About this Author
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
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Category Archives
April 3, 2008
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”.
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+ TrackBacks (0) | Category: Animal Testing | Cancer | Cardiovascular Disease | Diabetes and Obesity | Drug Assays | Drug Development | Infectious Diseases | The Central Nervous System
January 29, 2008
Posted by Derek
I've had some questions about animal models and testing, so I thought I'd go over the general picture. As far as I can tell, my experience has been pretty representative.
There are plenty of animal models used in my line of work, but some of them you see more than others. Mice and rats are, of course, the front line. I’ve always been glad to have a reliable mouse model, personally, because that means the smallest amount of compound is used to get an in vivo readout. Rats burn up more hard-won material. That's not just because they're uglier, since we don’t dose based on per cent ugly, but rather because they're much larger and heavier. The worst were some elderly rodents I came across years ago that were being groomed for a possible Alzheimer’s assay – you don’t see many old rats in the normal course of things, but I can tell you that they do not age gracefully. They were big, they were mean, and they were, well, as ratty as an animal can get. (They were useless for Alzheimer's, too, which must have been their final revenge).
You can’t get away from the rats, though, because they’re the usual species for toxicity testing. So if your pharmacokinetics are bad in the rat, you’re looking at trouble later on – the whole point of tox screens is to run the compound at much higher than usual blood levels, which in the worst cases you may not be able to reach. Every toxicologist I’ve known has groaned, though, when asked if there isn’t some other species that can be used – just this time! – for tox evaluation. They’d much rather not do that, since they have such a baseline of data for the rat, and I can’t blame them. Toxicology is an inexact enough science already.
It’s been a while since I’ve personally seen the rodents at all, though, not that I miss them. The trend over the years has been for animal facilities to become more and more separated from the other parts of a research site – separate electronic access, etc. That’s partly for security, because of people like this, and partly because the fewer disturbances among the critters, the better the data. One bozo flipping on the wrong set of lights at the wrong time can ruin a huge amount of effort. The people authorized to work in the animal labs have enough on their hands keeping order – I recall a run of assay data that had an asterisk put next to it when it was realized that a male mouse had somehow been introduced into an all-female area. This proved disruptive, as you’d imagine, although he seemed to weather it OK.
Beyond the mouse and rat, things branch out. That’s often where the mechanistic models stop, though – there aren’t as many disease models in the larger animals, although I know that some cardiovascular disease studies are (or have been) run in pigs, the smallest pigs that could be found. And I was once in on an osteoporosis compound that went into macaque monkeys for efficacy. More commonly, the larger animals are used for pharmacokinetics: blood levels, distribution, half-life, etc. The next step for most compounds after the rat is blood levels in dogs – that’s if there’s a next step at all, because the huge majority of compounds don’t get anywhere near a dog.
That’s a big step in terms of the seriousness of the model, because we don’t use dogs lightly. If you’re getting dog PK, you have a compound that you’re seriously considering could be a drug. Similarly, when a compound is finally picked to go on toward human trials, it first goes through a more thorough rat tox screen (several weeks), then goes into two-week dog tox, which is probably the most severe test most drug candidates face. The old (and cold-hearted) saying is that “drugs kill dogs and dogs kill drugs”. I’ve only rarely seen the former happen (twice, I think, in 19 years), but I’ve seen the second half of that saying come true over and over. Dogs are quite sensitive – their cardiovascular systems, especially – and if you have trouble there, you’re very likely done. There’s always monkey data – but monkey blood levels are precious, and a monkey tox screen is extremely rare these days. I’ve never seen one, at any rate. And if you have trouble in the dog, how do you justify going into monkeys at all? No, if you get through dog tox, you're probably going into man, and if you don't, you almost certainly aren't.
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+ TrackBacks (0) | Category: Animal Testing | Drug Assays | Drug Development | Pharmacokinetics | Toxicology
December 5, 2007
Posted by Derek
I’ve had reports that some of the animal rights activists are getting loud and lively down in Connecticut, to the point of harassing employees of some of the drug companies there. I remember some of this going on in the early 1990s in New Jersey, but this is the first big outbreak of this stuff I can remember since then. This latest outbreak seems to be part of their long-running (and to my mind misguided) campaign against Huntingtdon Life Sciences.
