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
August 20, 2008
Posted by Derek
Well, today’s subject isn’t a cheerful data set, but it certainly deserves some thought. Over at Pharmalot, Ed Silverman has some data from consulting firm AVOS Life Sciences, who have sat down to estimate how well various drug companies will do with revenue from new drugs over the next few years.
As of 2007, they have the industry average at about 77 cents coming from new products (defined as those launched within the previous five years) for every dollar lost from patent-expiring older ones. That doesn’t sound very good, but the average is a bit misleading, since it runs from the highs of Eli Lilly ($6.64/1), Amgen ($4.50/1) and Roche ($4.03/1) down to Sanofi-Aventis (11 cents new per dollar loss on the old). But it’s true that most everyone else is well under a dollar. It would be a lot of work, but it would be interesting to know (calculating by the same methods) how that ratio has changed over the last twenty years – that would give us some perspective on where we stand now.
But AVOS has gone out to estimate the picture in 2012, and it makes today’s numbers seem like a free buffet. Of the fourteen drug makers on their list, only Schering-Plough shows a robust increase in terms of how much it’s expected to make from new products versus its declining ones. GSK shows a modest improvement – and everyone else goes down.
That’s as in down, dooby doo, down down. The hardest-hit in terms of the actual numbers are Pfizer, AstraZeneca, Roche, and Sanofi-Aventis, all of whom are projected to be making pennies (or, gulp, nothing at all) from new products compared to what’s heading down the chute for them by then. In percentage terms, Roche and Eli Lilly are worst off – they look good now, as mentioned above, but the eventual losses of things like Zyprexa kick the ratios over good and hard. (Sanofi-Aventis goes down to zero, but only from that $0.11 figure, so it’s at least not going to be such an adjustment for them!)
As I say, I don’t have access to the underlying data, but the broad picture seems about right. There are a lot of big patent expirations coming up in the next few years, and not enough promising products coming on to replace them. According to AVOS, Roche and Sanofi-Aventis aren’t projected to have any new product launches at all between now and 2012, which can’t be good.
It’s worth remembering that figures like these are likely to show big swings even under normal conditions. Imagine a company with a big product that it launches, which gradually turns into a blockbuster. Near the end of its patent life, it launches another winner of the same type, which grows into another big seller. Everything’s fine! But the ratio of new revenue/expiring revenue is going to swing around a lot as you follow those sales numbers, sort of like derivatives in calculus, veering from too-high to too-low, although the company itself is sailing along pretty well. Let’s hope that this is some of the background for these numbers as well. The problem is, I don’t think that can explain all of them. . .
Comments (11)
+ TrackBacks (0) | Category: Drug Development | Drug Industry History
July 24, 2008
Posted by Derek
I’m going to expand on one of the points brought up yesterday, about the reported drug industry executive who was confident that his company’s Alzheimer’s therapy was ready to go out and make billions of dollars. It was that word “confident” that set me off, I think.
Because that’s not a word that you hear much of in this industry. The strongest form that you’ll come across is something like “fairly confident”, which is how you feel when you send in a compound that’s a minor change off something that’s already active, or how you feel about screening a target that’s a close homologue of something you already have plenty of ligands for. You can be pretty sure in those cases that something’s going to hit – but you’ll note that both of those are pretty far upstream in the drug discovery process. As you move toward animals, that confidence begins to look pretty ragged, and depending on the disease, it can just flat-out evaporate.
Despite all our efforts to avoid the expensive little beasts, there is still no way to be sure about how your compound is going to act in an animal until you’ve put it into an animal. That goes for predicting its peak blood levels, its half-life, its metabolites, and the duration and degree of its efficacy. You can have your compounds all ranked in order of how you think they’ll perform, and that list will, every time, be reordered after a first round of animal testing.
And when you go further, you really have no idea. As I’ve said here before, if you don’t cross your fingers when you take a compound into two-week toxicity testing, you haven’t been doing this stuff very long. Despite all efforts to avoid this expensive step, two-week (and four-week and longer) tox testing in animals will always, always tell you things you didn’t know. (Most of the time it’ll tell you things you didn’t particularly want to hear). No one worth their salary will ever use the adjective “confident” before the first multiweek tox data come in.
So much for animals: how about people? Well, despite all our efforts, there are still surprises in Phase I dosing, the tip-toe clinical stage where you look for blood levels in healthy volunteers. The animal pharmacokinetic data tell you where to start the doses in humans, but you can still get ambushed. I worked on a receptor agonist project once where the human blood levels came back at just about 10% of what we’d predicted, so back to the drawing board we went. No, I’ve never heard anyone describe themselves as “confident” before Phase I.
And that’s an easy step compared to Phase II, where for the first time you put your drug into sick patients. The failure rate in Phase II is just abominable, and stands as an indictment of just how little we understand about the biochemistry of human disease and how to modify it. When you consider a central nervous system disease like Alzheimer's, the source of the "confident" quote that started this digression, the failure rate is over 90%. Our understanding of the causes and progression of Alzheimer's is very poor. That's as opposed to a more well-worked-out condition like, say, hypertension, where our understanding is merely quite inadequate.
But if you make it through that fine sieve, you move on to Phase III, a larger and more real-world look at the patient population. If your Phase II trial was designed to provide a robust test, rather than just to make you and your investors feel good, you can hope that your Phase III will work out. But the whole time it's going on, the prudent drug developer will remember that the biggest, most well-funded, and most competent research organizations in the world have all taken huge cratering dives in Phase III. You know a lot more about your compound by this stage, so these disasters don't happen as often - but that means that when they do, they rise right up out of the floor in front of you. No, you can feel better by Phase III, but "confident" is pushing it.
