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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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July 25, 2014

The Antibiotic Gap: It's All of the Above

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Posted by Derek

Here's a business-section column at the New York Times on the problem of antibiotic drug discovery. To those of us following the industry, the problems of antibiotic drug discovery are big pieces of furniture that we've lived with all our lives; we hardly even notice if we bump into them again. You'd think that readers of the Times or other such outlets would have come across the topic a few times before, too, but there must always be a group for which it's new, no matter how many books and newspaper articles and magazine covers and TV segments are done on it. It's certainly important enough - there's no doubt that we really are going to be in big trouble if we don't keep up the arms race against the bacteria.

This piece takes the tack of "If drug discovery is actually doing OK, where are the new antibiotics?" Here's a key section:

Antibiotics face a daunting proposition. They are not only becoming more difficult to develop, but they are also not obviously profitable. Unlike, say, cancer drugs, which can be spectacularly expensive and may need to be taken for life, antibiotics do not command top dollar from hospitals. What’s more, they tend to be prescribed for only short periods of time.

Importantly, any new breakthrough antibiotic is likely to be jealously guarded by doctors and health officials for as long as possible, and used only as a drug of last resort to prevent bacteria from developing resistance. By the time it became a mass-market drug, companies fear, it could be already off patent and subject to competition from generics that would drive its price down.

Antibiotics are not the only drugs getting the cold shoulder, however. Research on treatments to combat H.I.V./AIDS is also drying up, according to the research at Yale, mostly because the cost and time required for development are increasing. Research into new cardiovascular therapies has mostly stuck to less risky “me too” drugs.

This mixes several different issues, unfortunately, and if a reader doesn't follow the drug industry (or medical research in general), then they may well not realize this. (And that's the most likely sort of reader for this article - people who do follow such things have heard all of this before). The reason that cardiovascular drug research seems to have waned is that we already have a pretty good arsenal of drugs for the most common cardiovascular conditions. There are a huge number of options for managing high blood pressure, for example, and they're mostly generic drugs by now. The same goes for lowering LDL: it's going to be hard to beat the statins, especially generic Lipitor. But there is a new class coming along targeting PCSK9 that is going to try to do just that. This is a very hot area of drug development (as the author of the Times column could have found without much effort), although the only reason it's so big is that PCSK9 is the only pathway known that could actually be more effective at lowering LDL than the statins. (How well it does that in the long term, and what the accompanying safety profile might be, are the subject of ongoing billion-dollar efforts). The point is, the barriers to entry in cardiovascular are, by now, rather high: a lot of good drugs are known that address a lot of the common problems. If you want to go after a new drug in the space, you need a new mechanism, like PCSK9 (and those are thin on the ground), or you need to find something that works against some of the unmet needs that people have already tried to fix and failed (such as stroke, a notorious swamp of drug development which has swallowed many large expeditions without a trace).

To be honest, HIV is a smaller-scale version of the same thing. The existing suite of therapies is large and diverse, and keeps the disease in check in huge numbers of patients. All sorts of other mechanisms have been tried as well, and found wanting in the development stage. If you want to find a new drug for HIV, you have a very high entry barrier again, because pretty most of the reasonable ways to attack the problem have already been tried. The focus now is on trying to "flush out" latent HIV from cells, which might actually lead to a cure. But no one knows yet if that's feasible, how well it will work when it's tried, or what the best way to do it might be. There were headlines on this just the other day.

The barriers to entry in the antibiotic field area similarly high, and that's what this article seems to have missed completely. All the known reasonable routes of antibiotic action have been thoroughly worked over by now. As mentioned here the other day, if you just start screening your million-compound libraries against bacteria to see what kills them, you will find a vast pile of stuff that will kill your own cells, too, which is not what you want, and once you've cleared those out, you will find a still-pretty-vast pile of compounds that work through mechanisms that we already have antibiotics targeting. Needles in haystacks have nothing on this.

In fact, a lot of not-so-reasonable routes have been worked over, too. I keep sending people to this article, which is now seven years old and talks about research efforts even older than that. It's the story of GlaxoSmithKline's exhaustive antibiotics research efforts, and it also tells you how many drugs they got out of it all in the end: zip. Not a thing. From what I can see, the folks who worked on this over the last fifteen or twenty years at AstraZeneca could easily write the same sort of article - they've published all kinds of things against a wide variety of bacterial targets, and I don't think any of it has led to an actual drug.

This brings up another thing mentioned in the Times column. Here's the quote:

This is particularly striking at a time when the pharmaceutical industry is unusually optimistic about the future of medical innovation. Dr. Mikael Dolsten, who oversees worldwide research and development at Pfizer, points out that if progress in the 15 years until 2010 or so looked sluggish, it was just because it takes time to figure out how to turn breakthroughs like the map of the human genome into new drugs.