I won’t go into the specifics of what I’ve been hearing, because I don’t want to encourage the people who do it. What I’ll say is that all this shouting-on-the-street and ominous-flyers-under-the-windshield-wiper stuff doesn’t do the animal folks any credit, not that they care. A rational debate on the issues involved would be just fine by me, and I don’t think it would take very long. But since I doubt that my readership overlaps much with the kind of people who try to publicly intimidate scientists, and I further doubt that those people are open to rational debate. So I don’t see that happening here.
This, then, is just a heads-up for the researchers that do come here, most of whom work, directly or indirectly, with animal assays and the data they produce. Keep your eyes open. It wouldn’t be prudent to bet on all of these activists being harmless. Make sure you know who you’re letting into your building, and so on. The actions of True Believers can be difficult to anticipate, no matter what their cause.
And for my readers outside the industry – yes, we do indeed use animal testing. Mice take the brunt of it, followed by rats. It’s very difficult, expensive, and time-consuming, and we’d drop it in a minute if we could, just for those reasons. But no one knows enough about living organisms yet to do that. Not even close. For the foreseeable future, there’s no other way to do medical research, academic or industrial, basic or applied. Anyone who tells you differently is either misinformed or lying, and anyone who knows better but still tries to shut down the research is ethically deranged.
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April 26, 2007
Posted by Derek
When I wrote about lousy animal models of disease a few days ago, there was a general principle at the back of my mind. (There generally is - my wife, over the years, has become accustomed to the sudden dolly-back panorama shots that appear unannounced in my conversation). It was: that a bad model system is much, much worse than no model system at all.
I've been convinced of that for a long time. When you have no model for what you're doing, you're forced to realize that you have no clear idea of what's going on. That's uncomfortable, to be sure, but you at least realize the situation. But when you have a poor model, the temptation to believe in it, at least partially, is hard to resist. Even if it's giving you the right answers at a rate worse than chance, you can still take (irrational) comfort in knowing that at least you're not flying blind - even as you do worse than the people who are.
There are many reasons to hold on to an underperforming model. Sometimes pride is the problem. I've seen groups that stuck with assays just because they'd invented them, even though the method was slowly wasting everyone's time. Never underestimate cluelessness, either. People will use worthless techniques for quite a while if they're not in the habit of checking to see if they're any good. But the biggest reason that useless procedures hang around, I'm convinced, is fear.
Fear, that is, of being left out in the middle of the field with no models, no insights, and no path forward at all. It's a bad feeling, rather scary, and rather difficult to explain to upper management if you're a project leader. Better, then, to hold on to the assays and models you have, to defend them even if you're not sure you trust them. With any luck, the project will end (although probably not happily) before the facts have to be faced. As Belloc advised children in other situations: "Always keep ahold of Nurse / For fear of finding something worse."
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April 20, 2007
Posted by Derek
I was talking to someone the other day about animal models, and that got me to thinking: there are several therapeutic areas with reasonably good ones, but which indication has the most useless ones?
Naturally, just getting a compound into mice or what have you is going to tell you a lot that you'd never learn otherwise. (Try predicting oral absorption and let me know how well you make out, for example). That's the rough equivalent of a Phase I for animal studies. But finding an animal model of disease (the rough equivalent of Phase II) is a lot trickier. (One of the better ones I can think of is diabetes, and even there you have to work carefully, because a mutant db/db mouse really didn't get to its condition by the same path a human type II patient did).
By "worst animal model", I mostly mean "least predictive". There are some that are a major pain to set up and run, but give you some data that you can at least believe in a bit, and I wouldn't put them in the same class. My nominee are the traditional models that have been used for Alzheimer's. No rodent (heck, no other animal at all) develops the real AD pathology, so there's one strike against you. Years of work on mutants of all stripes haven't (to my knowledge) been able to get around that problem.