How about when your drug goes to the FDA? Try asking any drug company executive if they'd like to go on record as being "confident" of regulatory approval. And when your drug actually goes to market? Is anyone really confident about those projections from the people in marketing? Pfizer sure talked a good game about Exubera, remember. Don't forget, too, that nasty side effects can always be waiting out there in the larger patient population. Even after your drug goes out and starts earning a living, it can be completely torpedoed at any time. Baycol, Vioxx, Avandia - you can name more.
So that's the story: you can never kick back and relax in this business. For all the perception that some people have of the drug industry as a sure-fire money machine, it sure doesn't look that way from inside. Anyone who describes themselves as "confident" about their new experimental medication is trying to fool their listeners. Or themselves. Maybe both.
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+ TrackBacks (0) | Category: Drug Development | Drug Industry History | Patents and IP
July 11, 2008
Posted by Derek
Here's an interesting idea: Merck, Lilly, and Pfizer are bankrolling a startup company to look for new technologies for drug development. Enlight Biosciences will focus on the biggest bottlenecks and risk points in the process, including new imaging techniques for preclinical and clinical evaluation of drug candidates, predictive toxicology and pharmacokinetics, clinical biomarkers, new models of disease, delivery methods for protein- and nucleic acid-based therapies, and so on.
It's safe to say that if any real advances are made in any of these, the venture will have to be classed as a success. These are hard problems, and it's not like there's been no financial incentive to solve any of them. (On the contrary - billions of dollars are out there waiting for anyone who can truly do a better job at these things). I wish these people a lot of luck, and I'm glad to see them doing what they're doing, but I do wish that there were more details available on how they plan to go about things. The opening press release leaves a lot of things unspoken, no doubt by design. (For instance, where are the labs going to be? What's the hoped-for balance of industry types to academics? How many people do they plan to have working on these things, and how will the companies involved plan to share the resulting technologies?)
Enlight is a creation of Puretech Ventures, a Boston VC firm that's been targeting early-stage ideas in these areas. Getting buy-in from the three companies above will definitely help, but their commitment isn't too clear at present. For now, it looks like they're getting to take a fresh look at some areas of great interest, without necessarily having to spend a lot of their own money. The press release says that Enlight will "direct up to $39 million" toward the areas listed on their web site, but those problems will eat thirty-nine million dollars without even reaching for the salt. Further funding is no doubt in the works, with the Merck/Pfizer/Lilly names as a guarantee of seriousness, and if any of these projects pan out, the money will arrive with alacrity.
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+ TrackBacks (0) | Category: Business and Markets | Drug Assays | Drug Development
July 8, 2008
Posted by Derek
There was a story yesterday about GlaxoSmithKline taking what’s being called an unusual step to prioritize their clinical candidates. According to the Wall Street Journal, they invited officials from the national health care plans of several European countries to a presentation on the company’s pipeline and asked them which ones they’d be more likely to pay for (and what they’d need to see in the clinic to convince them to do that).
Actually, I think the unusual thing here is that they made a formal meeting out of the whole process. I believe that this sort of thing goes on already – after all, drug companies spend a lot of time trying to figure out the size of potential markets and what the eventual purchasers will be willing to pay. In Europe, those are the national health care systems, and if they’re not willing to pay, your drug will go nowhere. In the US, you’re going to want to sound out the big health insurance companies for the same kind of reality check.
And I don’t see how GSK showed these officials anything that you wouldn’t see (or haven’t seen) at an investor’s conference – otherwise, we’d have seen some Regulation FD disclosures, since the company’s stock is listed on the NYSE. This seems to have been a one-stop rundown of what’s already been disclosed about the whole pipeline, but with opinions specifically solicited along the way– and the company’s not obliged to say what those opinions were or what they’re doing in response to them. GSK got a lot more previously unavailable information out of this process than the health care officials did.
How much, though, will this help? For one thing, I suspect that the officials didn’t say much that GSK didn’t know about what everyone wants for a new drug. They want it to work better than anything that’s currently on the market, with fewer side effects, and for less money. (There, that was easy). And predicting the future doesn’t always work too well. The medical landscape could always change by the time the drugs make it up to the regulatory stage. There will also be a lot more information (good and bad) about the compounds themselves by that time, much of which could make these earlier discussions moot. “Remember that oncology drug we were developing? Well, turns out that it doesn’t work against quite as many different tumors as we were hoping, but. . .” or “Remember that CNS drug we were telling you about back in ’08? Well, turns out that it also has this little cardiovascular thing going, too, and. . .” In the end, the drugs will do what they will in the clinic, and the company will have to bring what it has, not what the regulators asked for.
And even though companies are already supposed to be doing this kind of legwork, there are still some spectacular disconnects. Sanofi-Aventis, for example, did manage to get Acomplia (rimonabant) on the market in Europe (which is more than they ever managed in the US), but they didn’t get the national health care to pay for it. More recently, as in "yesterday", the UK's health care system just told Glaxo itself that they're not going to pay for Tykerb/Tyverb (lapatinib), because they don't see the benefit for the price. And when we’re talking about totally mistaken ideas about market size and acceptance, how can we not mention Pfizer’s Exubera?