Ah, but bacterial genomes were sequenced before the human one was (and they're more simple, at that). Keep in mind also that proof-of-concept for new targets can be easier to obtain in bacteria (if you manage to find any chemical matter, that is). I well recall talking with a bunch of people in 1997 who were poring over the sequence data for a human pathogen, fresh off the presses, and their optimism about all the targets that they were going to find in there, and the great new approaches they were going to be able to take. They tried it. None of it worked. Over and over, none of it worked. People had a head start in this area, genomically speaking, with an easier development path than many other therapeutic areas, and still nothing worked.

So while many large drug companies have exited antibiotic research over the years, not all of them did. But the ones that stayed have poured effort and money, over and over, down a large drain. Nothing has come out of the work. There are a number of smaller companies in the space as well, for whom even a small success would mean a lot, but they haven't been having an easy time of it, either.

Now, one thing the Times article gets right is that the financial incentives for new antibiotics are a different thing entirely than the rest of the drug discovery world. Getting one of these new approaches in LDL or HIV to work would at least be highly profitable - the PCSK9 competitors certainly are working on that basis. Alzheimer's is another good example of an area that has yielded no useful drugs whatsoever despite ferocious amounts of effort, but people keep at it because the first company to find a real Alzheimer's drug will be very well rewarded indeed. (The Times article says that this hasn't been researched enough, either, which makes me wonder what areas have been). But any great new antibiotic would be shelved for emergencies, and rightly so.

But that by itself is not enough to explain the shortage of those great new antibiotics. It's everything at once: the traditional approaches are played out and the genomic-revolution stuff has been tried, so the unpromising economics makes the search for yet another approach that much harder.

Note: be sure to see the comments for perspectives from others who've also done antibiotic research, including some who disagree. I don't think we'll find anyone who says it's easy, though, but you never know.

Comments (58) + TrackBacks (0) | Category: Business and Markets | Drug Development | Drug Industry History | Infectious Diseases


COMMENTS

1. David on July 25, 2014 8:44 AM writes...

Are there potential drugs where the toxicity is too high for current acceptance, but -- in the absence of *any* working antibiotics -- might be usable?

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2. Cato the Elder on July 25, 2014 9:06 AM writes...

The prospect of an era without routine-use antibiotics is honestly terrifying--I can understand the lack of interest from pharma, but why don't the academic funding agencies provide more of an emphasis on finding/developing new antibiotics?

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3. Wavefunction on July 25, 2014 9:41 AM writes...

I would think that old school natural product extract screening would still be one of the best ways to discover new antibiotics - it worked spectacularly well in the past after all. Is any company investing again in such approaches?

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4. Hap on July 25, 2014 9:46 AM writes...

I wouldn't think that there are too many academic groups (some, but not a lot) that could manage drug development. They could find leads for antibiotics relatively cheaply, but if the incentives for development aren't sufficient, then funding for finding leads won't help much in finding new antibiotics. Biomedical funding isn't likely to go up, so any funding for antibiotics has to come from somewhere else, and if the funding is for developing antibiotics, then a lot of funding would be required, which would make lots of other people (current grantees who would lose funding, people employed by them) unhappy.

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5. Puff the mutant dragon on July 25, 2014 10:02 AM writes...

There IS some very innovative stuff going on in this field, and I know 'cause I work in this area, so this is my kind of stuff. there are some tough challenges though as you point out, and I'm not sure whether the NYT author appreciates that. On the plus side, however, 1) our phenotypic screens and animal models are actually relevant (not true for many other areas) and very good predictors of efficacy in humans which makes life a lot easier. compare that to the situation for CNS disorders

Also @1, we kind of do have drugs like that we're already using. Doctors are now using colistin and polymyxin B for some otherwise untreatable gram-neg infections and WOW are those some nasty drugs. If they'd been invented today they wouldn't be approved because of their nephrotoxicity.

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6. SP on July 25, 2014 10:03 AM writes...

1- They've started pulling chloramphenicol into more routine use, it's pretty nasty.

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7. Matthew Herper on July 25, 2014 10:12 AM writes...

Another thing I rarely see mentioned is that when pharma backed out of antibiotics, a whole generation that knew about developing these compounds was put out to pasture, without training replacements. NIH could have hired these people and given them a home, but it didn't. The result is that, to some extent, the industry started from scratch when companies tried to get back into the field.

But I agree the biggest problem is that nobody's figured out how to get good actionable targets, and nobody's proven the business incentive. This is exactly the area where big cash prizes could work.

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8. Calvin on July 25, 2014 10:14 AM writes...

Sorry Derek but in many ways I fundamentally disagree with you. I don't belive that anti-bacterial drug discovery is any more difficlt that any other area. In fact it has one advantage that almost no other area possess. Animal models are beuatifully predictable in their correlation to man. The PK/PD relationship is pretty solid. But I think you confuse the total failure of a essential gene/target based approach of the last 20 years as being somehow indicative that it is somehow inherently difficult. It's pretty clear now that this is all about compounds and the fact that bug are pretty damn good at preventing compounds, specially drug-like (for getting inside human cell that is)compounds, from getting inside them. It's pretty obvious that a totally different bit of chemical space needs to be explored. But I'd argue strongly as to whether this was any harder than any other area. Given the predictive models it has much that is attractive.

