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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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November 12, 2013

Leaving Antibiotics: An Interview

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Posted by Derek

Here's the (edited) transcript of an interview that Pfizer's VP of clinical research, Charles Knirsch, gave to PBS's Frontline program. The subject was the rise of resistant bacteria - which is a therapeutic area that Pfizer is no longer active in.

And that's the subject of the interview, or one of its main subjects. I get the impression that the interviewer would very much like to tell a story about how big companies walked away to let people die because they couldn't make enough money off of them:

. . .If you look at the course of a therapeutic to treat pneumonia, OK, … we make something, a macrolide, that does that. It’s now generic, and probably the whole course of therapy could cost $30 or $35. Even when it was a branded antibiotic, it may have been a little bit more than that.

So to cure pneumonia, which in some patient populations, particularly the elderly, has a high mortality, that’s what people are willing to pay for a therapeutic. I think that there are differences across different therapeutic areas, but for some reason, with antibacterials in particular, I think that society doesn’t realize the true value.

And did it become incumbent upon you at some point to make choices about which things would be in your portfolio based on this?

Based on our scientific capabilities and the prudent allocation of capital, we do make these choices across the whole portfolio, not just with antibacterials.

But talk to me about the decision that went into antibacterials. Pfizer made a decision in 2011 and announced the decision. Obviously you were making choices among priorities. You had to answer to your shareholders, as you’ve explained, and you shifted. What went into that decision?

I think that clearly our vaccine platforms are state of the art. Our leadership of the vaccine group are some of the best people in the industry or even across the industry or anywhere really. We believe that we have a higher degree of success in those candidates and programs that we are currently prosecuting.

So it’s a portfolio management decision, and if our vaccine for Clostridium difficile —

A bacteria.

Yeah, a bacteria which is a major cause of both morbidity and mortality of patients in hospitals, the type of thing that I would have been consulted on as an infectious disease physician, that in fact we will prevent that, and we’ll have a huge impact on human health in the hospitals.

But did that mean that you had to close down the antibiotic thing to focus on vaccines? Why couldn’t you do both?

Oh, good question. And it’s not a matter of closing down antibiotics. We were having limited success. We had had antibiotics that we would get pretty far along, and a toxicity would emerge either before we even went into human testing or actually in human testing that would lead to discontinuation of those programs. . .

It's that last part that I think is insufficiently appreciated. Several large companies have left the antibiotic field over the years, but several stayed (GlaxoSmithKline and AstraZeneca come to mind). But the ones who stayed were not exactly rewarded for their efforts. Antibacterial drug discovery, even if you pour a lot of money and effort into it, is very painful. And if you're hoping to introduce a mechanism of action into the field, good luck. It's not impossible, but if it were easy to do, more small companies would have rushed in to do it.

Knirsch doesn't have an enviable task here, because the interviewer pushes him pretty hard. Falling back on the phrase "portfolio management decisions" doesn't help much, though:

In our discussion today, I get the sense that you have to make some very ruthless decisions about where to put the company’s capital, about where to invest, about where to put your emphasis. And there are whole areas where you don’t invest, and I guess the question we’re asking is, do you learn lessons about that? When you pulled out of Gram-negative research like that and shifted to vaccines, do you look back on that and say, “We learned something about this”?

These are not ruthless decisions. These are portfolio decisions about how we can serve medical need in the best way. …We want to stay in the business of providing new therapeutics for the future. Our investors require that of us, I think society wants a Pfizer to be doing what we do in 20 years. We make portfolio management decisions.

But you didn’t stay in this field, right? In Gram negatives you didn’t really stay in that field. You told me you shifted to a new approach.

We were not having scientific success, there was no clear regulatory pathway forward, and the return on any innovation did not appear to be something that would support that program going forward.

Introducing the word "ruthless" was a foul, and I'm glad the whistle was blown. I might have been tempted to ask the interviewer what it meant, ruthless, and see where that discussion went. But someone who gives in to temptations like that probably won't make VP at Pfizer.

Comments (51) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Infectious Diseases


COMMENTS

1. watcher on November 12, 2013 1:02 PM writes...

Interesting exchange. Demonstration of one of the key skills to be a Sr. VP in Pharma --- how to repackage without admission of an action or decision that the majority of people in the country would fully appreciate.

