Corante

About this Author
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

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily
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

« GSK's Published Kinase Inhibitor Set | Main | The Atlantic on Drug R&D »

May 15, 2013

And The Award For Clinical Futility Goes To. . .

Email This Entry

Posted by Derek

I was talking with someone the other day about the most difficult targets and therapeutic areas we knew, and that brought up the question: which of these has had the greatest number of clinical failures? Sepsis was my nomination: I know that there have been several attempts, all of which have been complete washouts. And for mechanisms, defined broadly, I nominate PPAR ligands. The only ones to make it through were the earliest compounds, discovered even before their target had been identified. What other nominations do you have?

Comments (32) + TrackBacks (0) | Category: Clinical Trials | Drug Industry History


COMMENTS

1. Wage Slave on May 15, 2013 2:11 PM writes...

For therapeutic area - I nominate Obesity. Sure, two approvals last year, but look at the history. Phen-Fen anyone?

For target, althouh I am/was a nuclear receptor person myself, and think your PPAR choice is excellent - does it beat ion channels in terms of futility? Perhaps that's too broad, but take you're pick on one family!

Permalink to Comment

2. Electrochemist on May 15, 2013 2:19 PM writes...

There is a summary of various PPAR related issues on the FDA website at the link below. Some of the fonts chosen are barely legible, but perhaps that is appropriate....

http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm119071.pdf

Permalink to Comment

3. bhip on May 15, 2013 2:43 PM writes...

indication- stroke
mechanism- chemokine antagonists(HIV notwithstanding)

Permalink to Comment

4. David Formerly Known as a Chemist on May 15, 2013 3:01 PM writes...

Indication = Alzheimer's Disease
Target = phosphatases, especially PTP1B

And @1...there are plenty of ion channel inhibitors that have been successful, the mainstay of antiarrhythmia therapy!

Permalink to Comment

5. DCRogers on May 15, 2013 4:23 PM writes...

Anti-aging should get an award for the most unproven treatments (in terms of $ spent) and the fewest proven treatments (0).

If mechanism == strong immune response to HIV viral coat, then HIV vaccines have been the graveyard of a LOT of money and effort.

Permalink to Comment

6. weirdo on May 15, 2013 4:30 PM writes...

p38 has to be number one with a bullet for failed mechanism, no?

One company alone put ~10 molecules into the clinic. (Or, so I hear.)

Sepsis for indication, I agree.

Permalink to Comment

7. BioBritSD on May 15, 2013 5:18 PM writes...

I swear that Ghrelin (antagonists for metabolic diseases) has led to the job loss of pretty much everyone who ever worked on it.

Permalink to Comment

8. BioBritSD on May 15, 2013 5:29 PM writes...

although perhaps it was too much of a graveyard to even make it into the clinic for anyone

(*must*read*post*properly*before*responding)

Permalink to Comment

9. johnnyboy on May 15, 2013 5:53 PM writes...

I'm not surprised that sepsis would be a graveyard - though I am surprised that companies would actually try to devise a drug for, considering how poorly-defined, multisystemic and variable in its symptoms and effects it is.
But at least there are already some treatments for sepsis, namely IV fluids and various symptomatic methods. As for one indication that arguably has no effective treatment at all, I would nominate Alzheimer's (aricept notwithstanding).

Permalink to Comment

10. 5-HT on May 15, 2013 6:04 PM writes...

The PPARs are a great choice. For reasons I can't comprehend, Roche is continuing to pursue aleglitazar (dual PPAR). Could be the surprise of the decade... or a waste of a billion dollars in Ph3 studies.

Permalink to Comment

11. Oligodendrocyte expert on May 15, 2013 6:27 PM writes...

@ #4: David has it right: Alzheimer's disease, hands down as the indication.

amyloid/amyloid plaques (and the ill-fated Amyloid Hypothesis, in general) as the target. Amyloid plaques are simply the downstream pathological footprint of Alzheimer's disease, certainly not its CAUSE.

Permalink to Comment

12. HFM on May 15, 2013 8:06 PM writes...

Alzheimer's. I don't even want to think about how many zeros are on the bill for that one, and we're still arguing over what it is, never mind how to fix it.

HIV vaccines have to be up there too. I'm of the (probably still a minority) opinion that conventional vaccines for HIV are never going to work, but there's a clear need and a shortage of better ideas, so that horse will continue to be beaten.

Show me a company with one of these targets in late-stage trials, and I'll show you a great investment...for a short-seller.

Permalink to Comment

13. Iain on May 15, 2013 8:08 PM writes...

Very interesting question.

Does anybody know of a database that would record if a trial was successful or not? It doesn't seem to easy to mine this information from clinicaltrials.gov

Permalink to Comment

14. Iain on May 16, 2013 2:40 AM writes...

Nope there isn't.

http://www.alltrials.net/

Permalink to Comment

15. Erebus on May 16, 2013 3:25 AM writes...

As far as targets are concerned, I'd have to second Ghrelin... and, furthermore, suggest all of the other appetite-modulating gut-'n-neuropeptides, such as Leptin & NPY.