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+ TrackBacks (0) | Category: Clinical Trials | Drug Development | Regulatory Affairs
May 21, 2008
Posted by Derek
I’ve been in this business for almost 19 years now. That means that the drugs that were discovered during my first few years of work are now either on the market or expected to be there soon. Fine, I spent my first eight years at Schering-Plough, so what do I see when I look back? There’s ezetimibe, discovered by sheer chance (but developed by sheer determination, though) and the thrombin receptor antagonist, squirrelly chemical matter from a failed Alzheimer’s program, a compound that a lot of medicinal chemists wouldn’t have even made in the first place. Well, now.
This is not a whack at Schering-Plough. Far from it. These are compounds that any organization would have been glad to find, but they weren’t exactly found by direct routes. This is a general phenomenon. You’d think, surveying the industry, that a lot of drugs are discovered, at least partly, by outright luck. And as far as I can tell, you’d be right. Realizing that tends to bring on several different reactions, depending on your world view:
That can’t be right. I’ve seen this one mostly from people outside the immediate realm of drug discovery, well-meaning people who just can’t believe that this is how it works. The harm comes when these well-meaning folks decide that the problem is that the industry is just behind the times, and that we wouldn’t have to do it this way if we’d just adopt some modern management techniques – ISO whatever-thousand, umpteem-sigma, Quality Assurance Tiger Team Circle Continuous Improvement Metrics, or what have you. Harm generally ensues.
That shouldn’t be right. Some of the people in this category are actually offended by the sight of luck calling so many of the shots, while others are just hoping for a more productive way of doing things. A lot of computational approaches have come from this attitude: “We wouldn’t have to run around stumbling over stuff if we’d just turn on this great new flashlight that’s just been invented” Nothing’s quite illuminated the landscape in the way that people have hoped, though, although efforts continue, as they should.
OK, if we’re stumbling around, let’s stumble faster. This is the basic idea behind the improvements in high-throughput screening and combichem in the late 1980s and the 1990s. For a while, the more optimistic folks thought that this would be enough: just crank out millions of compounds, and the drugs would come – they’d have to. It didn’t work that way, partly because the space of usable chemical structures is much, much larger than we can usefully deal with. But that’s not to say that cranking out more compounds and screening them more quickly isn’t a good idea – it’s just not the good idea.
Well, stumble more purposefully, then. I think that this is where most drug discovery organizations are (or should be). You admit that luck has a big role to play, but you go for the “Fortune favors the prepared mind” approach. Don’t rely just on random runs of odd structures to fill your screening banks – but be sure to put some in, because you never know. Turn over every rock – but recognize that you can’t turn over every rock everywhere, so try to pick the most likely place to start.
The problem with this approach is that it doesn’t promise much, at least compared to the various You’re Doing It Wrong approaches, and it doesn’t make a very compelling PowerPoint slide. But although it’s the blood-toil-tears-and-sweat option, I think that for now it’s the right one. Until something better comes along, that is, and the fascinating problem is that something better is always coming along. Given this state of affairs, why shouldn’t it?
I have no room to talk, of course. I can be as much of a sucker as the next medicinal chemist for some new approach that’s going to change everything – mainly because I look around and realize that a lot of what we do would be better off changing. All the wasted effort. . .you can get downright melancholy if you look at the business from the saddest angles. For all my self-proclaimed realism, I probably have more of that second response in me than I like to admit. The idea is to keep trying for something dramatically better, while realizing that even a smaller improvement would still be worth a lot. . .
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+ TrackBacks (0) | Category: Drug Development | Drug Industry History
May 13, 2008
Posted by Derek
Schering-Plough has had its share of troubles over the years, but the company has also seen itself saved by some pretty unlikely compounds. Vytorin (ezetimibe) is the example I’ve spoken about here, and if the drug doesn’t seem like a savior at the moment, well, you have to keep in mind that it was the biggest thing for them since Claritin went off-patent ten years ago.
Now there’s another one potentially coming up. Expectations are building for a thrombin receptor antagonist compound, SCH 530348. And I have a history with this one, too: while the labs down one hallway from me were discovering ezetimibe, down the other hallway they were laying the foundation for this one. There’s a big difference, though, in the way I saw the two.
This thrombin antagonist is an unlikely drug for several reasons. For one thing, its structure is not the sort of thing most medicinal chemists would go out of their way to make. But there’s a good reason for that: to a first approximation, it wasn’t made with medicinal chemistry in mind. 530348 is based on a natural product called himbacine, whose fame, such as it is, rests on its properties as a semi-selective muscarinic antagonist. And that’s how Schering-Plough got interested in this class of compounds; thrombin had nothing to do with it.
At the time (early to mid 1990s) the company had a team working on Alzheimer’s disease, and I’ll go ahead and mention again that I was one of the people involved. (Five minutes on SciFinder would tell you that, anyway). We were quite interested in selective muscarinic antagonists, particularly for the m2 subtype, and himbacine was at the time one of the more selective compounds with that profile. So one of the group leaders at the company, Sam Chackalamannil, decided to synthesize it and do some SAR around the structure.
That was no small undertaking. Himbacine’s not one of the most complex natural products by any means, but it’s no stroll to the beach, either, especially when compared to the usual sorts of drug structures. It took a lot of time, a lot of ingenuity, and (most importantly) a lot of effort to do it. And I. . .well, I thought this was a terrible idea.