But the real problem is that return on investment is always negative (by miles I'd add). This is more about a market failure (with a bit of a regulatory balls up too) than anything else. If you could make money people would still be in infection. But it was obvious 10 years ago that you couldn't make money. Look at it another way, HCV is area where it took more than a decade to find something that resembles a cure and it involved a lot of failure, but they reason people felt it was worth doing was becasue it was hugely commerically attractive (well there was one company that claimed it wasn't but that's another story). Gilead just made, what, $5.6B in the last 6 months.... Nope, this is really all about the cash. If it's worth it peolpe will solve the problems.

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9. Bring the Movies on July 25, 2014 10:23 AM writes...

When hundreds are dying each day in the hospitals due to anti-biotic resistant infactions that is when you will get industry and government interested.

The problem is, the hospitals will do anything they can to cover-up antibiotic resistance bacteria deaths, so nothing will happen until 100,000's lives are lost.

My advice? Don't work with sharp objects.

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10. Grim Reaper on July 25, 2014 10:25 AM writes...

@1 I think the worst place to see any advance in drug development in any meaningful way is the academy. All the incentives, structure, knowledge base and sociology are wrong. Ditto the NIH. So pharma is still the best of the worst entity to move a compound from discovery to commercial reality. In antibiotics it would help if you could make a buck along the way.

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11. Grim Reaper on July 25, 2014 10:26 AM writes...

@1 I think the worst place to see any advance in drug development in any meaningful way is the academy. All the incentives, structure, knowledge base and sociology are wrong. Ditto the NIH. So pharma is still the best of the worst entity to move a compound from discovery to commercial reality. In antibiotics it would help if you could make a buck along the wy.

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12. SP on July 25, 2014 10:44 AM writes...

The PCAST report addressing this will be out soon, there are some suggestions in there about ways to solve the market incentives. For example, if you're a company that develops an antibiotic that has to be kept in reserve and therefore won't make a profit, instead you could be reimbursed in something like a (tradeable) credit for an X year patent extension on an existing patent (X around 2-3 I believe is the rough idea). If you don't have any of your own patents to extend you could sell the credit to a company that wants it.

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13. Cato the Elder on July 25, 2014 10:57 AM writes...

I would agree that most academic groups would be ill-suited towards developing a drug for the clinic, but what about increased funding for isolation chemists? Perhaps a better question: how many antibiotics are purely human-designed in origin and how many are isolated from nature/derivative of a natural product?

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14. supplement joe on July 25, 2014 10:59 AM writes...

This NYT agenda article must conclude there is a vacuum here and the solution is: government. No surprise there, just more evidence of the demise of the NYT.

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15. johnnyboy on July 25, 2014 11:06 AM writes...

On the BBC a couple of weeks ago there was a piece about a mixed organization getting set up to look at ways to go around the economics issues going against antibiotics development. The organization involved pharma (GSK was mentioned), academia and government agencies, and they were starting to look at how to change the incentives to development, possibly involving government funding; David Cameron had a sound bite in the piece, so it seemed like relatively high level stuff, with some likelihood of actually happening (cue in the reflexive politician-bashing here). It sounded to me like it was at a very early stage and still quite far away from starting some actual research, but at least the problem is getting recognized and solutions getting discussed, at least in Europe.

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16. daveh on July 25, 2014 11:08 AM writes...

Calvin Nailed It. Saved me a bunch of typing.

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17. EU on July 25, 2014 11:09 AM writes...

The EU has started risk sharing the development of new antibiotics, see:
http://vimeo.com/87291478

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18. Anon on July 25, 2014 11:29 AM writes...

@13: It's been difficult for a LONG time to get funding for natural product isolation. And in recent years, it's got worse as the clearest route to facilitating isolation would be by guiding isolation with bacterial genomics. However, powers that be at NIH seem openly hostile to that idea, favoring translation over early stage discovery. And NSF won't fund medicinal exploration.

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19. Hap on July 25, 2014 11:32 AM writes...

NIH, etc. could fund more isolation people (it worked before), but if no one is interested in developing the output, then they haven't helped to get more antibiotics, or gotten anywhere other than to give total synthesis people more targets of opportunity. Even with the people who were laid off from such programs, there still would have to be a lot of money for gov't or academia to develop it themselves (to build up development capacity and expertise and then develop drugs), and I don't know where it would come from. Arguments from lack of imagination aren't authoritative, though.

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20. Anon on July 25, 2014 11:33 AM writes...

companies got out when the business model changed. dr wanted limited access and pharma wants widespread. look at Cubist as an example - too small for Lilly and good in short run for Cubist

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21. David on July 25, 2014 11:43 AM writes...

@5 & 6: Thanks!

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22. Miramon on July 25, 2014 11:44 AM writes...

Shouldn't the government offer some kind of x-prize for drugs that are obviously in the public interest but are unlikely to be very profitable?