And the disease is affecting higher brain functions that are very poorly modeled in any of the small animals, which is strike two. When I used to work in the field, I would occasionally wonder about the relevance of watching a rat ran into one half of his cage or another to a person forgetting an important appointment. Some of the techniques also have the lotsa-work factor going for them, too, like the infamous Morris Swim Maze, which needs its own special room, full of special equipment, and a full-time person trained in its complications to generate the data that you still don't quite trust.
So, that's my candidate. Readers are invited to submit their own - remember, arduous but trustworthy doesn't make the cut. The winner will be arduous and useless.
Comments (41)
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June 20, 2006
Posted by Derek
A comment to the last post asked a good question, one that occurs to everyone in the drug industry early in their career: how many useful drugs do we lose due to falsely alarming toxicity results in animals?
The answer is, naturally, that we don't know, and we can't. Not in the world as we know it, anyway. The only way to really find out would be to give compounds to humans that have shown major problems in rats and dogs, and that's just not going to happen. It's unethical, it's dangerous, and even if you didn't care about such things, the lawyers would find some thing you did care about and go after it.
But how often does this possibility come up? Well, all the time, actually. I don't think that the industry's failure rates are well appreciated by the general public. The 1990s showed that about one in ten compounds that entered Phase I made it through to the market, which is certainly awful enough. But rats and dogs kill compounds before they even get to Phase I, and the failure rate of initiated projects making it to the clinic at all is much higher.
So it's not like we take all these rat-killers on to humans, despite what the lunatic fringe of the pharma-bashers might think. Nope, these are the safe ones that go on to cause all the trouble. "Oh, but are they?" comes the question. "How do you know that your animal results aren't full of false green lights, too?" That's a worrisome question, but there are a lot of good reasons to think that the things we get rid of are mostly trouble. For all the metabolic and physiological differences between rodents, dogs, and humans, there are even more important similarities. The odds are that most things that will sicken one of those animals are going to land on a homologous pathway in humans. And the more basic and important the pathway is, the greater the chance (for the most part) that the similarities will be still be strong enough to cause an overlap.
But there are exceptions in both directions. We know for a fact that there are compound that are more toxic to various animal species than they are to humans, and vice versa. But we play the odds, because we have no choice. Whenever a compound passes animal tox, we hope that it won't be one of the rare ones that's worse in humans. But when a compound fails in the animals, there's simply no point in wondering if it might be OK if it were taken on. Because it won't be.
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+ TrackBacks (0) | Category: Animal Testing | Clinical Trials | Toxicology
June 19, 2006
Posted by Derek
So, you're developing a drug candidate. You've settled on what looks like a good compound - it has the activity you want in your mouse model of the disease, it's not too hard to make, and it's not toxic. Everything looks fine. Except. . .one slight problem. Although the compound has good blood levels in the mouse and in the dog, in rats it's terrible. For some reason, it just doesn't get up there. Probably some foul metabolic pathway peculiar to rats (whose innards are adapted, after all, for dealing with every kind of garbage that comes along). So, is this a problem?
Well, yes, unfortunately it is. Rats are the most beloved animal of most toxicologists, you see. (Take a look at the tables in this survey, and note how highly the category "rodent toxicology" always places). More compounds have gone through rat tox than any other species, so there's a large body of experience out there. And the toxicologists just hate to go without it. Now, a lot of compounds have been in mice, for sure, but they just aren't enough of a replacement. The two rodent species don't line up as well as you'd think. And there's no other small animal with the relevency and track record of the noble rat. (People outside the field are sometimes surprised to learn that guinea pigs aren't even close - they get used in cardiovascular work, but that's about it).
So if your compound is a loser in the rat, you have a problem. You can pitch to go straight into larger animals, but that's going to be a harder sell without rat data. If your project is a hot one, with lots of expectations, you'll probably tiptoe into dog tox. But if it's a borderline one, having the rats drop out on you can kill the whole thing off. They use up a lot of compound compared to the mouse, they're more likely to bite your hand, and they're an order of magnitude less sightly. But respect the rat nonetheless.
