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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: Twitter: Dereklowe

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In the Pipeline

« Decisions, Decisions | Main | Fish Nor Fowl? »

March 7, 2007

Quietly Disappearing From the Skies

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Posted by Derek

Failure's an orphan, sure enough. We get to hear about the really big clinical failures in the drug industry, the Vanlevs and the torcetrapibs, because they hit the greasy chute just when they're bounding up on the stage, while all the spotlights are on them. But there are plenty of other projects that just sort of evaporate, with no one wishing to call attention to them.

That's well illustrated in the recent case of GlaxoSmithKline. The company updated its research pipeline in its annual report last week, and analysts noticed that eleven drugs had disappeared from clinical trials since the last listing. No press releases were sent out at the time, no conference calls were made. None of the drugs were, individually, expected to be huge parts of GSK's future by themselves - but losing nearly a dozen compounds from the clinic has to hurt.

Among them were a beta-3 agonist for diabetes (solabegron) and a glycoside-based thrombin inhibitor (odiparcil). I wouldn't have been putting a lot of money down on either of them, myself - not that I have any information about the compounds in particular, just that those mechanisms have been graveyards for drug development. Counting the number of beta-3 agonists or thrombin inhibitor projects that have been reported over the years would be a nasty job, and none of them (so far) have made it to market.

There were also several oncology compounds missing, and that's no huge surprise, either. Cancer drugs have the highest failure rates in the clinic - the last estimate I saw was around 95%, which is the sort of number that makes you want to thoughtfully look out the window for a while.

I almost wish that more were made of these failures. It would be painful for the companies involved, but it would give people a better idea of how painful drug discovery can be. I had a friend who was always worried about flying anywhere, and I kept wanting to pop in every few seconds, all day long, with news of yet another plane that had landed safely in Chicago, Atlanta, LAX or wherever, just to get the point across. In the drug industry, though, we have the reverse situation - almost everything we try to put into the air crashes. There should be some way to get the point across that most of our drug candidates never make it, taking all their development money down with them.

Comments (21) + TrackBacks (0) | Category: Drug Development


1. milkshake on March 7, 2007 12:41 PM writes...

Death of beautiful projects does not bother me - what I think should be publicized more is the hype surrounding the high-profile research projects. The half-baked projects are often continued past any scientific reason by smaller companies into late clinics because it is hard for them to cancell and deal with the resulting stock price dive.

(and then there is the opposite problem, the culture of avoiding any imagined risk by middle management in big pharma)

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2. Tom Womack on March 7, 2007 3:11 PM writes...

Presumably, odiparcil vanished because the clinical trial that calls NCT00244725 didn't work. Will the results of that trial be written up somewhere, or is the vanishing of the drug write-up adequate for all practical purposes?

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3. Anonymous on March 7, 2007 3:50 PM writes...

"(and then there is the opposite problem, the culture of avoiding any imagined risk by middle management in big pharma)"

This is indeed a big problem, but there are hints it is going away. Pfizer is "de-layering", for example, which theoretically will address this issue (I know, I know, it's all just hype right now). I hear J&J doesn't even have those layers. Ruffalo seems to say they don't have layers at Wyeth, either.

I definitely agree that killing good molecules is as bad as pushing forward bad molecules, whatever the reason. The patients lose in the end.

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4. Klug on March 8, 2007 11:06 AM writes...

Derek's comments about crashing 'planes' is evocative of the start of "operations research" in WWII.

You'd think that if pharma was smart, they'd jointly fund some sort of committee or group that would get around the proprietary/IP issues, look at all the participants' loads of data and try to figure out how to keep the planes in the air.

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5. David Young on March 8, 2007 5:54 PM writes...

This is an interesting subject.

As an oncologist interested in clinical research, I tend to follow along the development of new drugs. It is always disheartening to learn of the abandonment of a drug that seemed during most of its development life to be promising. Take, for instance, Becatecarin, an anticancer agent initially developed by the NCI and then by Exelixis. For the past 8 years, news about the drug was "looking good,.. looking good,.. looking good,... looking good....... failure" and then the drug was out of research, off the pipeline list and out-of-mind.

GSK had their share. I recall their work on Enuracil and development. Enuracil inhibits dihyhdropyrimadine dehydrogenase, the enzyme that metabolizes Fluorouracil, an old chemotherapy drug. In those few patients who have a genetic lack of DPD, Fluorouracil becomes very toxic. GSK planned on developing Enuracil as an adjunct to Fluorouracil, making the drug more effective or able to be used as an oral preparation. It seemed to me that his was the foolish case of "developing a thousand dollar drug so that the cost of a dollar drug could be reduced to ten cents." I couldn't figure out why blocking the enzyme would have a therapeutic advantage. Wouldn't the side effects increase to the same degree as the anticancer effect? For what ever reason, GSK abandoned the drug.

But wait! Now Enuracil has been bought by Adherex, for the same development indication. Is there something I don't know?

Now, I am a practicing oncologist and not a medicinal chemist, but it would occur to me that if one created a small molecule fluoropyrmidine that retained the DPD blocking power of Enuracil with the tumor-directed metabolism of Capecitibine and administed especially low doses with Capecitibine that it might block DPD in the tumor cells only and thereby giving a therapeutic advantage. I don't know if such a drug exists, but if some medicinal chemist looked at the structure of both drugs and synthesized the correct analogue it might just happen. Excuse me for making the suggestion if it has been done before and it just doesn't work in the lab.


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6. GATC on March 8, 2007 6:43 PM writes...

It pretty much comes down to the looney British. They just do science differently and it is finally beginning to show. Time for another merger.

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7. Bruce Grant on March 9, 2007 11:19 AM writes...

Wonderful post. As usual, your thinking not only makes my day,but your writing makes it delightful.