I really did. By the time himbacine itself got made, the project team had muscarinic compounds that were more selective and more potent (and a lot easier to make, to boot). I would listen to Chackalamannil’s people presenting their long, difficult routes during meetings, and I’d sit there imagining the company going slowly bankrupt if everyone adopted this approach, the revenue slowly sinking as the number of JACS communications rose. I couldn’t see the point, and although I don’t think I ever quite had the nerve to say so to Chackalamannil himself (hi, Sam!), I said it to plenty of other people.
So, is it time for me to eat crow? Well, one plateful, at least. Some of the himbacine analogs hit in the high-throughput screen for thrombin activity, to everyone’s surprise, and some further compounds (now shed of their muscarinic activity) were even better. The drug discovery effort culminated in 530548, which now might be about to benefit a huge number of people and make the company a ton of money, if everything goes well.
Of course, if these things hadn’t hit in the thrombin assay, I could have remained secure in my opinion. After all, they were never worth very much as muscarinics, as far as I know. (Of course, our muscarinic compounds, in the end, never were worth very much as Alzheimer’s drugs, which is something to keep in mind). So that’s the question: how likely is it for molecules like this to work? It’s very hard to answer that, but given this data point, I guess the answer is “at least a little more likely than I thought”. The very fact that they didn’t look like most other things in the screening deck was probably in their favor. I still think that these compounds were a long shot, but this is a business that lives on long shots. This one came through, and congratulations to everyone involved.
Comments (8)
+ TrackBacks (0) | Category: Alzheimer's Disease | Cardiovascular Disease | Drug Development
May 2, 2008
Posted by Derek
One recent drug industry setback I haven't noted around here - well, OK, to be more specific, it's a Merck setback, and boy must they be getting sick of those - is the FDA's "not approvable" letter for the Singulair/Claritin combination pill.
As the folks at the InVivoBlog note, it sure was hard, from one perspective, to see that one coming. After all, Claritin (loratadine) has an exemplary safety record and has been on the market for many years now, and Singulair (montelukast) has been selling in the billions of dollars as a stand-alone drug. No doubt many people have taken, and are taking, the two as separate pills. So you combine them and get a "not approvable": right.
The In Vivo people speculated that this might be a safety problem, since the agency has been mighty jumpy about that area recently, but Merck has now told them that safety and tolerability weren't raised in the FDA letter.
Well, what does that leave? Manufacturing? Hardly possible, given the way that these two drug substances are already being cranked out. That, as far as I can see, leaves good old efficacy. You could always argue that putting the two compounds into one pill improves patient compliance, etc., if the combination itself is useful in the first place. But in this case, I'd guess that the problem is that the combo has turned out to offer no benefit over either drug taken alone. Hard to make a case under those circumstance, it is.
And if you look into the history of a Singulair/Claritin idea, that appears to be just the problem. As the Wall Street Journal's Health Blog notes, the companies had already found no benefit for seasonal allergies, compared to either drug standing alone. Supposedly they were able to come up with some sort of nasal congestion data (what a joy that must be) that showed an edge this time, but yikes - how desperate do you have to be to take things to that point, after you've already seen no benefit in the main endpoints?
So why are Merck (and Schering-Plough) spending money on this kind of last-gasp line extension? Surely there are better places to burn cash. I've never been sympathetic to the argument that money spend on promotion is somehow stolen from R&D, but this sort of thing is another matter. Stupid R&D most definitely steals money from smarter R&D, and here's some of it that's made off with the swag.
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+ TrackBacks (0) | Category: Drug Development
April 29, 2008
Posted by Derek
So why is Merck's stock dropping - again?
The FDA just unexpectedly handed them a "not approvable" letter for their latest drug, Cordaptive. Actually, we should stop calling it that, since they also told the company that they're not going to approve that name, either. What Merck's going to do with all their promotional freebies now, I can't imagine.
What's Cordaptive, or whatever it's called, anyway?
That's Merck's newest cardiovascular drug - although the active ingredient isn't new. It's niacin, also known as vitamin B3. It's been known for many years that niacin can both lower LDL cholesterol and raise HDL, as well as lowering triglycerides - in fact, it's probably one of the only things that can do all of those significantly at the same time.
So this is a rip-off, then? Merck's trying to sell vitamin B for $20 a pill?
No, it actually isn't, at least not to the extent you're thinking. The problem with niacin as a cholesterol therapy is that you have to take whopping amounts of it to see an effect. And there's a side effect - flushing of the face, which is basically uncontrollable blushing that can last for hours in some cases. That may not sound like much, but the great majority of people who take niacin at these levels have a problem with it, and a lot of people discontinue the therapy rather than put up with it. If the drug is taken for a few weeks, the flushing reportedly eases off some, but not everyone makes it to that point. By all reports, it's very irritating - and since patients can't feel their cholesterol being high, but can feel their faces burning and turning red, they solve the problem by not taking the niacin.
So why doesn't Cordaptive do the same thing?
A lot of people have tried to find a way to keep the lipid effects of niacin and get rid of the flushing. Merck added a prostaglandin receptor antagonist, laropiprant, to try to block the pathway that leads to the vascular effects. And it seems to help quite a bit, which made the combination a potential winner. Abbott already has Niaspan, a slow-release version of niacin, which also has reduced flushing problems and does about $600 million of sales a year. Niacin therapy itself seems to be pretty safe, although you do want to make sure that liver and kidney function are normal before you start, so the only big question has been what blocking that DP1 receptor might do on the side: can you take that pathway out without causing more trouble?
Well, can you?