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2. Cellbio on November 12, 2013 1:21 PM writes...

I thought he was rather clear in response.

He stated the market (society) does not realize the value so further investment did not offer a return, the science was not leading to clinical candidates and they had the responsibility to the company and its investors to take appropriate action so they are in business in 20 years.

Is it just that I am an insider that I see this clearly?

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3. John Ping on November 12, 2013 1:31 PM writes...

Unless I missed something (which is completely possible), they excised the vast majority of this in the program that aired. Good on them for providing the transcript, but this is a much more complete picture.

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4. Reverend J on November 12, 2013 1:36 PM writes...

I feel like this shows that synthesis of new antibiotics really needs to be taken out of the hands of pharma companies since the point of the drug is to make ones that only get used when they have too. From a business standpoint that's not a way to make a company that lasts. Personally I feel like we should massively scale back antibiotics usage (I'm looking at you cattle and chicken farmers) and put antibiotic research into the public realm (NIH, FDA, etc.) Yes this could cost taxpayers money, but so does a hospital full of people with MRSA.

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5. Hap on November 12, 2013 1:44 PM writes...

I wish he had asked the interviewer if they like being paid, since their intimation seems to be that companies should be making antibiotics for everyone's good, and not to make money. I would like to see if the interviewer would like to work under such conditions, too. I'm guessing no.

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6. emjeff on November 12, 2013 2:17 PM writes...

Well said, #5. Companies have finite resources, and must make decisions about where to put those resourses to yield the highest return. Whether you are making Twinkies or antibiotics, the same rules apply.

#4 - good luck with that - The government's foray into healthcare hasn't exactly been a great success so far has it?

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7. paperclip on November 12, 2013 2:22 PM writes...

I wager that the average person on the street thinks that making antibiotics must be one of the easier tasks a pharmaceutical company can handle. Penicillin was accidentally discovered from a moldy petri dish back in the 20s, after all! And since bacteria are so different from us humans, there must be a million ways to nuke them without harming ourselves. Should be a breeze. (Wish I were right!)

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8. NMH on November 12, 2013 2:24 PM writes...

His repeated use of the word "portfolio" to dissemble the truth allowed his ascent to by VP at Pfizer.

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9. NU chemist on November 12, 2013 2:41 PM writes...

I watched that documentary. It seemed as though the producers wanted to blare the message "Somebody do something!" Well, demonizing the people (the pharma industry and medicinal chemists) who have helped cure countless infectious diseases isn't the way to do it.

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10. OldLabRat on November 12, 2013 2:44 PM writes...

@ #7. Indeed. Fleming isolated penicillin in 1928; it only took another 10 to 12 years for production to be scaled for widespread use. I agree that the average person is ignorant of drug production and the resource invested to do it.

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11. Chemjobber on November 12, 2013 2:44 PM writes...

The transcript of the interview gives a good sense of how useless the term "de-risk" is.

Also, the bit about how turnover was good for project teams was interesting.

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12. watcher on November 12, 2013 2:56 PM writes...

#10: And also the urgency brought on by WWII.

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13. anon the II on November 12, 2013 3:00 PM writes...

I understand both sides of this battle pretty well. They're largely talking past each other. My bigger concern is that most pharma completely ridded themselves of their natural products groups over the last 20 years. It would take only a sliver of a fraction of the profits from past successes (think Lipitor) to keep a couple of microbiologists and isolation chemists tinkering around for decades. I'm afraid we'll have to slowly relearn a lot of this stuff when the bugs start winning again.

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14. DannoH on November 12, 2013 3:02 PM writes...

Ruthless = "Pharma wants sick people to die."

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15. Chemjobber on November 12, 2013 3:03 PM writes...

In that Frontline is being sold to the general public, Dr. Knirsch could have used a healthy dose of Up Goer Five-speak:

"We were not trying to be mean. We have to think hard about how we spend all of our money; sometimes we spend money on some things and not on others.

We want to make things to help people not be sick as long as we can be in business. The people who give us money want that, I think the people that we live with want that. We have to think hard about how we spend our money.