BTW, the "Mail to a Friend" function on Corante seems to be hosed. Returns the following error message:

Not Found
The requested URL /cgi-bin/mt/mt-send-entry.cgi was not found on this server.

Additionally, a 404 Not Found error was encountered while trying to use an ErrorDocument to handle the request.

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8. Retired Med. Chemist on March 10, 2007 3:43 PM writes...

David Young is just complicating the issues. Drugs can be directed specifically to tumors by use of antibodies with specific ligands. The concentration will be high enough that blocking
its metabolism becomes mostly an overkill.
Capecitabine is close to the ideal drug you can get with that DNA-based mechanism. Move on to signal transductions.

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9. Retired Med. Chemist on March 10, 2007 3:56 PM writes...

Talking about pipelines:
Kosan Biosciences received a lot of undue glory
for 'inventing' the Hsp90 inhibitors (C&EN,
cover story, 2/26/2007). How did they get away
with the fact (not mentioned in the report) that
they licensed the compounds from NCI/NIH, which,
btw, IS clearly posted in their website ???

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10. David on March 11, 2007 1:54 PM writes...

"David Young is just complicating the issues. Drugs can be directed specifically to tumors by use of antibodies with specific ligands. The concentration will be high enough that blocking
its metabolism becomes mostly an overkill.
Capecitabine is close to the ideal drug you can get with that DNA-based mechanism. Move on to signal transductions."

You make is sound so easy! Tell me about all those drugs that cure cancer by being antibody directed to tumors. I mean, there is Mylotarg (Gemtuzamab ozogamicin) for acute myeloid leukemia where Calicheamicin is brought to the leukemia cells by antibody. But Myelotarg is still a tough drug and is just used against leukemia. What solid tumor has an antibody based chemotherapy product? I wish it were so easy!

And Capecitibine an ideal drug? It is a good drug! But not an ideal one. I have seen plenty of Breast cancer patients where Capeciticine has absolutely no anticancer effect.

I thought that my idea with finding a compound with the DPD inhibiting power of Enuricil and the three step prodrug metabolism of Capecitibine to be a worthy one. I also understand that there may not be such a compound, or it may have unexpected side effects, or someone has tried already and it just didn't work out.

I'm not a medicinal chemist, but I don't want to be ingnorant of chemistry as well. (Hence why I read this blog and others.)


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11. Retired Med. Chemist on March 11, 2007 6:53 PM writes...

David Young is correct to a certain degree. You
need the Ab because it's too difficult to add
targeting to small molecules. The chemical modifications for targeting usually ruin the
activity of the lead molecule.
Capecitabine is close to ideal AS a prodrug of
5-FU, NOT as a stand-alone agent. DNA-based mechanism is no longer attractive--too many side-effects.

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12. Retired Med. Chemist on March 11, 2007 7:04 PM writes...

DAVID--By the way, if you can't target your '5-FU'-like compound only to tumor cells, the higher the cellular conc., the more deadly that it will be---patients will expire.

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13. Ryan K. on March 12, 2007 3:47 PM writes...

Becatecarin was probably never going to become a drug. People have been unsuccessfully pursuing Rebeccamycin analogs for almost 20 years. It's great for the biologists, but just not a good drug target.

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14. David on March 12, 2007 8:53 PM writes...

DAVID--By the way, if you can't target your '5-FU'-like compound only to tumor cells, the higher the cellular conc., the more deadly that it will be---patients will expire.

That was the whole idea. The idea is to find a Enuracil-like compound that a) targets DPD and c) targets certain tumors because it is a prodrug metabolized in the tumor cells to a higher degree than in normal cells. This is what Capecitibine does, or, at least we presume it is what Capecitibine does. Again, I don't know if such a drug exists, but if I were a medicinal chemist I would create a small molecule fluoropyrimidine that has the part of Capecitibine that renders it more active in tumors cells and that part of the Enuracil that blocks the DPD enzyme. Now, if that were possible, and there was no interference between the two parts of the molecule I might have something. I presume that there would be interference and probably such a molecule does not exist..... I would just like to see someone try.

Don't worry... I have made this suggest to reps from both Roche and GSK. Whether my message gets back to the medicinal chemists, maybe, maybe not.

Whatever the case, if a major pharmacology company is willing to put out major dollars on a drug such as Enuracil, they should at least listen to my suggestion.

Too bad about Becatecarin and too bad for Exelixis. They did go all the way to phase III studies with a smile on their face. I have suggested that Abraxis give the drug a try in their nanoparticle technology, just to give the compound one last chance, with perhaps a little edge. But I don't think that they will try it.


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15. daen on March 13, 2007 12:09 AM writes...

Didn't AstraZeneca's thrombin inhibitor Exanta actually make it to market before it was pulled?

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16. David Young on March 14, 2007 11:13 PM writes...

Well, congratulations to GSK for one accomplishment, they got Lapitinib (Tykerb) on the market today. Looks like a winner for HER overexpressing breast cancer and perhaps inflammatory breast cancer as well.


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17. Retired Med. Chemist on March 17, 2007 9:37 AM writes...

Tykerb is another successful example of 'signal
transduction' approach. More are coming:
VEGF, c-Met,.............
All oral drugs too!

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18. marion mccracken on September 16, 2007 5:04 PM writes...

I am presently taking capecitibine for recurrent breast cancer. I also have neuropathic problems with my arm. How long, in your opinion does the drug take to kick in. I have just finished my second cycle.

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19. John65 on October 22, 2009 10:55 AM writes...

What does this all mean? ,

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20. John65 on October 22, 2009 10:56 AM writes...

What does this all mean? ,

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21. John65 on October 22, 2009 10:57 AM writes...

What does this all mean? ,

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