Apparently not. Actually, that should be "apparently there isn't enough evidence to say yet" - that's probably more in the spirit of the FDA's letter. They want to see more information about the drug. Problem is, the FDA treats this (properly) as a matter between the agency and the drug company, so they aren't saying what the problem is. And Merck, for its part, isn't saying, either. Investors feel rather left out in these situations - perhaps the most striking one in recent years was Sanofi-Aventis's absolute wall of silence for months about why the FDA wasn't approving their potential blockbuster Acomplia (rimonabant).
Why's this so unexpected, if there wasn't enough evidence given to the FDA?
Well, there seems to have been enough evidence in the same pile of data for the European Union, whose regulators approved recommended the drug for approval a few days ago. Merck must have felt reasonably confident that they'd get the same treatment here. No such luck. And as just mentioned, we don't know if the problem is not enough evidence of efficacy, not enough evidence of safety, or a bit of each.
Why don't you people just make cholesterol-lowering drugs that work better, then, so there's no doubt about efficacy?
Would that we could. Statins basically only lower LDL - they don't raise your HDL. And if you push the statins too hard, patients start coming down with rhabdomyolysis, and you don't want that - ask Bayer. Raising HDL has proven to be a real challenge, too. There are a lot of ideas about how to do it, but the most obvious ones aren't working out too well - ask Pfizer.
OK, then, why don't you just make safer versions of what you already have?
Would that we could. But in almost every case, we have no idea of how to do that. For the most part, either the safety concerns are tied up with the beneficial mechanism of the drug, or they're occurring through side pathways that we don't understand well and don't know how to avoid. And some of those are things that you don't even get a read on until your drug gets out into the market, which is no way to do things, either.
So, why is the drug business considered such a safe bet?
Now, that one I don't have an answer for. Unless it's the conviction that people are always going to get sick, which I guess is a pretty safe bet. And that's coupled with a conviction, apparently, that we're always going to be able to do something profitable about that. And some days, I have to wonder. . .
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+ TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Drug Development | Toxicology
April 10, 2008
Posted by Derek
As mentioned yesterday, I would have to say that Mannkind is in big trouble. I’d never heard of the company until the Wonder Drug Factory was closing back in Connecticut, but Mannkind was moving some of their operations into the state around then and interviewed a number of my former colleagues.
The whole inhaled-insulin idea had already taken some pretty severe blows. The massive failure of Exubera was the biggest, although a creative person could always argue that a better product with a more convenient delivery system could succeed in its place. But then Novo Nordisk and Eli Lilly (serious diabetes players, both of them) got out of the area before they’d even launched, deciding that it was better to write off their whole investment than to try to bring it to market. That didn’t help, which is one reason that Mannkind stock was down in the single digits, despite the company's efforts.
Well, as of yesterday it’s down in the really low single digits. And I honestly can’t see how they’re going to revive their flagship program if the Pfizer lung cancer data are real. The FDA is going to be very, very cautious about allowing any sort of inhaled insulin trials to proceed. I’d think that you’d have to show that your product is different from Exubera in its carcinogenic risk just to get one off the ground, and frankly, I have no idea how you’d do that. Anything that could will take years to develop and validate.
This latest result also shows some of the real difficulties and risks of drug development. After all, Pfizer and Nektar spent a very long time developing Exubera. The product was delayed and delayed while more and more clinical work was done. But in a slow-starting condition like lung cancer, those years may still not enough to quite pick things up by the time a product makes it to market. Think of what might have happened if Exubera had been a success. . .
And that brings us back to the regulatory pre-emption topic of the other day. This illustrates why either extreme of that argument is untenable. On the make-‘em-pay side, you have trial lawyers arguing that if companies just wouldn’t put defective products on the market, well, they wouldn’t have anything to worry about, would they? Test your drugs correctly and things will be fine! But Exubera’s pre-approval life was as long and detailed as could be. The testing went on and on – and after all, insulin itself has been on the market for more than half a century. What more would a company need to say something is safe?
Then there’s the other side – total pre-emption, which says that the FDA is there to regulate and sign off on safety and efficacy, and by gosh we should have them do it. Once this mighty agency gives its stamp of approval, that settles it. But again, the FDA put Exubera through all kinds of paces. If every drug took that long and cost that much to develop, we’d be in even worse shape than we are now, believe me. So what’s the agency to do?
The truth, as far as I can see, is that no one can guarantee the safety of a new drug. If you want to take that further, guaranteeing the safety of an existing drug isn’t possible, either. Every known drug is capable of causing trouble at some dose, and every known drug is capable of causing trouble at its normal dose in some people. Every new drug has the possibility of doing things no one ever anticipated, once it gets into enough patients for enough time. Every single one.
Complete safety doesn’t exist, and never has. You can have more safety, if you’re willing to take enough time and spend enough money. But you can take all the time we have on earth, and spend all the money available, and you still won’t be able to promise that nothing bad will ever happen. Pretending that either the drug companies or the regulatory agencies can make that fact go away is a position for fools and demagogues.
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+ TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Toxicology
April 7, 2008
Posted by Derek
There's talk again about an idea that's been kicking around for some years: are drug companies shielded from liability after the FDA has approved their drugs for sale?
Obviously, the current answer is "Not at all": consider the lawsuits over Vioxx. But the decision by the Supreme Court in February in Riegel v. Medtronic has the idea being taken seriously again. That ruling seems to shield medical device companies from lawsuits over safety or efficacy after the FDA has signed off on those issues - as long as the device is the same, and used in the approved manner. And no, for the politically motivated among the readership, this wasn't some barely-realized 5:4 scheme from Justice Scalia; the decision went 8 to 1.