For example how about $500M or even $1B or more for a really effective new antibiotic released to the public domain? Yes, I know, Congress won't approve money for anything but war, earmarks, and their own salaries -- but in principle, shouldn't something like this be done?

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23. a. nonymaus on July 25, 2014 12:58 PM writes...

Perhaps there could be some way to front-load sales (or buy options, etc.) of drugs that are destined to be kept in cabinets marked "break glass in case of vancomycin resistance." In the antibacterial field there are also some areas that should, but haven't, seen drugs, such as going after quorum sensing and biofilm synthesis. I also wonder if it would work to take some older antibiotics off the market until a lack of selection pressure excises resistance to them from bacteria in the wild.
On the other hand, if you want a tough row to hoe, take a look at antiprotozoals. There, you're up against a less-foreign molecular biology, and almost all of the potential patients are very poor. This is also a showcase for #1's question, since you can still be taken seriously while writing a prescription for an arsenic-based drug.

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24. Morten G on July 25, 2014 1:04 PM writes...

Why wouldn't it be possible to price new antibiotics at cancer drug prices? If it works doctors will prescribe it. Heck, they'll even prescribe it if it doesn't. So expensive it must be good.

You forgot to mention Longitude Prize by the way http://www.longitudeprize.org/ £10 mill but as per usual, the deadline is too short.

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25. Ann O'Nymous on July 25, 2014 1:46 PM writes...

Besides the difficulty of discovering the drug and getting it through trials, there is a difficult ethical problem about who gets it.

Suppose little johnny and mary come down with potentially-fatal X, and the usual antibiotics don't work. It's a tough doctor who can tell their parents, "sorry, they cannot have X." News cameras parked outside and the hospital CEO explaining why drugs are being rationed is not pleasant. Kadcyla springs to mind.

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26. Cattleya on July 25, 2014 2:56 PM writes...

Your belief that every potential mode of action has been explored suggests that once a drug has been found for one mechanism, one must move on to the next. However, just to pick one site of action, the five decade history of natural product beta-lactams ... from penicillin through cephalosporins to carbapenems and monobactams ... shows that there are many, often unexpected, ways to "skin a cat", each of which solved the then current problems in bacterial resistance. I well remember the reaction of our medicinal chemists, "we would never have dreamt of that structure" following structural elucidation of new natural products that implemented, in unexpected ways, the same motif. "There are more things in heaven and earth .. than are dreamt of in your philosophy."

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27. will on July 25, 2014 3:45 PM writes...

On natural product sources, the USPTO is now of the opinion that a compound isolated form a natural source is no longer patentable, per the myriad BRCA decision. whether or not their interpretation of the law is correct or permanent remains to be seen, but that can only serve as a further disincentive to NP/antibiotic research

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28. Anonymous Big Pharma Researcher on July 25, 2014 3:48 PM writes...

I work for one of the companies that spent a lot of money on antimicrobial drug discovery in the 1990s and early 2000s. When I was hired, microbial genomics was my full time job. We found lots of potential targets by various methods including both phenotypic screens and targeted knockouts.

Our first challenge was that back then many of these bacterial genes had unknown or partially-known biological functions, so we expended much effort figuring that out. Today, that part would be less of an issue, because people like me published papers describing how we determined the fuctions of these target genes.

However, once you've got a target and figured out its function, your difficulties making a drug have just begun. Bacteria and fungi have been engaged in mutual chemical warfare for over 500 million years, so bacteria are really good at defending themselves from antibiotics. As Derek says, all the obvious ways to kill bacteria -- and many non-obvious ones -- have been tried.

After spending many person years on antimicrobial drug discovery, my employers eventually gave up. For over 10 years, I have worked on antivirals instead. In the antiviral field, my company has built up a very impressive pipeline of compounds, some of which are on the market right now and others that we hope soon will be on the market.

So, based on my experience I strongly agree with Derek: antimicrobial drug discovery really is a lot more difficult than antiviral drug discovery at the current state of the art. The dearth of new antibiotics is not because we have not tried. We have, expensively, and failed. My company won't try again unless there are some public policy interventions that make it worthwhile for us to have another crack at the problem.

My favorite policy idea: a special patent clock for drugs in designated key areas that ties loss of exclusivity not to when the patent is filed, but to when the drug goes on the market.

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29. Good shot on July 25, 2014 3:55 PM writes...

If only there was a toxicologist smart enough to tease out the toxicity of quinolones with the help of a team of med chemists. Yes, resistance can rear it's ugly head, but the excellent PK is so seductive.

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30. An Old Chemist on July 25, 2014 4:30 PM writes...

Andy Myers should be nominated for the $1 billion prize if any of the tetracyclines come to market as the last resort, even after vancomycin has failed. Tetraphase has already got compounds in phase-II.

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31. SM on July 25, 2014 4:39 PM writes...

Off topic: Derek when will the chemistry book be out?

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32. sad on July 25, 2014 5:55 PM writes...

It is sad to see that we are talking about CASH incentives to convince companies to CURE PEOPLE. By the time our drugs will be useless, it will be too late.

