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

« Vytorin Numbers | Main | Another Cholesterol Medication Goes Down (Or Does It)? »

April 3, 2008

Whose Guess Is Better?

Email This Entry

Posted by Derek

I was having a discussion the other day about which therapeutic areas have the best predictive assays. That is, what diseases can you be reasonably sure of treating before your drug candidate gets into (costly) human trials? As we went on, things settled out roughly like this:

Cardiovascular (circulatory): not so bad. We’ve got a reasonably good handle on the mechanisms of high blood pressure, and the assays for it are pretty predictive, compared to a lot of other fields. (Of course, that’s also now one of the most well-served therapeutic areas in all of medicine). There are some harder problems, like primary pulmonary hypertension, but you could still go into humans with a bit more confidence than usual if you had something that looked good in animals.

Cardiovascular (lipids): deceptive. There aren’t any animals that handle lipids quite the way that humans do, but we’ve learned a lot about how to interpolate animal results. That plus the various transgenic models gives you a reasonable read. The problem is, we don’t really understand human lipidology and its relation to disease as well as we should (or as well as a lot of people think we do), so there are larger long-term problems hanging over everything. But yeah, you can get a new drug with a new mechanism to market. Like Vytorin.

CNS: appalling. That goes for the whole lot – anxiety, depression, Alzheimer’s, schizophrenia, you name it. The animal models are largely voodoo, and the mechanisms for the underlying diseases are usually opaque. The peripheral nervous system isn’t much better, as anyone who’s worked in pain medication will tell you ruefully. And all this is particularly disturbing, because the clinical trials here are so awful that you’d really appreciate some good preclinical pharmacology: patient variability is extreme, the placebo effect can eat you alive, and both the diseases and their treatments tend to progress very, very slowly. Oh, it’s just a nonstop festival of fun over in this slot. Correspondingly, the opportunities are huge.

Anti-infectives: good, by comparison. It’s not like you can’t have clinical failures in this area, but for the most part, if you can stop viruses or kill bugs in a dish, you can do it in an animal, or in a person. The questions are always whether you can do it to the right extent, and just how long it’ll be before you start seeing resistance. With antibacterials that can be, say, "before the end of your clinical trials". There aren’t as many targets here as everyone would like, and none of them is going to be a gigantic blockbuster, but if you find one you can attack it with more confidence than usual.

Diabetes: pretty good, up to a point. There are a number of well-studied animal models here, and if your drug’s mechanism fits their quirks and limitations, then you should be in fairly good shape. Not by coincidence, this is also a pretty well-served area, by current standards. If you’re trying something off the beaten path, though, a route that STZ or db/db rats won’t pick up well, then things get harder. Look out, though, because this disease area starts to intersect with lipids, which (it bears saying again) We Don't Understand Too Well.

Obesity: deceptive in the extreme. There are an endless number of ways to get rats to lose weight. Hardly any of them, though, turn out to be relevant to humans or relevant to something humans would consider paying for. (Relentless vertigo would work to throw the animals off their feed, for example, but would probably be a loser in the marketplace. Although come to think of it, there is Alli, so you never know). And the problem here is always that there are so many overlapping backup redundant pathways for feeding behavior, so the chances for any one compound doing something dramatic are, well, slim. The expectations that a lot of people have for a weight-loss therapy are so high (thanks partly to years of heavily advertised herbal scams and bizarre devices), but the reality is so constrained.

Oncology: horrible, just horrible. No one trusts the main animal models in this area (rat xenografts of tumor lines) as anything more than rough, crude filters on the way to clinical trials. And no one should. Always remember: Iressa, the erstwhile AstraZeneca wonder drug from a few years back, continues to kick over all kinds of xenograft models. It looks great! It doesn’t work in humans! And it's not alone, either. So people take all kinds of stuff into the clinic against cancer, because what else can you do? That leads to a terrifying overall failure rate, and has also led to, if you can believe it, a real shortage of cancer patients for trials in many indications.

OK, those are some that I know about from personal experience. I’d be glad to hear from folks in other areas, like allergy/inflammation, about how their stuff rates. And there are a lot of smaller indications I haven’t mentioned, many of them under the broad heading of immunology (lupus, MS, etc.) whose disease models range from “difficult to run and/or interpret” on the high side all the way down to “furry little random number generators”.

Comments (9) + TrackBacks (0) | Category: Animal Testing | Cancer | Cardiovascular Disease | Diabetes and Obesity | Drug Assays | Drug Development | Infectious Diseases | The Central Nervous System


COMMENTS

1. milkshake on April 3, 2008 10:20 AM writes...

we need a nude minihuman model - I hear that there are suitably inbred ones to be found in hills of Arkansas...

Permalink to Comment

2. WC on April 3, 2008 11:07 AM writes...

I'm in agreement with the oncology difficulty. Our preclinical work was helpful with respect to predicting dose scheduling in humans but that was about it. In hind sight, we should have been more open minded with respect to our preclinical criteria, but that's difficult to sell to an executive committee. They like conviction, even if you're wrong.

Permalink to Comment

3. fat old man on April 3, 2008 6:22 PM writes...

and stroke; the boulevard of broken dreams

Permalink to Comment

4. sroy on April 3, 2008 8:15 PM writes...

