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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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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« The 2012 Nobel In Chemistry. Yes, Chemistry. | Main | GSK Opens Up Its Trial Data »

October 11, 2012

IGFR Therapies Wipe Out. And They're Not Alone.

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Posted by Derek

Here's a look at something that doesn't make many headlines: the apparent failure of an entire class of potential drugs. The insulin-like growth factor 1 receptor (IGF-1R) has been targeted for years now, from a number of different angles. There have been several antibodies tried against it, and companies have also tried small molecule approaches such as inhibiting the associated receptor kinase. (I was on such a project myself a few years back). So far, nothing has worked out.

And as that review shows, this was a very reasonable-sounding idea. Other growth factor receptors have been successful cancer targets (notably EGFR), and there was evidence of IGFR over-expression in several widespread cancer types (and evidence from mouse models that inhibiting it would have the desired effect). The rationale here was as solid as anything we have, but reality has had other ideas:

It is hardly surprising that even some of the field's pioneers are now pessimistic. “In the case of IGF-1R, one can protest that proper studies have not yet been carried out,” writes Renato Baserga, from the department of Cancer Biology, Thomas Jefferson University in Philadelphia. (J. Cell. Physiol., doi:10.1002/jcp.24217). A pioneer in IGF-1 research, Baserga goes on to list some avenues that may still be promising, such as targeting the receptor to prevent metastases in colorectal cancer patients. But in the end, he surmises: “These excuses are poor excuses, [they are] an attempt to reinvigorate a procedure that has failed.” Saltz agrees. “This may be the end of the story,” he says. “At one point, there were more than ten companies developing these drugs; now this may be the last one that gets put on the shelf.”

But, except for articles like these in journals like Nature Biotechnology, or mentions on web sites like this one, no one really hears about this sort of thing. We've talked about this phenomenon before; there's a substantial list of drug targets that looked very promising, got a lot of attention for years, but never delivered any sort of drug at all. Negative results don't make for much of a headline in the popular press, especially when the story develops over a multi-year period.

I think it would be worthwhile for people to hear about this, though. I once talked with someone who was quite anxious about an upcoming plane trip; they were worried on safety grounds. It occurred to me that if there were a small speaker on this person's desk announcing all the flights that had landed safely around the country (or around the world), that a few days of that might actually have an effect. Hundreds, thousands of announcements, over and over: "Flight XXX has landed safely in Omaha. Flight YYY has landed safely in Seoul. Flight ZZZ has landed safely in Amsterdam. . ." Such a speaker system wouldn't shut up for long suring any given day, that's for sure, and it would emphasize the sheer volume of successful air travel that takes place each day, over and over.

On the other hand, almost all drug research programs, or never even make it off the ground in the first place. In this field, actually getting a plane together, getting it into the air, and guiding it to a landing at the FDA only happens once in a rather long while, which is why there are plenty of people out there in early research who've never worked on anything that's made it to market. A list of all the programs that failed would be instructive, and might get across how difficult finding a drug really is, but no one's going to be able to put one of those together. Companies don't even announce the vast majority of their preclinical failures; they're below everyone else's limit of detection. I can tell you for sure that most of the non-delivering programs I've worked on have never seen daylight of any sort. They just quietly disappeared.

Comments (11) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History


COMMENTS

1. 1 on October 11, 2012 7:45 AM writes...

This disappoints me, as I am a big IGFR fanboy. Seldom has a field seemed so promising but shown so little results.

Permalink to Comment

2. Evorich on October 11, 2012 7:50 AM writes...

Sort of interesting to be reading about this on the day that GSK released all it's clinical data.

The time for more open-source, pre-competitive drug discovery has long since come. No company can afford all these collective failures.

Permalink to Comment

3. Michael Tomasson on October 11, 2012 8:06 AM writes...

Great piece. I heard the hype of IGFR, but had no idea why I hadn't heard anything lately. Open source would help, but IMHO the Pharmaceutical Age is drawing to a close. Prevention, prevention, prevention.

Permalink to Comment

4. Boghog on October 11, 2012 8:28 AM writes...

> A list of all the programs that failed would be instructive
It is fairly easy to compile a list of programs that have failed (look for "no recent development reported" in Integrity for example). They key is finding out why they failed. Unless a compound has reached at least phase II clinical trials, companies rarely release this type of information.

Permalink to Comment

5. David Formerly Known as a Chemist on October 11, 2012 8:32 AM writes...

"A list of all the programs that failed would be instructive, and might get across how difficult finding a drug really is, but no one's going to be able to put one of those together."

Such a list exists! It's called Journal of Medicinal Chemistry and Bioorganic & Medicinal Chemistry Letters.

Permalink to Comment

6. Petros on October 11, 2012 9:57 AM writes...

And it is still rare for major companies to disclose causes of phase ii failures

Permalink to Comment

7. Rock on October 11, 2012 10:29 AM writes...

Think about it though. There is a fine line between informing the public about the vast number of failed drug programs, and scaring off the few investors we have left!

Permalink to Comment

8. barry on October 11, 2012 11:30 AM writes...

all is not a loss (at least for small-molecule approaches). Recall that Gleevec emerged from a program to inhibit PDGFr even as PDGFr was found to be an invalid drug target.
Score one for those sloppy small molecules over mAb approaches! The efforts spend on anti-IGFR mAbs can't be repurposed.

Permalink to Comment

9. Anonymous on October 12, 2012 3:55 PM writes...

The problem with failures is knowing why they failed.

If you are sure you have a great compound and have all the biomarker data to show you have tested the mechanism (eg show you have achieved at least 10x Ki at the receptor for the course of treatment and mechanistic data to show you really are showing pharmacological changes due to receptor interaction and that the trial was really done to a high standard) then publishing it to stop research in that area is a great idea.

However, in the real world, things are rarely that clean cut. There is always the doubt that there was some other reason for the failure other than 'the mechanism doesn't work'. Hence, lots of others continuing to work on the target/approach after the first bad news leaks out.

I am a supporter of publishing negative results but all the supporting data must be published to see for sure what has really been shown in the study and whether a definitive conclusion about the approach can be made.

Permalink to Comment

10. anonymous on October 14, 2012 7:55 AM writes...

@9 - 10X Ki??? Me thinks you pulled that number out of your arse....

Permalink to Comment

11. finchmarket avis on May 21, 2014 11:05 AM writes...

I almost never leave remarks, however i did a few searching and wound up here IGFR
Therapies Wipe Out. And They're Not Alone.. In the Pipeline:.
And I do have a couple of questions for you if you do not mind.
Could it be just me or does it appear like a few
of these comments appear as if they are left by brain dead folks?

:-P And, if you are writing at additional sites, I'd like to keep up with everything fresh you have
to post. Would you list of the complete urls of your community sites
like your Facebook page, twitter feed, or linkedin profile?

Permalink to Comment

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