Comments (21)
+ TrackBacks (0) | Category: Animal Testing | Toxicology
May 9, 2006
Posted by Derek
Many readers will have heard of the years-long campaign in England against Huntingdon Life Sciences, a research animal breeding and testing company. (These tug-of-war articles from Wikipedia on HLS and the campaign against it are detailed overviews, as well as a good example of that site's simultaneous strengths and weaknesses).
Now shareholders of GlaxoSmithKline, one of Huntingdon's customers, are getting anonymous letters from activists, threatening them with release of (unspecified) personal information if they don't sell their shares. These are similar tactics to the ones these groups used when HLS was trying to list on the Hew York Stock Exchange last year. You'd think that these attacks would have slowed down after the recent convictions of several anti-Huntingdon activists for terrorist activities, but apparently not.
In that case, names and addresses of researchers and investors were listed on a web site as well, but the defendants claimed that they had nothing to do with the violence and harassment that often followed. This defense was undermined by the evidence of their own statements, some posted on the web and some caught on videotape, friendly things like "The police can't protect you!"
Now, if anyone has been writing passionate, outraged books and screenplays about the researchers who've been carrying on through all this, I've missed them. That's because no one likes the idea of animal experimentation - it's not going to sell popcorn at the multiplex, that's for sure. And, to be frank, it's not like those of us who design, order, and carry out the experiments are high-fiving each other about how many rats we've gone through, either.
It's true: I don't actually like the fact that every successful modern drug has risen to its place on top of a small mountain of dead animals. But not liking doesn't keep it from being true, and not liking it doesn't mean that I have an alternative, either. I don't. What the animal rights campaigners - the more rational ones, anyway - don't seem to realize is that tens of millions of dollars are waiting for the person who can come up with a way of not using so many mice, rats, and dogs. (The less rational ones wouldn't care even if they knew).
They're expensive, you know, animals are. We don't just have them running around in rooms with a bunch of straw on the floor. They live in facilities that are expensive to build and expensive to maintain, and you have to hire a lot of people whose only job is to take care of them. The anti-testing people seem to have visions of drug company employees cackling at the thought of getting to use more animals, when the truth is that we'd dump them in a minute if we could.
But here's the hard part: we can't. Not for now, and not for some time to come. We don't know enough biology to do it. As it stands, if you were able to model every relevant system in a rat, well enough to use your model for predictive screening, you'd have basically built a rat yourself. We get surprised all the time when our compounds go into animals, and every time it happens, it shows how little we really know.
No, the system we have isn't pretty, and it sure isn't cheap, but there's nothing yet that can replace it. In the meantime, the rats die or the people do. I don't have a hard time choosing.
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January 18, 2005
Posted by Derek
I've mentioned before that one of our big problems in the drug industry seems to be finding compounds that work in man. I know, that sounds pretty obvious, but the statement improves when you consider the reasons why compounds fail. Recent studies have suggested that these days, fewer compounds are failing through some of the traditional pathways, like unexpectedly poor blood levels or severe toxicity.
In the current era, we seem to be getting more compounds that make it to man with reasonable pharmacokinetics (absorption from the gut, distribution and blood levels, etc.) and reasonably clean toxicity profiles. Not all of them, by any means - there are still surprises - but the stuff that makes it into the clinic these days is of a higher standard than it was twenty years ago. But that leaves the biggest single reason for clinical failure now as lack of efficacy against the disease.
That failure is the sum of several others. We're attacking some diseases that are harder to understand (Alzheimer's, for example), and we're doing so with some kind of mechanistic reason behind most of the compounds. Which is fine, as long as your understanding of the disease is good enough to be pretty sure that the mechanism is as important as you think it is. But the floor is deep with the sweepings of mechanistically compelling ideas that didn't work out at all in the clinic - dopamine D3 ligands for schizophrenia, leptin (and galanin, and neutropeptide Y) for obesity, renin inhibitors for hypertension. I'm tempted to add "highly targeted angiogenesis inhibitors for cancer" to the list. The old-fashioned way of finding a compound that works, and no matter how, probably led to fewer efficacy breakdowns (for all that method's other problems.)
