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Diabetes and Obesity

Avandia Goes Down: A Research Rant

So now Avandia (rosiglitazone) looks to be withdrawn from the market in Europe, and heavily restricted here in the US. This isn’t much of a surprise, given all the cardiovascular worries about it in recent years, but hindsight. Oh, hindsight: all that time and effort put into PPAR ligands, back when rosi- and pioglitazone were still in development or in their first few years on the market. Everyone who worked on metabolic diseases took a swing at this area, it seems – I spent a few years on it myself.
And to what end? Only a few drugs in this class have ever made it to market, and all of them were developed before we even knew they they hit the PPAR receptors at all. The only two that are left are Actos (pioglitazone) and fenofibrate, which is a PPAR-alpha compound for lack of any other place to put it. Everything else: a sunk cost.
Allow me to rant for a bit, because I saw yet another argument the other day that the big drug companies don’t do any research, no, it’s all done at universities with public funds, at which point Big Pharma just swoops in and makes off with the swag. You know the stuff. Well, I would absolutely love to have the people who hold that view explain the PPAR story to me. I really would. The drug industry poured a huge amount of time and money into both basic and applied research in that area, and they did it for years. No one has to take my word for it – ask any of the academic leaders in the field if GSK or Merck, to name just two companies, managed to make any contributions.
We did it, naturally, because we expected to make a profit out of it in the end. The whole PPAR story looked like a great way to affect metabolic disorders and plenty of other diseases as well: cancer, inflammation, cardiovascular. That is, if we could just manage to understand what was going on. But we didn’t. Once we all figured out that nuclear receptors were involved and got busy on drug discovery on that basis, we didn’t help anyone with any diseases, and we didn’t make any profits. Big piles of money actually disappeared during the process, never to be seen again. You could ask Merck about that, or GSK (post-rosiglitazone), or Lilly, or BMS, or Bayer, and plenty of other players large and small.
No one hears about these things. We’re understandably reluctant to go on about our failures in this industry, but the side effect is that people who aren’t paying attention end up thinking that we don’t have any. Nothing could be more mistaken. And they aren’t failures to come up with a catchy slogan or to find a good color scheme for the packaging – they’re failures back at the actual science, where reality meets our ideas about it, and likely as not beats them down to the floor.
Honestly, I don’t understand where these they-don’t-do-any-research folks get off. Look at the patent filings. Look at the open literature. Where on earth do you think all those molecules come from, all those research programs to fill up all those servers? There are whole scientific journals that wouldn’t exist if it weren’t for a steady stream of failed research projects. Where’s it all coming from?
Note: previous posts about PPAR drug discovery can be found here, here, and here. Previous posts (and rants) about research in the drug industry (and academia, and the price of it all) can be found here, here, here, here, here, here, here, here, and here.

49 comments on “Avandia Goes Down: A Research Rant”

  1. Petros says:

    Ironic to note that rosiglitazone has been around a long time, originally known as BRL 49653, which places its first synthesis in the 1980s (at the former Beecham Research Laboratories).

  2. Data Police says:

    Hi Derek,
    After reading several threads here, this is the first time I have seen a posting where you actually defend the drug industry as a whole. This is most likely a reflection of selective reading on my part. But I am pleased to see balanced blogs once in a while.
    I love your postings.

  3. Chris D says:

    Drug companies could do a better job of communicating this–for example, by being more truthful in general so that it’s not safer to assume they’re lying. When they insist that U.S. prices have to be high to cover costs, then blithely lower prices elsewhere, then refuse to explain the discrepancy, that doesn’t engender much trust.
    The amount spent on marketing doesn’t help, although the numbers I’m seeing combine it with “Administrative,” so I don’t know if it’s as egregious as my perception.

  4. processchemist says:

    So much for PPAR ligands. In 5 years or so, we will see if DPP4 are a step forward or what. The interesting thing is that GSK was in the DPP4 race too, with little luck (denagliptin – any medchem considerations about the “butterfly” structure?).
    Anyway this is the business model as was meant to be: you spend 15% or so in research, if you’re successful you get huge rewards.
    The main problem is a business environment oriented towards win-win scenarios – I don’t spend in research (risk) but in some way I get huge rewards. Deriskify and diversify – Witty’s word.