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33. Anonymous Big Pharma Researcher on July 25, 2014 6:55 PM writes...

@Sad: if a scientific project will take many person years then somebody must pay for it one way or another. Academics are not gonna make new antibiotics. Drug discovery isn't what academics ought to do; most don't have a clue what a real lead compound looks like. This does not mean any disrespect for academics -- like many industrial researchers I once was an academic myself. But I had a lot to learn when I made the move from Famous Medical School to Big Pharma.

The hard reality is, only industry knows how to discover and develop drugs. Academics are great at basic science, which we cannot do in Pharma. One of the biggest challenges I had when I moved to industry was learning to STOP my analysis and move on once I had the practical answer we needed. Bemoaning economic realities rarely makes them go away. As a member of multiple Discovery Working Groups at an industrial R&D organization, I do not get to pick which diseases we'll study. The folks who make such decisions cannot keep spending money in areas where we come up dry unless there is reason to think we'll make a profit in the end.

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34. Anonymous on July 25, 2014 7:57 PM writes...

As an oligonucleotide therapeutics researcher, I would disagree with the 'no innovation' gambit. There are many promising antimicrobials in the pipeline in the oligonucleotide Tx space (see http://www.sarepta.com/our-pipeline). The preclin data from them has been impressive. Also, in theory, any mutations that confer resistance can be overcome by tinkering with the oligo's sequence. A very promising area indeed.

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35. ElArteDePerder on July 26, 2014 2:44 AM writes...

@28 that patent extension proposition makes sense. But I would go even further: patent protection is very short for pharma. Compare with copyright lengths, it's 70 years in the US!. So, basically, the protection for a guy that signs a song is stronger than for the development of drugs, although the investment and benefits for society are ridiculously bigger in the last case.

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36. aa3 on July 26, 2014 12:09 PM writes...

I am glad to see they are coming to terms with the idea that in order to get more of something, you have to pay for it. The economy works like that, if I want a new car, I have to buy a new car. Researchers don't work for free, laboratories and equipment needs to be paid for, etc.

The old plan of cutting back reimbursements, then complaining of pharmaceutical downsizing was/is a bad plan. The way to increase innovation & increase the number of STEM jobs and STEM pay, and thus increase the number of graduates.. is to increase the rewards for successful innovation.

The first step is to extend the patent life. I believe adding 10 years to the life of the patents should be the medium term goal. Although that is politically too hard, a whole series of reforms that amount to the same thing, but fly under the political radar may be better.

For example a patent extension for the duration of time the drug was undergoing clinical trials. Or targeted increases, such as if there is a public health need for new antibiotics, extending patent life in that area. Then when the public is alarmed by say heart disease, extending patent duration in that area.

Also increasing public funding of the research.

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37. cdsouthan on July 26, 2014 12:38 PM writes...

Dereck, was that 1997 genome Helicobacter or Staph ? (HGS filed both genomes around then)

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38. cdsouthan on July 26, 2014 12:39 PM writes...

Derek, was that 1997 genome Helicobacter or Staph ? (HGS filed both genomes around then)

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39. lynn on July 26, 2014 1:48 PM writes...

Having been a Big Pharma antibacterial discovery researcher for many years, I agree with Derek. Because of the way we have historically utilized antibacterials for systemic standard [non-TB] pathogens, we rely on monotherapy. And single targeted antibacterials [just like single targeted anti-HIV and anti-HCV drugs and anti-TB drugs] are probably going to fail in monotherapy due to rapid resistance development [there are exceptions]. While there has been a path toward the development of combination therapeutic regimes and drug registration for HIV, HCV, TB in order to combat rapid resistance- there is no such developmental/regulatory path, as yet, for standard systemic antibacterials. So when Big Pharma and everyone were pursuing all those genomic single-enzyme targets, they were not thinking about the propensity for resistance development. Almost all our systemic monotherapeutic agents are encoded by multiple genes or the non-protein products of pathways - such that single target-based mutations cannot lead to high level resistance. For small molecules in order to avoid rapid resistance development due to preexisting mutations, we need either multi-targeted antibacterials, or combinations [although there is little strong proof that this will work for bacterial infections]. There have been many publications on bacterial enzyme inhibitors, fewer publications on such inhibitors getting into cells [especially gram negatives], and even fewer showing antibacterial activity of such inhibitors is due to inhibition of the in vitro target. And the proof that these inhibitors are hitting the right targets is usually based on the ability to get mutations in that target at reasonable frequency [Catch 22!] So, when Big Pharma [and little pharma] kept going after single targets, there was little that came out of it [well, a few rare things]. Much more productive was the modification and optimization of "old" drugs with proven multi-targets [like the rRNA targeted protein synthesis inhibitors, beta-lactams]to overcome resistance. The latest broad efforts involve hitting both DNA gyrase and topoisomerase IV at sites different from those targeted by the fluoroquinolones - and these should produce compounds that someone will develop. So target choice has been a problem.