Another basic problem is that our methods of evaluating efficacy, short of just giving the compound to a sick person and watching them for a while, aren't very reliable. If I had to pick the therapeutic area that's most in need of a revamp, I'd have to say cancer. The animal models there are numerous, rich in data, and will tell you things that you want to hear. It's just that they don't seem to do a very good job telling you about what's going to work in man. I will point out that Iressa, for one, works just fine in many of the putatively relevant models.
The journal Nature Reviews: Drug Discovery (which is probably the best single journal to read for someone trying to understand pharma research) published a provocative article a couple of years ago on this subject. The author (the now late) David Horrobin, compared some parts of modern drug discovery to Hesse's Glass Bead Game: complex, interesting, internally consistent and of no relevance to the world outside. They got a lot of mail. Now the journal has promised a series of papers over the next few months on animal models and their relevance to human disease, and I'm looking forward to them. We need to hit the reset button on some of our favorites.
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+ TrackBacks (0) | Category: Animal Testing | Drug Assays | Drug Development
August 1, 2004
Posted by Derek
The phrase "guinea pig" entered the language a long time ago as slang for "test animal", but I've yet to make a compound that's crossed a guinea pig's lips. Guinea pigs are still used for a few special applications, but since the beginning of my career, I've been surrounded (metaphorically!) by rats and mice.
Of the two, I prefer the mice. That's probably because they're smaller, and need correspondingly less effort from people like me to make enough drugs to dose them. The animal-handling folks prefer them for similar reasons: rats are more ornery, and they can fetch you a pretty useful bite if they're in the mood. When I was working in Alzheimer's disease, we had a small group of elderly rats that we were checking for memory problems. If that makes you think of rat-sized rocking chairs, think again. These were big ugly customers, feisty, wily critters that knew all the tricks and were no fun to deal with. Give me mice any day.
Of course, there are mice and there are mice. "Wild-type" mice are pretty hearty, but we don't use rodents captured out in the meadow. They're too variable, not to mention being loaded down with all sorts of interesting diseases. Every rodent we use in the drug industry comes from one of the big supply houses. Even our wild-types are a particular strain, identified with a catchy moniker like "K57 Black Swiss."
You're in good shape if you can use regular animals for your drug efficacy tests, but we often work on diseases which have no good rodent equivalents. People in diabetes projects, for example, often use mutant mice such as the db/db and ob/ob strains, which are genetically predisposed to put on weight. Eventually they can show some (but not all) of the signs of Type II diabetes. They can get pretty hefty - you'd better plan on making more compound if you're going to be testing things in those guys. Meanwhile, cancer researchers go through huge number of the so-called nude mice, a nearly hairless mutant variety with a compromised immune system. You've got to know what you're doing when you have a big group of those guys, because you can imagine how a contagious rodent disease could tear through them.
All the mutant animal lines are damaged in one form or another, since they're supposed to serve as a model of a disease. (Actually, most mutants in any animal population are damaged, since in a living system it's a lot easier to make a random change for the worse than it is to make one for the better.) They're just not as robust as the wild types. They need special handling, and they can't tolerate all the methods of compound dosing that a normal animal can. In some cases, you're restricted to the mildest, tamest vehicle solutions. (You know, the ones you can't get any of your compounds to go into.)
And there's always that nagging doubt about how valid your animal models might be. Some research areas have worked out a pretty good correlation between what works in people and what works in mice, but many of us are still stumbling around. The more innovative your work, the less of an idea you have about whether you're wasting your time. 'Twas ever thus.
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July 25, 2002
Posted by Derek
I've had some e-mail asking if the diabetes drug I mentioned the other day is dead or not, and if not, why not. I don't have any direct contacts in the companies involved, not that they'd tell me all about it even if I did, but I can make some informed guesses. They'll illustrate what happens in these cases.