We tried a lot of things that didn't work. The people who allow us to sell things to make people better are confused about what they will allow. If we made something new that worked, we did not think we could make money at it."

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16. Rod on November 12, 2013 3:09 PM writes...

#7, 10, & 12

And coincidentally...

On March 1, 1944, Pfizer opened the first commercial plant for large-scale production of penicillin by submerged culture in Brooklyn, New York.

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17. Vaudaux on November 12, 2013 3:31 PM writes...

At the very beginning of the interview, Knirsch makes the excellent point that development of penicillin was not done by any one company but by a public-private partnership. It took government funding to develop the technology for large-scale cultivation of Penicillium.

We need something like that again. Antibiotics are not ever going to give a good return on investment, unless there is another very lucky streak like that of the 1950s through 1970s, or we develop some new technology that is more rapidly successful than what we have today. The funding will need to come from the federal government, not from for-profit companies. The research should be done by industrial and academic scientists working together.

And it should be soon. #13 is right. There are a lot of experienced microbiologists and antibacterial chemists (both synthetic and natural product) whose knowledge will have to be relearned if they can't go back to work.

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18. Chemjobber on November 12, 2013 3:41 PM writes...

Is anyone else bothered by the fact that this is an edited transcript? I think that if you're going to release edited video, and then something that looks like a full transcript (but is actually edited), but is not, then the least you could do is post unedited audio.

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19. lynn on November 12, 2013 3:44 PM writes...

Big Pharma worked in the antibacterial discovery area for many years, certainly into the early 2000's [and a few still do] - but the success rate for NOVEL classes being registered has been pretty much nil for 26 years [as I usually state it - the last discovered class to eventually be registered was discovered in 1987]. This was not through lack of trying. It is, as Derek said, very very hard to do [I've written a number of reviews on why]. And discovery of novel developable antibacterial compounds is not something that small pharma is much better at. However, small pharma, if able to bring a drug to the FDA, might be able to find profit in a compound with a smaller market value. On the other hand - discovering modifications and adjuvants for old classes of antibacterials has worked for many years - and has kept and will keep us at least treading water ahead of the tide of antibiotic resistance. I had spoken to the Frontline people last Spring and told them it would be good to speak with some of the companies working on such combinations -- especially the new beta-lactamase inhibitors in combination with cephalosporins or carbapenems. These are in the works at Big Pharma [AZ and Merck] and small [Fedora, Rempex and others]. It's too bad that this wasn't brought up in the program when interviewing the AZ people. But it did seem as if Frontline had its story to tell and Big Pharma made a better goat than hero.

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20. Mike on November 12, 2013 4:20 PM writes...

"OK, … we make something, a macrolide, that does that. It’s now generic, and probably the whole course of therapy could cost $30 or $35. Even when it was a branded antibiotic, it may have been a little bit more than that."


"So to cure pneumonia, which in some patient populations, particularly the elderly, has a high mortality, that’s what people are willing to pay for a therapeutic. "

Partial hyperole there: Dificid, a macrolide, costs $2800 for a 10 day prescription. On the other hand Dificid is the only recent new drug that could ever hope to cover its R&D costs with sales of only $23M per year.

Considering the pace of multiply resistant strains, could anyone expound on what could eventually be charged for a last resort antibiotic that knocks out a life threatening case of sepsis, pneumonia, etc that nothing else will touch? Why would it be less than the $100k charged for a round of an antibody cancer drug?

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21. Ted on November 12, 2013 5:01 PM writes...

I thought the interview was fair. Pfizer has indeed been ruthless in shedding divisions and even whole sites. I suspect in most cases Jeff Kindler or Ian Read would view 'ruthless' prioritization as a complement.

A fair portion of that antimicrobial group that Pfizer laid off came from Pharmacia, which itself came from Upjohn, which had an active antimicrobial effort.

Steve Brickner was the driving force that developed the oxazolidinone antibiotics while still at Upjohn. Everyone else had given up on the class due to toxicity concerns (even within the company....). Linezolid is widely considered to be one of the 'last resort' gram-positive antibiotics.

So, exactly how much of a pass should a predatory pharmaceutical giant be awarded? If a company doesn't want harsh scrutiny for abandoning a research area because the work is too hard, maybe they shouldn't be buying and gutting the companies that were doing the work?