There's a roughly similar case before the court now, Wyeth v. Levine. At issue is the labeling and usage of Wyeth's histamine antagonist Phenergan (promethazine), with the suit being brought by a patient who was injured after the drug was used in a method warned against on the label. This one hinges on a federal/state dispute, though, as the petition for certiorari (PDF) makes clear:
"Whether the prescription drug labeling judgments imposed on manufacturers by the Food and Drug Administration pursuant to the FDA's comprehensive safety and efficacy authority. . .preempt state law product liability claims premised on the theory that different labeling judgments were necessary to make drugs reasonably safe to use".
This seems, if it goes Wyeth's way, as if it would keep various state jurisdictions from coming in with different liability claims, but the situation seems less stark to me if a state's standards were the same as the federal government's. Would this really pre-empt liability suits entirely? I'll let actual lawyers set me straight on that if I'm looking at it incorrectly.
There's another case that was granted cert. last fall, Warner-Lambert v. Kent, which could also have a bearing on the whole issue. This hinges on the approval (and later withdrawal) of the PPAR drug Rezulin (troglitazone), and whether Michigan state law on pre-emption of lawsuits is in conflict with the federal law. Again, I would have thought this one would probably be decided as a state-versus-federal issue, without extending to any sweeping thoughts on pre-emption in general. But that Medtronic decision makes a person wonder if the Court is in the mood for just that.
So, there's the background. Arguing will now commence on whether pre-emption is a good idea or not. I've thought for some time that all approved medications should be labeled as "investigational new drugs", and that everyone taking them agrees that they are participating in a post-approval clinical study of their safety and efficacy. (I suppose that's my own form of pre-emption). But there's room to argue if the FDA is ready to take on the full responsibility of drug approval, without the option of later redress in the courts if something goes wrong. (Counterargument: that's what they're supposed to be doing now. . .) And all of these schemes have to make room for new information turning up, or for outright fraud (which is most definitely in the eye of the beholder). Personally, I'm glad not to be a judge.
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+ TrackBacks (0) | Category: Drug Development | Press Coverage | Toxicology
April 4, 2008
Posted by Derek
This is turning into Cardiovascular Week around the blog, I have to say, and not in a good way. The latest news is the failure of a drug candidate from Takeda, TAK-475 (lapaquistat). They were in the lead in the field of squalene synthase inhibitors for cholesterol lowering (many other companies have taken a crack at this target, and dropped out along the way)., and their compound once had hopes of being a pretty big deal.
Not any more. In retrospect, the bell sounded late last year, when the company had to stop dosing at their highest level. Elevated transaminase levels were being seen in the treatment groups as the dose went up, which is a sure sign of trouble, as in liver damage trouble. Some investors seem to have held out hope for the compound to show enough efficacy at the lower doses, but Takeda has announced that the safety/efficacy ratio doesn’t justify taking the drug forward.
Liver enzymes are definitely one of those things you worry about when you go into man. There are all sorts of assays that are supposed to give you a read on that problem beforehand, and it’s safe to assume that Takeda ran them. But you’re never sure until you hit humans. Animals can react very differently to some compounds, although that can go either way. But if you set off liver enzyme trouble in rats or dogs your compound is probably dead, no matter how it might act in humans. You won’t get the chance to find out, most of the time.
The alternative is to use human liver tissue, but cultured human liver cells rapidly lose their native abilities and become untrustworthy as a model for the real world. Human liver slices are another alternative, but those are rather hard to come by, as you can well imagine, and the data from them have a reputation for being hard to interpret and hard to reproduce. No, for now, there’s no way to really know what will happen in humans without, well, using humans.
The big question that always gets asked in these failures is whether this is a compound-specific effect, a compound class effect, or a mechanistic effect. Most of the time it’s one of the first two. There are particular compounds, and particular structural series, that are known to be Bad News for liver enzymes. There will be some lingering doubt, though, because there’s plenty of squalene synthase activity in the liver, and it’s not impossible that any compound that hits it could cause the same trouble.
There are a number of other inhibitors out there – interestingly enough, they may have other uses besides lowering cholesterol. For some time, it’s been thought that such compounds might be useful antibiotics, since many bacteria need cholesterol synthesis pathways to survive. And there’s a recent report in Science putting this to the test in a particularly relevant system, particularly virulent strains of Staphylococcus aureus.
The “aureus” part of the name refers to the yellow hue that many strains of the bug exhibit, which seems to be correlated with how nasty they are as an infectious agent. The color comes from staphyloxanthin, a pigment that seems to be used as a defense agent by the bacteria by neutralizing reactive oxygen attacks from a host’s immune system. As the current work shows, the first enzyme in the biosynthetic pathway for staphyloxanthin (known as CrtM) has a lot of structural similarities to human squalene synthase. The authors prepared a number of known squalene synthase inhibitors from the literature, and found that one class of them (the phosphonosulfonates) also inhibit CrtM.
They went further, showing that one of these compounds (a BMS clinical candidate from about ten years ago) actually works quite well as an antibiotic in vitro and in an in vivo mouse model. I'm not sure why this compound didn't go further, but perhaps it (and the others in its class) will have a second life in the antiinfectives world. . .