As was mentioned by Calvin above and highlighted in the GSK paper Derek referred to, another big problem is that synthetic chemical space in most libraries is different from the physicochemical space needed to enter bacteria [especially Gram negatives]. And Big Pharma either just didn't recognize or want to take the time to address the chemistry problem [although there was some work in that area]. So - with everyone working feverishly on new single targets and not working on better synthetic libraries [and getting out of Natural Products, see below] - Big Pharma spent a lot of time and money [over 20 years] with little "novel" to show for it...although they [and biotech] have come up with improved classical agents to overcome resistance. I think the fact that the massive commitment toward genomics, which led basically nowhere for antibacterials, was a major factor in Big Pharma's getting out of the area. Note that there have been a lot of reviews on the obstacles to antibacterial discovery, written by people who have been involved in discovery, that lay out the thoughts above [and others]. Natural Products were indeed a great source of antibacterials. The fact that the low-hanging fruit was picked early was a big problem. if you look at the first 10,000 extracts of actinomycetes that have antibacterial activity [and, about 50% of actinomycetes produce antibacterials under one condition or other] against MRSA, maybe 1 will be novel [not seen or described before]. And most of the undeveloped ones will be toxic. It is easy to kill MRSA; but hard to do it without harming the host. The big problem with natural products is finding novelty [and safety], identifying the interesting bioactives that have not been seen before, and discarding the rest without having to do a lot of fractionation and purification. Although isolation chemistry has improved greatly in doing this chemical "dereplication", I believe the key to finding novelty is in the use of directed and hypersensitive phenotypic screening. Knowing how to integrate this sort of screening with excellent chemistry is sort of an art - and one of the things that is being lost by the dissolution of Big Pharma activities in the area. But I think a lot of these problems are finally being recognized, and not just in the press. There have been a number of European initiatives toward consortia aimed at solving some of these problems. In the US, NIAID and NCATS are starting to talk about going after these problems [the rate limiting steps], as are non-profits in the US and UK. I agree in general with those, above, who say that academe is not the setting for drug discovery, but it is probably the place to do the basic science needed to overcome the obstacles - and the not-dead-yet refugees from Big Pharma can...and will...help.

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40. been there on July 26, 2014 3:47 PM writes...

I was at Replidyne when the FDA rejected our NDA for faropenem daloxate. It was novel, the only penem you could give by mouth. It had a fantastic safety profile. The FDA killed it because we had not done a novel study that the FDA had never previously required and randomly decided they wanted to see. The company had to close soon after.

So, I was sorry not to see some mention of the FDA in where we are today in antibiotic discovery. Frankly, they are lost in the weeds. I have no idea when they will ever get their act together. Am I bitter? Sure.

As Glenn Reynolds likes to say, I will believe its a crisis when the people telling us its a crisis start acting like its a crisis.

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41. Anonymous on July 26, 2014 6:52 PM writes...

Resistance mechanism for Penicillin is Beta-lactamase production. How about developing Beta-lactamase inhibitors? If a good compound is found, it can be combined with antibiotic to overcome resistance to old classic antibiotics.

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43. lynn on July 26, 2014 10:49 PM writes...

There are a number of new beta-lactamase inhibitors in clinical development, for example avibactam. These have been worked on for years to be used in combination with various cephalosporins and carbapenems. See Pucci, M. J. and Bush, K. (2013) Investigational antimicrobial agents of 2013. Clin. Microbiol. Rev. 26:792-821. for a review of these plus the other antibacterials in the pipeline.

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44. Anon on July 27, 2014 4:52 PM writes...

I can haz clavulonic acid?

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45. re 39, dissed by the FDA on July 28, 2014 9:04 AM writes...

"Don't fight the Fed" is relevant as a Pharma launch strategy, too. If the FDA is the only problem, then register your dossier in Europe.
In Wiki, I see that faropenem (but not the prodrug) is already registered in Japan, so patients do have some sort of choice: they could travel to Japan.

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46. newnickname on July 28, 2014 9:26 AM writes...

"Research into new cardiovascular therapies has mostly stuck to less risky “me too” drugs." Aliskiren is the first FDA approved renin inhibitor (hypertension). It has some problems, but are others still working on renin?

(I posted a better version of this Comment the other day; it uploaded successfully and then it disappeared. Was it taken down deliberately? Software error / reversion to an earlier Pipeline archive? Vandalism / hacking? It's the 3rd or 4th time my posts have disappeared.)

There are also groups working on bacterial MDR (multi-drug resistance; inhibitors of MDR) to try to extend the utility of existing antibiotics.

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47. anon on July 28, 2014 10:16 AM writes...

the realization must also be not everyone needs an antibiotic when they think they do. MDR and NMD1 from India will defeat the best intentions of limited access.

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48. Ryan on July 29, 2014 1:09 PM writes...

Seems like Derek took issue with the NYT implying that drug discovery 1) should be easy, or 2) isn't being worked on.

However, the main point of the article seemed to me to be that our ability to treat certain infections is on the brink of back-sliding, which Derek seems to agree with, or at least does not refute.

Am I missing something?