Pfizer is quite happy to pull in a couple of hundred million a year in Zyvox sales.

Turning up the heat on big Pharma makes more sense to me than the alternative. Kudos to Frontline for asking hard questions and not backing down from pat answers.

-t

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22. DrugA on November 12, 2013 5:02 PM writes...

Derek, I think you and others are over-interpreting the use of the word "ruthless". The Frontline piece attempted, quite successfully, to show the risks of resistance and the dim prospects of the current antibiotics pipeline. Pfizer's part of that story is its withdrawal from antibiotic development. The interviewer was, in my view, asking the same question multiple ways: why is antibiotics less attractive to invest in than other areas. "Ruthless" in this context simply means based on an assessment of facts, without sentiment. I see no prejudice here.

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23. Don Monroe on November 12, 2013 5:20 PM writes...

The show and the interview suggest that the companies were making these "ruthless" decisions in part because you only use antibiotics for a few days per episode, ideally, so it's hard to make money at it. All true, I'm sure. But Pfizer got out of that business to focus, in part, on vaccines, which you take a few times in your *life*, so you would expect them to be even harder to make money at. That was a major plot hole.

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24. Anonymous on November 12, 2013 6:18 PM writes...

Antibacterial drugs aren't that bad: the ones I worked on were estimated at $400 - 600M pa for standard gram positive agents that treat some resistant strains. Of course we were shut down before we could deliver one but that's another story involving Moncef Slaoui and some bull$h!t.

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25. Shanedorf on November 12, 2013 6:35 PM writes...

@ 23- Only the people who get sick need antibiotics while everybody needs a vaccine. Much larger market

One small company in San Diego- Trius Therapeutics has done well in the anti-microbial space leading to a recent purchase by Cubic. They are in Phase 3 now with Tedizolid

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26. lynn on November 12, 2013 8:30 PM writes...

@25 Trius [now Cubist] has indeed done well - but note that tedizolid was in-licensed from Dong-A for development. On the other hand, they have interesting novel things in preclinical stages. Cubist/Trius could become an antibacterial power-center.

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27. BigSky on November 12, 2013 10:36 PM writes...

Knirsch clearly wanted the viewer to swallow the canard about 'antibiotics vs vaccines' but Pfizer has only a very small vaccine effort in any area except Prevnar (acquired from Wyeth). They even sold off their animal vaccine unit to raise cash for the purpose of ??? His implication that capital resources were reallocated from antibiotics to vaccines is ridiculous. Being a corporate carpet-sider he didn't have the moxie to say "Yeah, we got out of antibiotics and vaccines because we can make more money from business and accounting transactions for our shareholders that we can by preventing or treating disease."

Big Pharma left antibiotics when it got hard and now they are leaving vaccines for whatever stated reason but I wonder what the Big 5 are going to look like in another decade.

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28. Anonymous on November 12, 2013 11:25 PM writes...

I'm just astounded that anyone would even intonate that the reason that big pharma got out of antibacterial research was not because there was no money in it for them. Really? Is that what you're going with? Of course, that's why they got out of it. DUH. How stupid can you be? I mean seriously? They didn't have a profit margin they wanted and projected sales value that the bean counters wanted to pursue. Given that those big pharma companies piss away more in a day than a small company uses in a year, that's really not too surprising that only small companies are still pursuing that area.

Oh, it's just so hard. Really? My ass. As far as a therapeutic area, there's no easier. It's a bug. You kill it. And the Pfizer guy says, "and a toxicity would emerge either before we even went into human testing." Really!!! REALLY! That's unique to antibiotics. Yeah, the reporter is stupid and so is the public but........cry me a river. Tell me a therapeutic area that is easier. I'm all ears.

No, antibiotics are not going to save big pharma but just fess up and admit that the ONLY reason they got out of that line of R&D was because of the money. There wasn't enough there based on how they operate and the fact that new ones wouldn't be first line therapy. I'm okay with that but anyone who denies that simple fact has their head up their...........oh nevermind. And too bad for the VP of Pfizer where some dumb ass reporter tried to call him out on it and use big bad words like 'ruthless'. Suck it up for his salary and tell the truth. Pauvre, bebe. Hey, here's a response, "We feel that smaller biotech companies will serve that niche more efficiently than we would". And then shut up. Replies like "We were not having scientific success, there was no clear regulatory pathway forward, and the return on any innovation did not appear to be something that would support that program going forward" just want to make me puke. I really don't want that person in my living room. Just say two words: "No money." And then shut up. Because you could say what he said about every single therapeutic area in the business that they're currently working on.