  5. Xmas says:

    Hey…you’ve got an unclosed Italics at the end of your post…

  6. RB says:

    I think that your comments are well made, and it’s important that a highly articulate voice like yours is raised to counter the anti-big pharma hysteria.
    However, when the dust settles, when people think about Avandia, they’ll think about the research and the lost money, but also the shameless data manipulation, bullying of academics, burying of inconvenient data etc etc. Is it unfair to think that at the end of the day, GSK managed to spin out a few more dollars from a compound that they knew was doomed?
    The Industry is really not helping itself make the sort of important arguments you mention. Once the pharma corporate types stop behaving like the Cosa Nostra, there will be a chance that the general public will be receptive to pro-pharma arguments.

  7. Virgil says:

    What’s really odd, is that the “business end” of the glitazones pio/tro/rosi/ci is pretty much the same, making it hard to understand why one would be toxic and the other not. Based on the current state of rosi, with tro (rezulin) having been pulled years ago, and cig’ never being sold, I think it’s only a matter of time before pio gets yanked.
    Incidentally, a lot of other drugs have a similar functional group… that 5-membered ring with a couple of carbonyls hanging off (e.g. TDZD-8 and SB216763, both GSK3b inhibitors).
    The funny thing is, PubMed is teeming with basic science animal studies on heart attack, showing cardioprotection by pio/trog/ci/rosi (e.g. PubMed IDs 1572185, 16306807, 16900441). The GSK3b inhibitors are also cardioprotective.
    What all of this really tells us, is that no amount of animal studies can prepare you for what happens when the drug gets into the human population for a prolonged period of time.

  8. AR says:

    Virgil # 7. Totally agree. One statistic often used in the Drug Safety part of the industry is how correlative animal safety data is to human clinical safety. It’s poor, hovering around ~ 50% for hepatotoxicity. But it was thought to be better for cardiotoxicity with a value near 80%. So what went wrong with cox-2 and ppar inhibitors? Were they in the 20% that animal tox and safety pharmacology studies failed to find? Or were they, which I suspect, noted in pre-clinical work but somehow written off by the industry and agreed to by the regulators to have a good enough safety margin to approve?

  9. watcher says:

    Yes, from someone who also was involved in PPARs for a long time, the effort was tremendous, time and money very high. Unfortunately, in our organization the work continued too long because of the large amount of resource, emotional, and “personal” assignment which had been spent; continuing well beyond the lack of success for new drug potential had been written on the wall.
    Unfortunately, too, was the lack of success for the industry to recover the investments…another example of the great cost of doing this business, and the type of contributor as to why profits are eroding, companies are “merging”, stock prices are flat and/or declining.

  10. alig says:

    Actos is just a me too drug. Why do we let drugs get approved that hit the same target and don’t show any increased efficacy?

  11. alig says:

    Actos is just a me too drug. Why do we let drugs get approved that hit the same target and don’t show any increased efficacy?

  12. cynical1 says:

    Pharma spent a whole bunch of time and money targeting receptors that regulate gene expression and found that they were basically all toxic. Gee, what a surprise.

  13. Chemjobber says:

    No offense, processchemist, but “derisk” is one of the most disturbing words in the big pharma lexicon.

  14. RM says:

    Why do we let drugs get approved that hit the same target and don’t show any increased efficacy?
    Different side effect profile? Different pharmacokinetics? Different counter-indications? The chance that there may be sub-population differences in efficacy that can’t be found in clinical trials, but might be found by an individual patient and their doctor with a “hmm, that doesn’t work. Let’s try this one, instead” approach?
    Heck, there’s even just a pure capitalism argument. If both GSK and Pfizer have a similar product for the same set of customers, supply and demand would say that the price for patients will be lower than if just one of them gets a monopoly on it. Besides, it’s a little unfair to tell a drug company to eat a decades worth of development costs just because their competitor filed some paperwork slightly before them.

  15. processchemist says:

    none taken. Probably my sarcasm was not evident.

