
    the cost of a new drug at $2.6billion, putting the claimant of such a
    $2billion prize firmly back in the red.
    Worse, when he writes that ” any new antibiotics that might be
    developed to fight these drug-resistant bacteria are likely to be used
    very sparingly under highly controlled circumstances, to slow the
    development of resistant bacteria and extend their usefulness” he
    ignores the history that shows we can expect a pirate lab
    (traditionally in India) to immediately start producing the same
    compound in violation of the patent. “[H]ighly controlled
    circumstances” might apply within the U.S., but new resistant
    organisms would be cultivated elsewhere by over-use of the pirate
    product.
    But he’s not done. By the end of the column, what had been a
    $2billion dollar prize is now $2billion per year. Surely the merit of
    a plan that depends on cash incentives depends on knowing what it
    costs.
    No patient should trust a physician as lawyerly as Dr. Emanuel. No
    nation should be guided by his counsel.

  31. bradpalm1 says:

    “Ceftaroline fosamil, an antibiotic approved in the U.S. in 2010, costs around $600 for a 7-day course, whereas Yervoy for melanoma costs $120,000 for a 12-week course. It’s pretty easy to see why cancer is a hot area for research, not antibiotics.”
    Ironically, if new antibiotics aren’t discovered soon we may be forced to use CTLA-4 and PD-1 checkpoint inhibitors to help treat resistant bacterial and fungal infections in the future.
    http://ccforum.com/content/pdf/cc12711.pdf

  32. Josh B says:

    First of all, it’s already being done. Dave Shlaes discusses this in his blog. http://antibiotics-theperfectstorm.blogspot.com/2015/02/antibiotics-as-orphans-ny-times-and.html
    Second, Emanuel conveniently forgets to mention the biggest reason that we are in this mess—a terrible policy change by the FDA in the early 1990s, which would have forced companies to double the size of phase III trials. For no reason. It is no coincidence that drug companies went flying out of the area right after this change took place.
    Dr. Henry Miller of the Hoover Institution (and the founding director of the FDA Office of Biotechnology) sums this up yesterday in his letter to the Times:
    “Dr. Emanuel neglects the role of flawed public policy in discouraging the development of desperately-needed new antibiotics. A 2002 change in F.D.A. requirements for the clinical testing of antibiotics helped to create the shortage of new ones: To enhance the statistical power — and therefore, the confidence level — of Phase III antibiotic clinical trials, F.D.A. more than doubled the number of patients required. This made already-difficult clinical trials even more unwieldy and expensive.”
    Emanuel is full of crap.

  33. Dr. Manhattan says:

    ” we may be forced to use CTLA-4 and PD-1 checkpoint inhibitors to help treat resistant bacterial and fungal infections..”
    You do know that bacteria don’t have those checkpoints in their replication cycles, don’t you?

  34. bradpalm1 says:

    I was obviously alluding to the conclusion in the attached paper that checkpoint inhibition may reverse the immunosuppression related to bacterial and fungal septicemia. This phenomena may be related to T-cell exhaustion due to persistent antigenic exposure in sepsis.

  35. Eric says:

    Farmhand,
    When I first read your comment I was a little confused why you thought the Forbes article was a ‘crock’. After re-reading, I realized you don’t like the LaMattina/Big Pharma mindset. The comment you quoted accurately sums it up -it all comes down to dollars and cents. As much as you (and I) would like Big Pharma to act for prestige and good will, I highly doubt they care. As Gilead raked in $10 billion dollars in sales this past year for their Sovaldi treatment and got pilloried in the press they didn’t seem too concerned about good will. Return on investment rules all.
    You complained that a $2 billion prize should be enough to stimulate research in antibiotics. You and LaMattina are just haggling over price. Surely $100 wouldn’t stimulate anything but $100 billion would stimulate everybody. Somewhere in the middle is the magic number. That number is probably higher for big pharma than for academic centers.
    All of this gets back to my original comment. The current economics don’t work for antibiotics or for niche markets. We do need economic incentives for these fields. The prize is an interesting proposal. Implementation would be hard, but I’d like to see it.

  36. DrugA says:

    Suggesting that FDA is responsible for the lack of new antibiotics is, at best, incomplete. Reasonable people can debate about the appropriate design of a clinical trial. The relatively empty pipeline and the big pharma exits from the field predate that. Talk to anybody involved in antibiotic development and you will hear that their first problem is finding drugs with Gram negative activity.

  37. DrugA says:

    Suggesting that FDA is responsible for the lack of new antibiotics is, at best, incomplete. Reasonable people can debate about the appropriate design of a clinical trial. The relatively empty pipeline and the big pharma exits from the field predate that. Talk to anybody involved in antibiotic development and you will hear that their first problem is finding drugs with Gram negative activity.

  38. glinkst says:

    The only organizations that could benefit from such a proposal is big pharma, and for business reasons, most of these companies have either dissolved or “right-sized” their departments. They are too many to list; it would be easier to list the companies that have not dramatically reduced or eliminated their antibiotic R&D, since it would be much shorter.
    Does he really think that this will reinvigorate antibiotic drug discovery in big pharma? Probably not. Lynn S and Douglas K (@7, 16) are right – it needs to be earlier, and staged, so smaller companies, where there are a lot of heavy lifters, can capitalize quickly, rather than wait for big pharma CEO’s, to think quarter-to-quarter, slash their R & D budgets, then pull out their personalized coin, and flip it (homage to Ian Read).

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