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29. ScientistSailor on November 12, 2013 11:43 PM writes...

There are still public-private partnerships for new antibiotics:

http://www.achaogen.com/media-all/2013/4/24/achaogen-awarded-60m-contract-option-by-barda-for-the-clinical-development-of-plazomicin

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30. ScientistSailor on November 12, 2013 11:53 PM writes...

...and 28 has his head up his butt, and obviously not worked in antibiotics, especially Gram-negative...

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31. Robert Ross on November 13, 2013 2:37 AM writes...

And this is one of the main absurdities of extreme capitalism: "It is good for your shareholders if you let them die through inaction". Funny to watch how a train is going so fast that it is obvious it will eventually derail ...

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32. carlos danger on November 13, 2013 7:11 AM writes...

@9 not sure if the documentary demonized medicinal chemists - a bit sensitive are we? I thought it was a fine representation of the facts. Antibiotic resistance is a serious problem that a lot of folks in government and on wall street seem to ignore.

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33. Anonymous on November 13, 2013 9:23 AM writes...

Scientist Sailor - I actually DO work in antibiotics, for the past 5 years, both gram negative and positive. That's what makes his whole song and dance so absurd. (And I've worked in a lot of other therapeutic areas over the past 30 years.) Sure it's not easy, none of it is; but, relatively speaking, it's far easier than CNS, immunology, metabolic, and oncology. Those are some of the other areas I have worked in. The other ones that are relatively easy are antivirals and antifungals. They're bugs. You kill them without killing the host or damaging it too much and you got a drug. And the regulatory hurdles have been eased up recently as well. Go look up linezolid. Pretty toxic but it makes almost a billion dollars a year in the US alone. Look up the IMS numbers. Now go look up tedizolid and then go buy some Cubist stock. And if you have any Pfizer stock, sell it.

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34. Curt F. on November 13, 2013 9:37 AM writes...

@31. Robert Ross: I'm very confused. You are mad at big pharma for letting their shareholders die because they don't develop antibiotics?

Are you also angry that Walmart, Apple, and Exxon Mobil let their shareholders die of MRSA infections? Would it be fair to say that a main absurdity of Robert Ross's philosophy is "It is good for readers of Robert's blog comments if he lets them die through inaction"?

A core principle of justice in every society is that bad deeds are punished, not inaction. One of the many reasons for this is that the effects of an inaction often lie in the eye of the beholder. If I understand your blog comment correctly, you believe that big pharma's inaction on the antibiotic front is equivalent to letting their shareholders die. I don't think anyone in big pharma believes that. Many people outside the industry don't either. Even setting aside the inaction / action distinction, in the excerpted interview the company executive is saying, in effect, that people would die *despite* the company's best efforts, because making new antibiotics is hard. So if the counterfactual -- continuing to research new antibiotics -- doesn't lead to saving more lives, then there can be no validity to the idea that stopping antibiotics research will lead to more deaths, directly or indirectly.

Then there's the other part of your comment. Even if the inaction itself was some sort of moral problem, why would it be specific to capitalism? You could equally well say that government inaction, religious inaction, and Robert Ross inaction led to the deaths of these hypothetical shareholders. Your unsupported invocation of capitalism is the real the absurdity here.

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35. marcello on November 13, 2013 9:47 AM writes...

if Antibacterial Drug Development is not among the less challenging than I don't know what is. Even if not molecular - you have an easy cellular target. Animal models are relatively easy and clinical endpoints are relatively clear. The tough part is safety hence the right choice of indication is crucial

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36. Robert Ross on November 13, 2013 10:31 AM writes...

Curt, you get the non sequitur of the week. If you cannot see what is wrong with the current system I am not here to preach, just to laugh in amusement, you can carry on with your life, clearly confused and as if nothing happened.