  16. Todd says:

    I think the biggest part of the problem is the public face industries put out there as compared to academia. If the public wants to speak to a university about its research, you’ll get a PI, flesh and blood, speaking directly about the research he’s doing, how it works, the implications, etc. If the public wants to speak to a drug company about its work, most often a marketing rep will come forward and explain how it works. While an industry scientist and an academic won’t exactly have the same approach on science, both will sounds a lot more knowledgeable than your typical slick marketing rep.
    I think the key is that industry needs more scientists (on the pre-clinical and clinical sides) to speak to the public about How Stuff Works. The constant silence (from the public’s perspective) on how research is done in industry often results in a tabla rusa being created where people can freely draw their hopes and fears…and ultimately, that’s a BAD thing.

  17. Mark Senak says:

    Very nice post. If you ever expand it into a full fledged presentation, it would be very interesting to see. A presentation detailing the role of company development would be good perspective.

  18. Doubting Thomas says:

    If the industry really cared about the public health, drug companies wouldn’t keep their failures secret from one another. Any given company hopes that others will do the same failed research as it has done, so that its profit margin looks better by comparison.
    Also, where is the research on antibiotics? Why the endless me-too drugs?
    Call for an end to data exclusivity, and I’ll take you a lot more seriously. now we’re on the road for pharma to simply research the diseases of billionaires’ pets rather than neglected tropical diseases that kill hundreds of thousands of people annually. that’s the market at work.

  19. CMCguy says:

    I am not sure completely true to say “no ones hears about these things” since such failures are part of $800M to $1.2B cited as the cost of getting a drug to market. Critics are keen to jump on these figures as being over exaggerated so indeed is important to provide specific details such as elegantly expressed here that illustrate what is involved. These critics usually are the same ones suggesting the industry does not do any research.

  20. hell to the chief says:

    I noticed that the papers you linked to were in BMCL. Didn’t you say earlier that there was an increasing amount of junk published in there? I’m sure your work was the exception though.

  21. anon says:

    Actos may be going down as well, there was a convincing meta-analysis showing a link to bladder cancer.

  22. Anonymous says:

    “Actos is just a me too drug. Why do we let drugs get approved that hit the same target and don’t show any increased efficacy?”
    This is the funniest thing I’ve seen all day. I can only hope the poster said it ironically. Actos is a great example of why me too drugs are useful.

  23. zenscientist says:

    The Avandia “story” is yet another failure for those intimately involved in the R&D of this drug and other clinically relevant PPAR ligands (and for patients I might add), but (and I know this is cliche but it is still true) out of failure comes lessons learned and potential for better and smarter opportunities. For example, as you say in your blog about returning to the basic science, I would think that companies with the “know how” and desire would be paying attention to the fact that a number of solid papers have come out in recent years regarding upstream co-regulators of PPARgamma expression as well as the continuing investigation into how PPARgamma is post-translationally modified (like Spiegelman’s Nature paper that you featured on this blog earlier this year) and what the gene targets of PPARgamma really are and what they might actually be doing. Given that modulating PPARgamma activity (and maybe even expression) can clearly have clinical benefit, there appears to be here a golden opportunity for the discovery of a novel therapeutic that can hit PPARgamma or another protein that is either a regulator of PPARgamma expression or a clinically relevant target gene without (one would hope) the nasty side effects.

  24. Chemjobber says:

    processchemist: Sorry, my irony meter needs calibration, sometimes.

  25. barry says:

    re #12:
    Pharma did very well on a bunch of steroid drugs that act by modifying gene expression (albeit sometimes with impressive side-effects. Pleiotropy alone isn’t enough to nix a drug candidate. We hope to see soon if blocking Hsp90 (which has not less than 100 client proteins) is a tolerable therapy for cancer.

  26. Anonymous says:

    Doubting Thomas:
    Also, where is the research on antibiotics? Why the endless me-too drugs?
    [Infectious Disease Society of America] ISDA’s investigation has revealed that the incentives most likely to spur R&D within major pharmaceutical companies include those that provide financial benefits prior to a drug’s approval (e.g., tax credits for R&D), commence at the time of approval (e.g., wild-card patent extension), reduce the costs of clinical trials (e.g., FDA flexibility concerning the evidence necessary to demonstrate safety and efficacy; NIAID-sponsored research to develop rapid diagnostics tests, etc.), and reduce companies’ risks (e.g., liability protections). R&D at smaller biotechnology companies also could be stimulated through statutory and administrative changes.