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49. Heteromeles on July 29, 2014 4:37 PM writes...

Yeah, I love the idea of people with multiple-antibiotic resistant infections traveling to foreign countries to get drugs they can't get it at home. That's *certainly* not a public health nightmare. Not at all.

There are two separate ecological problems here. I agree that antibiotics are part of a chemical warfare arms race that's been brewing for something like four billion years. The odd thing about this is that, when we arbitrarily stuck our petri dishes in 4 billion years after the arms race started, we found drugs. Oddly enough, those drugs stopped working fairly soon after they were found. Now, the oddity here is that it seems like universal antibiotic resistance isn't the problem. If it was, we'd never have discovered antibiotics in the first place--they'd have disappeared billions of years ago when everything became resistant. Rather, the race between antibiotics and resistance is a rapidly changing Red Queen Race, and neither side probably will ever get the upper hand, although species do apparently get wiped out by diseases now and again (as with the chytrid wiping out various frogs at the moment).

This suggests that, somehow, we're thinking about antibiotics wrong. Possibly the whole "magic bullet," billion-dollar drug approach is wrong, and we've got to see it as an arms race more akin to what computer security experts deal with. I'm not sure how you turn this into a business, but I do know how to get the FDA to buy in. That's ecological issue #2.

The second issue is that the economics of antibiotics are actually wonderful, or they will be in a few years. Here's the thing: antibiotics are part of the infrastructure of medicine. Without antibiotics, surgery death rates soar, transplants become impossible, surgical appliances become impossible, c-sections become very dangerous, death rates from accidents and combat soar, etc. We think they're cheap because we haven't thought about how expensive it is not to have them. That alternative would be illustrated by any war prior to WWII. I think you'll find that, in those wars, more people died from disease than directly from battle injuries. Those were the bad old days when plagues nuked countries. Those were the bad old days when women died in childbirth, lives were cut short due to lack of cardiac surgery, limbs were amputated, because wounds couldn't be treated and gangrene had to be excised. And so forth and so on.

That's the cost of not having antibiotics. The medical industry as a whole is trying to offload this cost onto the poor schmucks developing new antibiotics, rather than realizing that whole medical fields will disappear without antibiotics. THe medical industry as a whole needs to collectively shoulder the burden across every field that needs those drugs. I'd suggest that nature will make this case to the industry and the FDA soon enough. Hopefully, the medical industry as a whole will then go through a minor revolution, excise everyone who puts greed first and survival second, and get on with saving those fields that will disappear when antibiotics disappear. Pure, craven self-interest may well get people to working on finding new ways to beat disease, simply when they realize that, not only will they be out of a job, but those they love may die horribly if they don't get to work.

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50. tangent on July 30, 2014 6:03 AM writes...

@lynn said: "While there has been a path toward the development of combination therapeutic regimes and drug registration for HIV, HCV, TB in order to combat rapid resistance- there is no such developmental/regulatory path, as yet, for standard systemic antibacterials."

As a bystander I've wondered about this. Isn't it head-smackingly obvious to take your drugs that fail from rapid resistance, and mix two or three together? If they have widely different kinetics I guess you'd need separate dosing, which is a pain, but still. Anyway, I know the general value of "why don't you just..." suggestions, but I'd be fascinated to hear *why*.

Also raised by the comment on "we need either multi-targeted antibacterials, or combinations [although there is little strong proof that this will work for bacterial infections]" -- are there specific issues leading to doubt that it would work, or unknown unknowns? (Surely it's been covered in animal models, or are those suspect for combinations?)

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51. newnickname on July 30, 2014 10:58 AM writes...

@49 Heteromeles: You make some good points but some of the progress in medicine you mention is due to biocides, not antibiotics. Ignaz Semmelweis cut the rate of puerperal fever by implementing hand washing with bleach. No one (at the time) accepted his approach and he was dismissed as a crank and crackpot. He ended up suffering a nervous breakdown and was institutionalized. He died imprisoned following severe beatings, probably from infections that could have been prevented using his hygienic regimen. Iodine and alcohol swabbing cut down on many infections. Steam sterilization keeps instruments germ-free.

Although some approaches to antibiotics accommodate rapid modification (e.g., Andy Myers' Tetraphase?), there is some question whether the FDA would allow equally rapid approval of a new antibiotic (even if effective against a resistant strain in vitro) without years of safety testing.

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52. Anonymous on July 30, 2014 12:12 PM writes...

What do you all think, that no antibiotic research is being done? There are many companies out there doing their best, spending 10's of millions to generate new and effective antibiotics, and they run into the same issues again and again. Lack of confidence by Big Pharma that they'll generate a drug that will gain blockbuster status. Then they have to go it alone.

Study the companies that have been successful-Cubist for example, went alone. Start small and grow big on only one drug- Daptomycin. And look at other companies in Boston as well, as there must be a half dozen I know of in Beantown alone! Tetraphase and the Myers work-great stuff but what will a drug from them cost? And where are the Big Pharma partners now they have a drug in PIII? Why no suitors? No where to be found! What about Paratek from Tufts Medical School? Another Ab from academia even. They created a great drug, sold it 4 different times to 4 different Big Pharmas and they all dragged their feet, dropped the ball, kicked them to the curb but still this company is fighting to bring their drug to market!