This is an interesting article from the archives of Nature Reviews- Drug Discovery

A bit old but very relevant to what we are talking about.

http://www.nature.com/nrd/journal/v2/n2/abs/nrd1012.html

_______________


Modern biomedical research: an internally self-consistent universe with little contact with medical reality?

David F. Horrobin

Abstract

Congruence between in vitro and animal models of disease and the corresponding human condition is a fundamental assumption of much biomedical research, but it is one that is rarely critically assessed. In the absence of such critical assessment, the assumption of congruence may be invalid for most models. Much more open discussion of this issue is required if biomedical research is to be clinically productive.

Permalink to Comment

5. Petros on April 4, 2008 4:51 AM writes...

Respiratory models

Asthma

Good up to a point, although the allergic sheep is not a good model (except for generating data). However, eosinophils aren't as significant as suggested by animal models and highlighted by the lack of efficacy of IL-5 antagonists.


COPD
Poor. Smoking mice represent the best model currently available but its a chronic model and poorly reflects the human situation.. There are no good models for mucus hypersecretion

Rhinitis
Relatively straightforward.

Permalink to Comment

6. Andrew on April 4, 2008 1:34 PM writes...

Good article but you are wrong about Iressa. In fact, in a recent clinical trial called INTEREST, it was proven that the patients treated with Iressa had 'equivalent survival to those treated with docetaxel.' AstraZeneca is now planning to get it approved for a certain subset of people once again.

Permalink to Comment

7. Wells on April 7, 2008 6:59 PM writes...

I think you are being a bit too glib with respect to Iressa and whether it works or not. My research, and experience, is that it works very well for 10 to 20% of lung cancer patients, those in fact with certain genetic variations, and that is why it failed in a general trialin humans and is helping very many people around the globe right now, despite those clinical trial results. Look at the real data and talk to the experts.

Permalink to Comment

8. Andrew on May 2, 2008 1:32 PM writes...

Lung cancer patients in Europe will hopefully soon have Iressa as an option to treat lung cancer, as AstraZeneca has just filed for approval based on the INTEREST study.

Permalink to Comment

9. BoneGuy64 on April 8, 2009 6:44 PM writes...

Osteoporosis: Excellent! Just saw this thread!! Among the best animal models across therapeutic areas that I have encountered are the ones for post-menopausal osteoporosis. The rat is at the head of the class.

Post-menopausal osteoporosis is a disease of low trauma fractures accompanied by low bone mass. It is characterized by ongoing bone loss, caused by excessive bone resorption. Stopping additional bone loss by using medications with selective anti-resorptive activity is today's frontline therapy for osteoporosis, reducing fracture risk by up to 70%. Examples are hormone replacement therapy, the bisphosphonate class of medications (Fosamax, Actonel, Boniva, and Reclast), and the SERM class (Evista).

Ongoing bone loss in post-menopausal humans is caused by estrogen deficiency. Bone loss in newly estrogen deficient adult female rats was characterized in the early 1980's, using the same techniques applied in humans. Estrogen deficiency in rats causes the same array of bone problems as it does in people, considering that reduced bone strength (shown by mechanical testing of excised bones) substitutes for increased fracture risk.

Once it was shown that hormone replacement in newly estrogen-deficient rats (ovariectomized [OVX]) blocked loss of bone mass and bone strength in rats, just as it does in post-menopausal women (in the mid 1980's), by reducing bone resorption, the pharmaceutical race was on to test families of anti-resorptives first in rats, then in human trials. The first drug (Fosamax) was approved in October, 1995. Other bisphosphonates, calcium supplementation, SERMs (Evista), Rank Ligand inhibitors (Denosumab), and Cathepsin K inhibitors (Balicatib, Odanacatib) are additional anti-resorptives that work fine using this basic paradigm. The earliest bisphosphonates are now generic; all will be so by 2013.

For pro bone formation drugs, the rat skeletal response to Forteo is essentially the same as the human skeletal response to Forteo. Investigation of formation stimulating drugs for use in severe osteoporosis continues today.

Estrogen deficient mice lose bone mass just like estrogen deficient rats and people, but the absolute amount of bone lost is sufficiently smaller that more specialized measurement techniques are required to detect the loss, negating the financial advantage in animal size for drug testing. Dogs are an inadequate osteoporosis model, because they do not experience estrogen deficiency bone loss. Estrogen-deficient rabbits and non-human primates work as well as the rat, but at higher cost, both for compound requirements and housing.

The adult OVX rat remains pre-eminent for its ability to predict how the adult human skeleton will respond to various pharmaceutical interventions. The timely development of this animal model in the early-mid 1980's led rapidly to the development of the first NCE's for osteoporosis that hit the market in 1995. The OVX rat has stood the test of time in hundreds of laboratories across the world for a quarter century.

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
The Worst Seminar
Conference in Basel
Messed-Up Clinical Studies: A First-Hand Report
Pharma and Ebola
Lilly Steps In for AstraZeneca's Secretase Inhibitor
Update on Alnylam (And the Direction of Things to Come)
There Must Have Been Multiple Chances to Catch This
Weirdly, Tramadol Is Not a Natural Product After All