  27. PacRim Jim says:

    I translate clinical trial documents from Japanese into English for clients around the world. Even though the present inefficient system maximizes translator income, it minimizes drugs that will be available in my dotage.
    Someday we’ll be buying all our drugs from China, so it seems.

  28. Eric says:

    @Doubting Thomas,
    Research failures are no secret, at least not to people working in the field. As Derek says, they are not publicly emphasized, but the information is out there for those who are interested (such as competitors).
    And as for research into antibiotics, a Google search for “investigational antibiotic” will bring up a few. Probably a lot more out there if you look into the scientific literature.

  29. Rich says:

    Excellent rant. Someone is currently pushing a good old fenofibrate on TV. Be warned that if you take one and are a young male then you may eventually need Viagra too, as fenofibrates can cause impotence.

  30. Anonymous says:

    “[Infectious Disease Society of America] ISDA’s investigation….”
    In other words, get The Stupid Taxpayer to fund everything and allow the Corporate Welfare Queens to legalize proprietary statistical mumbo jumbo as The Real Science of Drug Safety and Efficacy. Lol. Corporate Personalized Medicine Anyone?
    And so goes the Lotto Receptor Monkey Wrench Industry where Haavaad Chemistry is just as useless as Haavaad Economics.

  31. Jose says:

    The biggest barrier to new antimicrobials is the fact that any novel mode of action will be put on a *very* tightly controlled schedule to keep resistance from forming, which means the market will be miniscule.

  32. CA prof says:

    Some of the thinking that you’re ranting about stems from the fact that Pharma always appears to be making tons of money. This understandably arises from the perception (grounded in fact, I believe) that the profit margins for pharmaceutical companies are substantially larger than margins of other large companies.
    Marcia Angell (probably not one of the favorite writers of readers of your blog) write a few years ago:
    “Although the pharmaceutical industry claims to be a high-risk business, year after year drug companies enjoy higher profits than any other industry. In 2002, for example, the top 10 drug companies in the United States had a median profit margin of 17%, compared with only 3.1% for all the other industries on the Fortune 500 list.”
    Even before she had penned that one I had noticed that GE (a sorta successful enterprise) had margins of 4-5% and that MerckPfizerLilly were always in the double digits.
    If Pharma is making these huge bets and many of them are losing (and you guys aren’t getting any credit for those risks/losses, hence your rant), then how come profits are so high year after year? Is your line really a Risk Management business more than a product-driven business?

  33. Contract Researcher says:

    I work in business development for a contract research organization.
    In the course of a week I see hundreds of millions of dollars worth of study protocols come across my desk. I would estimate that 99.99% of those protocols come from pharmaceutical / biotech companies, not universities.

  34. Steve White says:

    On the ‘me-too’ drugs, I’m a practicing academic physician. Let me explain to the doubters one line of ‘me-too’ drugs.
    Remember Tagamet (cimetidine)? It absolutely revolutionized the treatment of peptic ulcer disease. It came out in the mid 1970s, just as I hit med school, and I was given a clear vision of how much better treatment of PUD was in the Tagamet era.
    I was also given a long list of side-effects and drug interactions to memorize for attending rounds.
    As it became clear that H2-blockers indeed made a difference in the treatment of PUD, we ended up with ‘me-too’ drugs. Those drugs ultimately had: better side-effect profile. Fewer drug interactions. More convenient dosing (Tagamet was four times a day, famotidine is once or twice a day, etc). Lower cost.
    Understand that the pharma companies would NOT have invested in these ‘me-too’ H2 blockers if the potential for making a buck hadn’t been there, and I’d be today torturing the current generation of medical students with that list of Tagamet side effects.
    In my experience as a practicing doc, there are few ‘me-too’ drugs. Just a thought.

  35. AlchemX says:

    Hey Derek, looks like John Stossel is on your and pharma’s side in his recent show “Lawyers win, you lose?”

  36. Detail man says:

    CA prof.
    Yes it does appear that the top 10 pharma companies are making money hand over fist but a large amount of the profit is from companies that are no more. The big boys bought up the little boys for their products. The problem is that there are not as many little guys to buy anymore and you are starting to see the outcome…fewer products and less profits.