Myostatin is another interesting case. All of the projects in development have failed -- including a few which seemed very clever at the time. Unfortunately, the biology of myostatin was (and remains) very poorly understood.

Permalink to Comment

16. petros on May 16, 2013 7:29 AM writes...

p38 inhibitors probably have it

30+ into the clinical, just two reached phase III
PH-797804 COPD
doramapimod psoriasis

papamapimod showed effects in phase II in RA with a dramatic rebound thereafter

GSK or SB probably had about 10 progress to the clinic over the years, with SB trademarking CSAID for the action of such compounds (before they were known as kinase inhibitor). The original lead was SK&F 86002

Permalink to Comment

17. Teddy Z on May 16, 2013 7:30 AM writes...

Umm, this may get lost, but Lilly had a approved drug for Sepsis, Xigris. It was on sale for a few years and then pulled because sales were so dissappointing. Also, it could kill you. But, if you were dying anyway and it MIGHT be able to save you, seemed like a decent trade off.

Permalink to Comment

18. CMCguy on May 16, 2013 7:38 AM writes...

Does it depend on how one measures? Without any statistical data I would suggest "cancer" has had greatest total number of clinical drop outs, largely because think has had the most attempts. Many projects do not make past preclinical and then the majority are probably Phase 1 or 2 halts so less spectacular then some of the other therapies mentioned and of course tempered by the occasion successes.

Along those lines for target would note "apoptosis" which like cancer is not necessarily a single defined entity to target.

However with both these I hold out hope the future will tip the balances where evaluations move to more positive outcomes therefore shift in categorization to a less futile summary

Permalink to Comment

19. Alchemyst on May 16, 2013 7:53 AM writes...

phosphatases, CNS- depression 'selective' 5HT with selectivity to which receptor subtype?

Permalink to Comment

20. cynical1 on May 16, 2013 8:19 AM writes...

How about the MMPs and small molecule integrin antagonists?

Permalink to Comment

21. biochembelle on May 16, 2013 9:31 AM writes...

This quote starts off a review on sepsis and has stuck with me for a while:

Success, according to Sir Winston Churchill, "is the ability to go from one failure to another with no loss of enthusiasm." From this perspective, the identification of novel sepsis therapeutics has been an unqualified success.

Permalink to Comment

22. Drug Developer on May 16, 2013 10:15 AM writes...

Acute stroke: One drug approved, 17 years ago

Permalink to Comment

23. MoMo on May 16, 2013 10:20 AM writes...

Matrix Metalloproteinases seconded! Still good targets though.

Permalink to Comment

24. JoJo on May 16, 2013 10:50 AM writes...

Good post, good comments.

Permalink to Comment

25. noko marie on May 16, 2013 11:25 AM writes...

I'll just second the nomination for PPARs.

Permalink to Comment

26. DCRogers on May 16, 2013 12:30 PM writes...

Speaking of Alzheimers, the study that shows that people with some types of skin cancer have an 80% reduced Alzheimer's risk is -- just, wow. Weird.

Somewhere in this fact there must be a target lurking, waiting to eat $1B!

Permalink to Comment

27. Anon on May 16, 2013 1:15 PM writes...

Anything preventative.

Permalink to Comment

28. KissTheChemist on May 17, 2013 6:49 AM writes...

I worked for a while on telomerase inhibitors as an anti-cancer treatment. Not an enormous money sink, but it deserves its place here for its way-more-complicated-than-we-first-thought-ness.

And after Rimonabant, I'll second the nomination of Obesity too !

Permalink to Comment

29. simpl on May 17, 2013 10:47 AM writes...

Bed-wetting always seemed to be last-ditch goal for cheinals that are neurally active but lacking a use.
Poverty is another medical condition that is hard to treat.

Permalink to Comment

30. anonymous on May 18, 2013 9:58 AM writes...

@15 Erebus
What were the clinical issue(s) that "killed" the myostatin inhibition approaches?

Permalink to Comment

31. Secondaire on May 19, 2013 10:55 AM writes...

Is there any distinction between "truly lousy targets" and "good targets that are hard to drug?" That being said, agreed with Alzheimer's/amyloid - poorly defined downstream target that's hard to test for efficacy against.

Permalink to Comment

32. Erebus on May 20, 2013 7:24 AM writes...

@30
All failed tox, I believe. Generally unfavorable side-effect profiles.

@31
PTP1B seems like a good target that's hard to drug -- high-potency/drug-like PTP1B inhibitors are very rare. (Do any exist? I know that trodusquemine is somewhere in clinical development, but it's a low-micromolar inhibitor at best.) PPARs, Ghrelin, Myostatin, etc., just appear to be lousy targets. They impact too many biological processes, or they're tied-up with too many other redundant pathways, or they are merely very poorly understood...

Permalink to Comment

POST A COMMENT




Remember Me?



EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
XKCD on Protein Folding
The 2014 Chemistry Nobel: Beating the Diffraction Limit
German Pharma, Or What's Left of It
Sunesis Fails with Vosaroxin
A New Way to Estimate a Compound's Chances?
Meinwald Honored
Molecular Biology Turns Into Chemistry
Speaking at Northeastern