I Want a New Drug

Big pharma has taken a new course over the past few years.  In the past, most useful drugs originated in some kind of living organism – penicillin,  quinine, insulin, etc etc.   Nowadays, big pharmaceutical companies use combinatorial chemistry and computer modeling.  Merck has sold off its biological-products research arm.  This new approach, combined with doubled spending on drug R&D, has been a resounding failure. The rate of development of fundamentally new drugs   – ‘new molecular entities’ -  is running about 40% of that seen in the 1970s. Since big pharma makes its money from drugs that are still on patent, this slowed innovation is  a real threat to their bottom line.

You get more complicated molecules from biological products, molecules that have been optimized by billions of years of evolution.  Sometimes they do what you want or need.

Big pharma’s criticisms of natural products: these more complicated molecules can be  can be hard to produce, or extract, or synthesize. They worry about patentability. They worry that the organism will suddenly  be declared an endangered species (which has happened exactly once) …  Of course, they ought to worry more about going broke, but hardly anything is as unstoppable as a bad idea whose time has come.

I have spoken to libertarians who explain that our exorbitantly expensive and inefficient medical system must naturally drive rapid medical innovation.  Except that it hasn’t.  And that if it doesn’t, it’s because of onerous FDA requirements. Except that it isn’t.

I can’t say that big pharma has entirely refused to respond to this crisis.  They’ve found that even if their current approaches to drug development aren’t performing very well, making up shit still works.  Many drug companies have a long history, and 100 years ago they had to make shit up, because there were probably only three genuinely effective drugs in the entire pharmacopeia.  I have a copy of the 1899 Merck Manual: it’s a hoot. Even when they get caught and have to pay a few billion in fines or court settlements, they generally make out.  They may kill 40,000 people when things go wrong – but hardly anybody really cares.  Right now caring about that sort of thing isn’t fashionable.

I think that this is an instance of a more general trend: often a modern, advanced  approach shows up, and it persists long after it’s been shown to be a miserable failure.  You can see some of the reasons why: the people trained in the new technique would lose out if it were abandoned.  Hard to imagine combinatorial chemists rooting around in a garbage can looking for moldy fruit.

 

 

 

 

 

 

 

 

 

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28 Responses to I Want a New Drug

  1. bgc says:

    The only major useful group of drugs that aren’t biological in origin may be dyes – starting with salversan and going through groups like the anti-histamines, antidepressants, antipsychotics (hah!) and SSRIs – certainly these dye products made a lot of money (most of Big Pharma are ex-dye manufacturers).

    Apparently the observation that led to all this was based on an analogy: that when dyes were apllied to animal tissue they coloured some structures but not others (the basis of histology – for example H&E – haematoxylin and eosin) then dyes might be a ‘magic bullet’ able to ‘kill disease cells/ germs etc’ but sparing the healthy cells.

  2. Disclaimer: I’ve worked in combichem.

    Nature has highly optimized natural compounds—but mostly not for the properties we care about.

    Finding synthetic compounds that do the right thing in vitro is relatively easy. Getting them through the subsequent development process is what is hard. There’s no obvious reason natural compounds would be better for that.

    The failure of the drug industry seems to me to be due to wrong incentives and big-company anti-innovation bureaucracy. Think Microsoft.

  3. dearieme says:

    I recommend highly James Le Fanu’s “The Rise and Fall of Modern Medicine”: scroll down at http://www.jameslefanu.com/books#1

  4. Ah, another reason they’re failing at developing new drugs is that they haven’t been listening to you. When a disease is really caused by an infection, trying to treat it as an “autoimmune disease” or a “metabolic disorder” is setting yourself up for a world of fail.

  5. Anonymous says:

    what about Todd Rider at MIT’s Lincoln Lab…anyone think his research could lead to antivirals which
    work?

  6. Daniel Newby says:

    Seriously? Natural product drugs are oriented to killing things. That is fine if you want to treat cancer or infection, or if you luck out and turn a venom into a drug. But that is not going to cut it for most health problems. You will probably not find a Tibetan osteoporosis tree, or a Puerto Rican macular degeneration moss.

    Is combichem really such a problem? A good portion of approved drugs started as endogenous ligands, and another good portion started as hand designed “drug-like compounds”. What fraction actually started by throwing a beaker of combichem sludge at the wall and seeing what stuck?

    • gcochran9 says:

      You’re giving me a headache. Think I’ll take an aspirin.

      • sr says:

        A somewhat speculative list of other, less stupid, reasons why drug development has declined:

        - The FDA has become stricter. This is because industry pulled, and pulls, a lot of shenanigans (bogus surrogate endpoints, file drawer bias, etc). It’s harder to push a crap drug like Avandia through the FDA now, though things are still far from perfect. If a drug like Avandia passed in the 90s but doesn’t pass today, then the success rate of drug discovery appears to have gone down, but really we’re better off without it.

        - Going back to the 70s, as you do in your post, there were multiple brand-name versions of the same drugs, because legally you couldn’t just prove bioequivalence and have pharmacies automatically substitute AB-rated generics for name brands. Do the old-time success rates you mention include multiple brands of the same drug, or ?

        - A lot of targets have inexpensive, good-enough drugs now, and insurance companies + the advent of cheap generics are mostly killing me-too drugs. If you develop yet another statin or ACE inhibitor, nobody’s going to buy it because the generics are good enough, unlike 15 years ago when everything was still patented and pharmacies were charging rip-off prices for drugs that were worth pennies. That means you have to develop something more original, like, say a CETP inhibitor, which may turn out to be a fundamentally unsound concept, and is more likely to crash and burn

      • gcochran9 says:

        The comparison over time refers only to fundamentally new drugs: ‘new molecular entities’.