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Infectious Diseases
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
March 28, 2008
Posted by Derek
It’s been a while since I talked about RNA interference here. It’s still one of those tremendously promising therapeutic ideas, and it’s still having a tremendously hard time proving itself. Small RNA molecules can do all sorts of interesting and surprising things inside cells, but the trick is getting them there. Living systems are not inclined to let a lot of little nucleic acid sequences run around unmolested through the bloodstream.
The RNA folks can at least build on the experience (long, difficult, expensive) of the antisense DNA people, who have been trying to dose their compounds for years now and have tried out all sorts of ingenious schemes. But even if all these micro-RNAs could be dosed, would we still know what they’re going to do?
A report in the latest Nature suggests that the answer is “not at all”. This large multi-university group was looking at macular degeneration, a natural target for this sort of technology. It’s a serious disease, and it occurs in a privileged compartment of the body, the inside of the eye. You can inject your new therapy directly in there, for example (I know, it gives me the shivers, too, but it sure beats going blind). That bypasses the gut, the liver, and the bloodstream, and that humoral fluid of the eye is comparatively free of hostile enzymes. (It’s no coincidence that the antisense and aptamer people have gone after this and other eye diseases as well).
Angiogenesis is a common molecular target for macular regeneration, since uncontrolled formation of new capillaries is a proximate cause of blindness in such conditions. (That target has the added benefit of giving your therapy a possible entry into the oncology world, should you figure out how to get it to work well here). VEGF is the prototype angiogenesis target, so you’d figure that RNA interference targeting VEGF production or signaling would work as well as anything could, as a first guess.
And so it does, as this team found out. But here comes the surprise: when the researchers checked their control group, using a similar RNA that should have been ineffective, they found that it was working just fine, too – just as well as the VEGF-targeted ones, actually. Baffled, they went on to try a host of other RNAs. Reading the paper, you can just see the disbelief mounting as they tried various sequences against other angiogenic targets (success!), nonangiogenic proteins (success!?), proangiogenic ones that should make the disease worse (success??), genes for proteins that aren’t even expressed in the eye (success!), sequences against RNAs from plants and microbes that don’t even exist in humans at all (oh God, success again), totally random RNAs (success, damnit), and RNAs that shouldn’t be able to silence anything because they’ve got completely the wrong sort of sequence (oh the hell with it, success). Some of these even worked when injected i.p., into the gut cavity, instead of into the eye at all, suggesting that this was a general mechanism that had nothing to do with the retina.
As it turns out, these things are acting through hitting a cell surface receptor, TLR3. And all you need, apparently, is a stretch of RNA that’s at least 21 units long. Doesn’t seem to matter much what the sequence is – thus all that darn success with whatever they tried. Downstream of TLR3 come induction of gamma-interferon and IL-12, and those are what are doing the job of shutting down angiogenesis. (Off-target effects involving these have been noted before with siRNA, but now I think we’re finally figuring out why).
What does this all mean? Good news and bad news. The companies that are already dosing RNAi therapies for macular degeneration have just discovered that there's an awful lot that they don't know about what they're doing, for one thing. On the flip side, there are a lot of human cell types with TLR3 receptors on them, and a lot of angiogenic disorders that could potentially be treated, at least partially, by targeting them in this manner. That’s some good news. The bad news is that most of these receptors are present in more demanding environments than the inside of the eye, so the whole problem of turning siRNAs into drugs still looms large.
And the other bad news is that if you do figure out a way to dose these things, you may well set off TLR3 effects whether you want them or not. Immune system effects on the vasculature are not the answer to everything, but that may be one of the answers you always get. And this sort of thing makes you wonder what other surprising things systemic RNA therapies might set off. We will, in due course, no doubt find out. More here from John Timmer at Nobel Intent, who correctly tags this as a perfect example of why you want to run a lot of good control experiments. . .
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+ TrackBacks (0) | Category: Biological News | Drug Development
March 25, 2008
Posted by Derek
There’s an interesting article in Angewandte Chemie by Richard Silverman of Northwestern, on the discovery of Lyrica (pregabalin). It’s a rare example of a compound that came right out of academia to become a drug, but the rest of its story is both unusual and (in an odd way) typical.
The drug is a very close analog of the neurotransmitter GABA. Silverman’s lab made a series of compounds in the 1980s to try to inhibit the aminotransferase enzyme (GABA-AT) that breaks GABA down in the brain, as a means of increasing its levels to prevent epileptic seizures. They gradually realized, though, that their compounds were also hitting another enzyme, glutamic acid decarboxylase (GAD), which actually synthesizes GABA. Shutting down the neurotransmitter’s breakdown was a good idea, but shutting down its production at the same time clearly wasn’t going to work out.
So in 1988 a visiting Polish post-doc (Ryszard Andruszkiewicz) made a series of 3-alkyl GABA and glutamate analogs as another crack at a selective compound. None of them were particularly good inhibitors – in fact, most of them were substrates for GABA-AT, although not very good ones. But (most weirdly) they actually turned out to activate GAD, which would also work just fine to raise GABA levels. Northwestern shopped the compounds around because of this profile, and Parke-Davis took them up on it. One enantiomer of the 3-isobutyl GABA analog turned out to be a star performer in the company’s rodent assay for seizure prevention, and attempts to find an even better compound were fruitless. The next few years were spent on toxicity testing and optimizing the synthetic route.