  37. Tim says:

    It’s too bad that PPAR Delta has been painted with the same brush as PPAR gamma. There was some very promising clinical data emerging but all companies stopped development of their PPAR delta compounds because of the belief the FDA would never approve a new PPAR. A lot of innovative research and investment was just shut down without adeqaute justifaction.

  38. Anonymous says:

    “I think it’s only a matter of time before pio gets yanked.”
    I really hope that doesn’t happen. If I ever needed to add a second antihyperglycemic to my metformin, my first choice would be pioglitazone.

  39. Carmen says:

    It’s been interesting to read this conversation right after reading Chembark’s post about Nobel odds. If this turns out to be the year for nuclear receptors I’ll be curious what the layperson spin on the prize turns out to be.

  40. Resveratorol Receptor says:

    Yet hacking out fat people’s stomachs with a mortality rate of .5-1% to treat diabetes is just fine.

  41. William B Swift says:

    Megan McArdle wrote about and linked to this in her blog in The Atlantic

  42. not a chemist says:

    Bariatric surgery is primarily effective for bariatric surgeons. Patients, not so much. Reported “revision” rates of up to 60% for for Roux-en-y gastric bypass patients, according to a 2007 article in Bariatric Times.
    Perhaps FDA should reconsider some of the drugs like lorcaserin and the topiramate/amphetamine combo for use in the morbidly obese. Which is worse: surgery that doesn’t work, may have to be redone, and might kill you; an additional diabetes drug that might cause bladder cancer, or a weight loss drug that might help you get off the diabetes meds, but may cause suicidal thoughts? I’m glad I don’t have to make those

  43. Perlhaqr says:

    Well, as an EMT (yes, this data, combined with my handle, implies I’ve got a long and convoluted career path…) I’d just like to say, thanks for fighting the good fight.
    More drugs are a win. Git’ er done!

  44. CMCguy says:

    #32 CA Prof Angell is one of those who thinks Pharma does not do any research and only exploits NIH funded work. She has demonstrated a visceral contempt for Industry with time and time again distorting or ignoring data regarding contributions on how drugs come to being to support her negative view.
    In terms of larger than normal profit margins it seems to me this is expected outcome with the current system although is a complicated picture. High risks reaps high rewards is generally accepted even when limited successes must burden the large failure rate. If investing money would you be more apt to go with a highly risky venture if the expected return is equivalent? I would also suggest GE Medical Imaging division operates at a much higher margin the other areas of that company so hard to compare unless doing like for like.
    Admittedly it will be interesting what happens in the Pharma future as unfortunately one mechanism of late to keep profits high is the merge and slash approach so research will suffer going forward although takes many years to see impacts. It may come true that pharma will become guilty of not doing as much real research because the ROI equations shows easier to wait till others have absorbed the risks and then can come in and yet still make money (consider Generics). I do believe having academics or government attempting to discovery and develop drugs, as some advocate, will be even more wasteful and less innovative than current inefficient model however guess profit is not a consideration there.

  45. Anonymous says:

    The loss of avandia is likely to trigger a major GSK downsizing. Nothing new over there! GSK is dying a death from a thousand cuts….however every pharma co. is struggling. Just a matter of time before the whole crap house comes down!!!!

  46. Anonymous says:

    The loss of avandia is likely to trigger a major GSK downsizing. Nothing new over there! GSK is dying a death from a thousand cuts….however every pharma co. is struggling. Just a matter of time before the whole crap house comes down!!!!

  47. To Echo #6 – the problem is not the lack of basic research conducted by Pharma – either the quantity of it or the quality.
    The problem is that higher up the corporate food-chain, they took potentially good and useful molecules, that may well have a proper role in a proper scientific universe – and they bullied, and they cheated. That’s what gets the “innovative research and investment shut down”.

  48. Avandia </3 says:

    GSK is bombing out man – Paxil Avandia. They still offer ALOT of other big drugs, but I hope them bomb after reading this in an article:
    “Documents released earlier this year by the Senate Finance Committee suggested that for more than a decade, GlaxoSmithKline deliberately hid study results showing that Avandia could worsen certain risk factors for heart disease.”
    10 years

  49. Experts estimate that Avandia has caused between 60,000 and 200,000 heart attacks and deaths due to cardiovascular problems in the U.S. from 1999 to 2006.

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