Readers in the industry will know that this situation (dramatically worse tox results in one species versus another) is a common one. You'd think that mice and rats, for example, would be pretty similar, but there are real differences at every level (from gross anatomy to molecular biology.)
To get off topic for a minute, that's one reason that I'm only partially impressed by figures showing how humans and (fill in the species) share (fill in some high percentage) of their DNA sequences. It's interesting, in one way, but the differences that do exist count for an awful lot.
Differences in toxicology between species, of course, are why the FDA (and drug companies themselves) want to see tox results from more than one species. The more, the better. Most of the time, it's rats and dogs, sometimes rats and monkeys, sometimes all three. Mice aren't considered quite as predictive a species - they're OK for rough-and-ready tox screening (and you need a lot less compound to do it that way,) but not for real decision making.
That's why I'm sure that Novo and Dr. Reddy's weren't thrilled at seeing bladder cancer in the rats, with much less of it in the mice. If it had been the other way around, the path forward might have been a little bit easier, but it'd be hard no matter what. Their compound isn't dead yet, I assume. But what it'll need to go forward is an idea of what the mechanism of the carcinogenesis might be.
Is is the parent compound causing trouble, or some metabolite? Which one? How much of it is in the urine, and how long does it stay there? As mentioned the other day, do rats make more of any of the metabolites, or are they just more sensitive to them? And, the big question once those have been answered: what do we know about how humans might behave?
If the companies have a backup compound waiting in the wings, then we can assume that it's already in intense tox trials. If it's clean, then the original drug is dead, of course, and the backup goes on, more or less as if nothing had happened. But the prudent course would be to do the work outlined above anyway, so you can use it to show why you got the clean tox results you did on the new compound. That's the only way to feel really sure.
I've had animal rights people make the argument to me that such differences in toxicity prove that animal models are worthless. Untrue, untrue. Without testing on animals, no one would have known that this compound could cause bladder cancer in any species at all. The known differences between humans and various animals can then be used to estimate the risks if the compounds proceeds.
If there were an in vitroway to determine the risk, we'd all be lining up to use it. It would, by definition, be much faster, much cheaper, and much easier to apply earlier in the project before all that time, money, and effort gets wasted. If PETA and their ilk would like to devote themselves to developing such tests, I'll cheer them on.
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+ TrackBacks (0) | Category: Animal Testing | Drug Development | Toxicology
July 23, 2002
Posted by Derek
I've had some mail asking a good (and Frequently Asked) question: how good are the alternatives to animal testing? How close are we to not dosing animals to get toxicology information?
My short answer to the second question is, simultaneously, "A lot closer than we used to be" and "Not very close, for all that." The root of the problem is complexity. Toxicological properties are, to use the trendy word, emergent. You need the whole living system to be sure that you're seeing all there is to see.
You could try to mix and connect cell cultures, where the compound, after being exposed to one type of cell, then flowed off to another, and the original cells got a chance, if they'd been changed, to affect other different cell types. . .and so on. But by the time you got all the connections worked out, you'd have built an animal.
An example of a emergent tox problem is the recent withdrawal by Novo Nordisk of a clinical candidate that they were developing with the Indian company, Dr. Reddy's. Bladder cancer was the problem, seen in long-term dosing. But it's mostly a problem in rats - mice showed enough to notice, but it was the rat data that really set off the sirens.
There aren't a lot of good in vitro methods to predict carcinogenic potential. It's for sure that this compound had been through screens like the well-known Ames test for mutagenicity, for example. If it hadn't passed, it's unlikely that they would have carried the compound as far as they did. (I'll be writing more on the Ames test at a later date.)
Bladder cancer's a bit unusual. Playing the percentages, you'd have to guess that the problem isn't the compound itself, but some metabolite produced in the body which concentrates in the urine. And the rodent differences might suggest that rats produce more of this metabolite than mice do (or, alternatively, that they produce the same one, but that rat bladders are more sensitive to it.) Something like this would be the way to bet.