And there are many other stories of Small Pharma beating Big Pharma in the development of antibiotics-too numerous to mention but here's the reasons: Big Pharma is too slow, has too many impediments to generating useful compounds and they finds ways to limit the time and effort needed for the proper attention needed to generate BY CHEMISTRY a valuable antibiotic.
Big Pharma spend too much time trying to find new targets, meanwhile only giving chemistry groups 3 years to get a SAFE compound to the clinic. 3 years? That's insane!


Second reason, and Lynn is right, the experienced masters of antibiotics are gone or are in hiding, and the newbies are too much in a hurry, unexperienced or pressured by the MBAs or in danger of losing their jobs. Pharma has lengthened the learning curve if not destroyed it when it comes to research on novel Abs and the morale is dismal.

But don't worry about antibiotics. The hype of resistance is just that, hype generated by physicians who blame it on agriculture meanwhile skipping over the part they prescribe them too much, creating a cottage industry for themselves. The doses you get from agricultural products are too low to spring resistance mechanisms so don't believe everything you hear and household products are even more effective at triggering resistance.

Then there are plenty of older and neglected antibiotics that can be pulled off the shelves and used in future and we are seeing those emerge now as well. Daptomycin was one of those and according to my ID pals, its replaced Vanco as the drug of last resort. And their are plenty of those derivatives as well and newer ones to be had to fight future scourges by the right people.

So the problem is not enough antibiotics, but not enough support of the scientists that study new antibiotics, especially by the government. In 2013 of the over 8K SBIR grants awarded about 900 fell into infectious disease space. In that subgroup only about 6 or 7 dealt with new compounds and chemistry and their activity against pathogens.

When it comes to Big Pharmas role, I am not even going to go there, but they need to study the past histories of their companies-especially Pfizer, for without Abs they probably wouldn't exist.

But to those of you out there still studying new antibiotics-keep up the good work, go to your job if you have one knowing that it's a hard roller-coaster ride- filled with Executive Funhouse Clowns and Evil Twist and Turns, but that its a noble cause- no matter how little you get paid.

And also relish the fact that journalists are still writing about antibiotic resisance and for 20 years have been saying the same things, and nothing has changed.

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53. DTX on July 30, 2014 1:10 PM writes...

Last year, the Wall St. J. had a good comparison that showed that people are willing to pay almost anything for a cancer treatment, but not for an antibiotic. They noted that Yervoy for melanoma cost $120K for a 12-wk course whereas Ceftaroline fosamil, an antibiotic approved in the U.S. in 2010, costs around $600 for a seven-day course.

This contrast is even more striking if you consider that the bacterial will kill you quickly, whereas the cancer treatment isn't even a cure.

To Sad who was disappointed that companies need a financial incentive to work on antibiotics: Apply this to yourself: quit your job, don't take any public assistance, and spend your days volunteering to take care of others problems (i.e., accept no financial incentives for your good work). When you've run out of money for food and a home and you're living on the street, you might realize that a financial incentive for doing good can be helpful.

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54. JP Craven on July 30, 2014 3:05 PM writes...

"...the experienced masters of antibiotics are gone or are in hiding.."

We are all in Area 51. Working on stealth projects.

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55. Anonymous on July 31, 2014 6:44 AM writes...

I believe this is one area that glycobilogy could help to revolutionize. For far too long we've only thought about life and drug targets in terms of genomics and proteins. We've now discovered that the glycome is orders of magnitude more complex than either the genome or proteome and has been described as the third language of life. Every cell, including bacteria, is covered in carbohydrates. Bacteria use profoundly different carbohydrates on their cell surfaces, which is one way to possibly exploit a new therapeutic target. People often scoff at the idea about trying to develop new drugs from carbohydrates because of their terrible pharmacological properties but it may just take some clever chemists to come up with newer ideas. The 3d nature of the carbohydrate is also attractive because of the huge amount of chemical space for derivitization that may be possible. Instead of killing bacteria outright, what about metabolically engineering the surface of bacteria with carbohydrate based medicines to alter the way bacteria can adhere to surfaces for example?

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56. newnickname on August 1, 2014 7:48 AM writes...

Cubist? I recall when Cubist began working out of labs at MIT (YK Shue; Jules Rebek). I don't remember the whole history, but their first target was H. pylori and their chemistry approach failed. Cubist bought Daptomycin from Lilly (see my comment elsewhere about "buying an NDA" to make the MBA's timeline work). I'm not sure, but I think that everything else in the Cubist pipeline was in-licensed or bought outright. Does Cubist even have chemistry R&D anymore or is it all clinical development?

Many others have licensed stalled projects OUT of Big Pharma (Neratinib / Puma / Pfizer) so I can't call this "wave of the [past] future" the Cubist model.

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