And by the way, I am a fervent supporter of capitalism not of this perversion we have put on its place, but thanks for your patronising pseudo intellectual critique.

Next time do please try to be informed as to really how difficult is to make antibiotics, compared to other therapeutic areas before going on a rant.

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37. glinkst on November 13, 2013 11:38 AM writes...

@28 anon,
Discovering new antibiotics is something pharma has tried to do for a long time, without much success (Payne Nature Reviews Drug Discovery 2007, 6, 29 is a great paper for anyone interested in learning why). In general, a better understanding of bacterial genomics has not lead to new drugs. The paper describes the huge effort of a single company (GSK); and beyond working with poor leads, even once you find something interesting after 1-2 years of chemistry you are now just beginning to be confronted with resistance mechanisms (contrary to popular belief, a new mechanism does not usually lead to a better resistance profile). So in general, you are stuck with the old mechanisms.
That business concerns played a role is obvious, but on top of that, if a CEO/CSO were told, you could continue to work in a therapeutic area, but only work on targets that already had drugs on the market (me-too drugs), would it make sense to continue working in that area? Even in other therapeutic areas, many drug companies have decided to move on when confronted with these choices.
Glinkst

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38. Anonymous on November 13, 2013 12:56 PM writes...

@glinkst. "So in general, you are stuck with the old mechanisms." Umm, okay. Do you really think that all of the old classes have no life left in them and can't be improved on? You might want to look up the bacterial resistance profile for oritavacin which has just been filed with the FDA. After all, it's just another glycopeptide antibiotic. And then compare it to all the other glycopeptides (approved or in development) and then tell me whether or not it blows every one of them away. And then find me a gram-positive bacteria that it won't work against. It turns out that you CAN get a much, much, better antibiotic from a VERY, VERY old drug class. And no, I was not involved in the discovery or development. But tell me that I have a VanA resistant enterococci infection and I won't care if you or someone else wants to call oritavancin a me-too drug because it looks a lot like vancomycin in the package insert because vancomycin actually won't work. But hey, they sort of look the same (especially to an MD). And lipitor is just another statin, right?

As for GSK, I recently read a paper of theirs based on their HTS screening against tuberculosis. (ChemMedChem 2013, 8, 313-321) I actually don't work on TB. Looks to me like they found an awful lot of hits with new mechanisms and they said in the paper that they were pursuing a "full lead optimization program".

So please don't patronize me. Look at the med chem literature for the last 15 years and you will see that the industry didn't try all that hard at all. What percentage of papers published around drug discovery target antibiotics? I understand the business decisions why almost all big pharma got out of the area and put minimal effort when they still were but making it because the science was too hard doesn't hold up to scrutiny. I could have questioned that guy from Pfizer on any therapeutic area that they dropped or decided not to work on and he would have said the exact same things. It's just formulaic prattle.

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39. Lyle Langley on November 13, 2013 1:19 PM writes...

@#9, NU chemist,

Where in the world did the program (the producers) demonize medicinal chemists? I know this site caters to the medicinal chemist and their inferiority vs. idiot MBAs, but extrapolating the program to denigrating medicinal chemists is very paranoid thinking.

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40. glinkst on November 13, 2013 1:54 PM writes...

@anon
This is a situation where two people looking at the same pieces of information come away with two different perspectives. I am not familiar with the details of oritavancin, but clearly it has had some issues since it has changed hands a few times and has had anything but a smooth path to approval. This is not an example of why pharmaceutical companies should work in this area. I am also not familiar with the details of telavancin, but it is lipoglycopeptide related to oritavancin of a similar class that is not being used much. Daptomycin is a pretty formidable competitor.
You mention statins – are you suggesting people keep working on this validated target? Avoiding “me-too” is a transition that is happening across other therapeutic areas.
I did write “in general”, there are definitely some bright spots as a previous poster mentioned beta-lactamase inhibitors – these are critical contributions but there is no question that the lack of success towards truly novel bacterial targets has caused the industry to pare back expectations.
G

Permalink to Comment

41. Anonymous on November 13, 2013 4:31 PM writes...

@glinkst. Oritavancin isn't even on the market yet and it would seem that you've decided what clinical impact it will have and how it's not an example of why companies should work in the area. Interesting.

It will be a single IV d