    • For osteoporosis, a vitamin D analog might be a good bet. (Vitamin D itself has promise, too, but the drug industry can’t patent that.) But for that matter, what makes you so sure that infection plays no role in macular degeneration or osteoporosis, and that “killing things” can’t help?

      • random mutation says:

        Now I understand why official-sounding reports about how bad Vitamin D is would be produced.

  7. statsquatch says:

    I think some in pharma understand their failure which is why they are getting into biologics: GSK (Human Genome Science), AstraZeneca (Medimmune), Sanofi (Genzyme), Roche (Genentech). Biologics are harder to develop and manufacture but they have lower failure rates in late stage development because their biology is usually better understood (see Rituxan, Hercepetin, Humira, Lucentis, Cetuxumab, Epogen etc). With BMS paying 5 billion for Amylin, the company built on Gilia monster spit, there may be further turning away from combochem.

    Pharma’s biggest problem is their poor management that too often came up as sales reps. Few of them have any real training in science or medicine and think every problem can be solved with sending out a fruit basket. This is not the kind of experience that helps you make decisions for “thick problems.”

    • melykin says:

      I take Enbrel for rheumatoid arthritis, which is apparently it is make from mice. I’m praying my rheumatologist doesn’t start nagging me to take Gilia monster spit.

      • Anonymous says:

        Although the cause of rheumatoid arthritis has neot been proven, infectious agents such as viruses, bacteria, and fungi have long been suspected…

  8. anon says:

    Cochrane,

    Well if you really want a new drug you could read my paper that looks at Actinobacterial (main producers of antibiotics/pharmaceuticals) distribution in the environment. I sent it to you about a month ago and never got a reply.

  9. Nanonymous says:

    Fact of life: getting new aspirins is just becoming harder and harder. Lots and lots of research went into natural products bioactives (marine organisms in particular). Lots and lots of leads that showed promise in vitro failed to deliver. And not because they are too hard to make. If anything, the biggest promise is chemists being smart enough to modify existing thing the way we want them. Alas, that, too is too hard. As usual with you, Greg, you think that it’s because everyone is so dumb. But try it – it really is hard.

  10. Many drug companies have a long history, and 100 years ago they had to make shit up, because there were probably only three genuinely effective drugs in the entire pharmacopeia.

    Wait a minute. Three specific ones, or approximately three out of (say) ten that may or may not have been effective? If it’s the former, I’m all ears, because I’m curious but ignorant about old pharmacy facts.

  11. Tschafer says:

    “I think that this is an instance of a more general trend: often a modern, advanced approach shows up, and it persists long after it’s been shown to be a miserable failure”

    I’m no expert, but to take a non-pharma example, it seems like the whole concurrent development – “Weapons System” concept might be an example of this with regard to defense. It seems that most of our really good, reliable aircraft like the B-47, B-52, F-14 were developed using the old “prototype” system, while a lot of our big flops with regard to aircraft, such as the B-58, F-111, C-5A fiascos were developed using the cool, modern sounding “Weapons System” concept. But the weapons system concept looks better on paper, and sounds more modern, so we keep using it, and keep getting crap like the F-35. The book “Flying Blind” which I read a long time ago, seems to bear this out. Is this accurate? If so, there would seem to be some parallels with Big, Pharms, which would lead one to believe that there is a systemic problem here.

  12. Myrmecodon says:

    Considering that the largest number of drugs are probably marketed to people with illnesses that tend to manifest past one’s prime reproductive years, I expect there’s very little natural or artificial selective pressure for anything other than what efficiently and reliably separates old people and their money.

    Though if I want a measured and scientific response on things like this, I usually prefer going to Derek Lowe, who covers most of the relevant chemistry and its pitfalls.

  13. anon. says:

    sorry about that Cochran, I not only miss spelled your name but also sent the article to your pal, knee deep in dwarves, Harpenden rather than you.

    Anyway, the story with antibiotics is as follows.

    We have been isolating microorganisms from the environment (usually actinomycetes, also fungi and myxobacteria), growing them on plates and seeing if they will kill or inhibit other bacteria since the end of the second war. We can still do this, but we never find anything new. We still keep finding the same old antibiotics (see http://www.springerlink.com/content/huxgxj675ke4b7gh/). So there are several approaches:

    -give up on antibiotics and try something completely new like viruses. No idea about this myself.

    -try working with the uncultivated fraction of bacteria in the environment and see if we can get
    their DNA out of the environment, put it into bacteria that we can grow in the lab and get the bacteria to express it (AKA metagenomics). A lot of technical challenges and not much progress so far. Google Sean Brady to see some limited results.

    -scale up our efforts. Richard Baltz thinks that metagenomics is a waste of time. We should just go back isolation of bacteria from the environment but on a much larger scale using robots.
    see http://www.springerlink.com/content/76700101q87513u6/

    How much of the reason for people getting out of the natural products is due to bad PR ? If you want a real PR horror story google bioprospecting and chiapas.

  14. Anon says:

    Sorry,

    knee deep in dwarves, Harpending.

  15. Pingback: Where Are All The New Drugs? | politicsandpolls-com

  16. dearieme says:

    For several days now, one of my comments shows as “Your comment is awaiting moderation.”

    How have I offended?

  17. alex says:

    i can’t believe the asprin line escaped comment. i have to say – brilliant response.

  18. Pingback: “Rising Plague” « Entitled to an Opinion

  19. chemist says:

    Combichem was abandoned years ago. These companies haven’t discovered much of anything for a while. That’s why they are all in decline.

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