How much are you willing to bet, though? Are you willing to give people bladder cancer, or even put them at risk for it? (And are you willing to invite some many liability suits to land on you that you'll think it's snowing?) Your chances of getting through (and the chances of your customers!) depend on what the mechanism of the tox might be, and whether it operates in humans, as opposed to rats.
Novo and Dr. Reddy's are certainly going to take their time to thoroughly investigate what the problem might be, and whether it can be fixed. There was really no way to anticipate it without animal testing, though, since we don't have an in vitro system that mimics the bladder. Even if we did, they might have run their compound through it and gotten a green light, if the problem is in fact some later metabolic product. There's no substitute for the whole animal.
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July 21, 2002
Posted by Derek
I mentioned the other day that I've usually had a good response when I tell people about what I do for a living. There are exceptions, though. A few years ago, my wife and I were walking through a shopping mall, when we were stopped by two scruffy teenage survey takers.
"Would you like to take a - "
"No."
" - survey about animal rights?"
That put a new light on things. "Actually, yes. . ."
So we split up, and started in on the questions. Was I familiar with the idea of animal testing? Yes indeed. Did I realize that the medicines I took had been tested on animals? I most certainly did. Was I in favor of this? Damn right I was.
That broke his stride a little bit, but he recovered. What would be my opinion of some medical product if I found out that it had been tested on animals? More favorable. Now my surveyor was bogging down, and he stopped to stare at me. "Well," I said, "I work in the pharmaceutical industry. I'm actually very happy when something I've made gets tested on animals, because that means it's something that might actually work."
I could see him briefly trying, and failing, to integrate that into his worldview. What, um, would my attitude be, er, about this list of products made by companies that had sworn to do no animal testing? My wife and her surveyor had reached this question, by a similar route, and I could hear her starting in on him: "I'm supposed to feel good because they're using stuff that's right out of the National Formulary? Because all the animal testing was done years ago by someone else, these people are more righteous?"
One of my wife's jobs, before we met, was in the lab at a cosmetics company, as fate would have it. Both of the teenagers stared at us, as if we'd pulled off latex masks and reveled ourselves as green-skinned aliens. "Any more questions?" A shaking of heads. We handed them back their lists of the elect and went on our way.
I'd like to think we left them, like Coleridge's wedding guest, sadder and wiser, but I'm sure we didn't. I think we left them wondering if they could just chuck our answers completely, since we were obviously pulling their legs. I mean, what other explanation was there?<
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February 14, 2002
Posted by Derek
That neuroscience business came up, I guess, because I have a minor background in it. I broke into the drug business doing work on schizophrenia, and followed that with several years on Alzheimer's.
If some of the people in the field read this - well, don't take it the wrong way - but I'd almost as soon have a job breaking concrete with my nose. The central nervous system is a very, very hard area to work in. That's partly because brain function is hideously complex: it's an interesting question whether a human brain even has enough ability to comprehend its own workings. But it's partly because a key part of the drug-testing cascade is often missing.
That's animal testing. (And it really is a key part - eventually I'll get into it with the anti-in vivopeople, and I'll argue that position as long as it takes.) The problem with many central nervous system targets is that the animal models either don't exist, or (even worse) exist but are untrustworthy. That last situation is a killer: the models persist because there is a constituency that believe in their relevance. You'll be running into those folks over and over if you try to do without, and they're going to refuse to believe in your drug candidate unless it's been through the wildebeest swim maze, the platypus tail flick assay, whatever.
The models are so hard because you're often trying to affect behavior that is unique to humans - like remembering phone numbers. Whether a rat can remember not to run into the electrified part of the cage is of doubtful relevance. I think that there are many kinds of memory storage, and I don't believe that rats partake of the kinds that we're most worried about. It's true that there must be common molecular mechanisms for all types of memory (at some level) but messing with those processes indiscriminately (the only way we know how, in many cases) is a recipe for trouble. Let's not even get started on the topic of animal models for schizophrenia.
There's been a lot of progress in Alzheimer's the last two or three years. I enjoy reading about it, and I wish everyone working there all the luck in the world. I may need your compounds some day, guys, so keep banging away. But I'm glad that I'm not having to bang away with you.
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