The IND paperwork to go into humans was filed in 1995, and clinical trials continued until 2003. The FDA approved the drug in 2004, and no, that’s not an unusual timeline for drug development, especially for a CNS compound. And there you’d think the story ends – basic science from the university is translated into a big-selling drug, with the unusual feature of an actual compound from the academic labs going all the way. Since I’ve spent a good amount of time here claiming that Big Pharma doesn’t just rip off NIH-funded research, you’d think that this would be a good counterexample.
But, as Silverman makes clear, there’s a lot more to the story. As it turned out, the drug’s efficacy had nothing to do with its GABA-AT substrate behavior. But further investigation showed that it’s not even correlated with its activation of the other enzyme, GAD. None of the reasons behind the compound’s sale to Parke-Davis held up, except the biggest one: it worked well in the company’s animal models.
The biologists at P-D eventually figured out what was going on, up to a point. The compound also binds to a particular site on voltage-gated calcium channels. That turns out to block the release of glutamate, whose actions would be opposed to those of GABA. So they ended up in the same place (potentiation of GABA effects) but through a mechanism that no one suspected until after the compound had been recommended for human trials! There were more lucky surprises: Lyrica has excellent blood levels and penetration into the brain, while none of the other analogs came close. As it happened, and as the Parke-Davis folks figured out, the compound was taken up by active transport into the brain (via the System L transporter), which also helps account for its activity.
And Silverman goes on to show that while the compound was originally designed as a GABA analog, it doesn’t even perform that function. It has no binding to any GABA receptor, and doesn’t affect GABA levels in any way. As far as I can see, a really thorough, careful pharmacological analysis before going into animals would probably have killed the compound before it was even tested, which goes to show how easy it is to overthink a black-box area like CNS.
So on one level, this is indeed an academic compound that went to industry and became a drug. But looked at from another perspective, it was an extremely lucky shot indeed, for several unrelated reasons, and the underlying biology was only worked out once the compound went into industrial development. And from any angle, it’s an object lesson in how little we know, and how many surprises are waiting for us. (Silverman himself, among other things, is still in there pitching, looking for a good inhibitor of GABA aminotransferase. One such drug, a compound going back to 1977 called vigabatrin, has made it to market for epilepsy in a few countries, but has never been approved in the US because of retinal toxicity).
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development | Pharmacokinetics | The Central Nervous System
March 24, 2008
Posted by Derek
A colleague and I were talking the other day about the (long) list of drugs that have been left for dead at some point during their development. There are some famous cases – Lipitor, for example, which wasn’t thought by many at Warner-Lambert to have a business case worth even taking into the clinic. But these things are all over the place.
One that I know about was Claritin (loratadine). Schering-Plough worked on nonsedating antihistamines for a while, without too much success, and the whole program was eventually killed. The head of research at the time stated flatly: “There are no nonsedating antihistamines”. Of course, when the first one (Seldane) came on the market, that made everyone rethink a bit. In the interim, one of the chemists had continued making compounds, despite several (increasingly testy) warnings to stop.
As it turned out, he (Frank Villani) and one of his associates (Charlie Magatti) had made loratadine itself, the nonsedating antihistamine which helped to pay everyone’s salary at Schering-Plough through the 1990s. But by the time that was worked out, Villani himself had been eased out the door (or not eased while on his way out, depending on who you talk to), in good part due to his continued work on the compounds. That head of research, to his credit, actually referred ruefully later on to his own “no nonsedating antihistamines” comment – there are plenty of other people who would have just Never Said Such a Thing At All in that position.
You can find a lot of other examples, going back a long way. Many of these are medical and marketing arguments: ACE inhibitors weren’t necessarily going to be of that much use for hypertension (how many people had high blood pressure because of problems with their renin-angiotensin system anyway?) And the K/H ATPase compounds weren’t going to be of much use for acid reflux, because the H2 antagonists had the market covered (Prilosec and its progeny managed to carve out a little market share for themselves, though). The Lipitor-won’t-make-any-money mistake falls squarely into this category.
My theory is that it’s always possible to find a list of plausible reasons why a given project, or a given drug candidate, won’t work. Finding those things is (comparatively speaking) the easy part. The hard part is working out which of those things you’re wrong about, because you’re sure to be wrong about some of them. (Of course, thinking about this stuff makes you start to wonder about the drugs that never quite made it, but would have done well if they had. Most experienced development people have a list of might-have-beens that they still wonder about, but some of those would surely have also blown up disastrously even later in the process, taking even more money with them).
Further that’ll-never-work examples are welcome in the comments. I know there must be plenty of them out there. . .
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March 19, 2008
Posted by Derek
One of the less appealing ways that companies have tried to fill their drug portfolios over the years has been to look through their current drugs in search of one with a main active metabolite. That altered structure then becomes a clinical candidate for the next generation. I’ve said bad things before about Clarinex (desloratadine), son of Claritin (loratadine), the most famous example of this practice. That “des” prefix tells you that the newer drug is just the older one minus some part of its structure, in this case, minus a carbamate group that the liver clips off anyway. Even non-chemists can see the change, looking at the top parts of the structures in those Wikipedia articles.
Now comes Pristiq (desvenlafaxine), spawn of Effexor (you guessed it, venlafaxine). This one's also a simple metabolic change, OH from O-methyl. Wyeth has done very well with Effexor over the last few years, and they’re not ready to give up on that market share once it goes off patent this year. The timing of this new drug is, as they say, no coincidence. The Carlat Psychiatry Blog, not a place to go to find lots of warm feelings for the drug industry, has its “Top Five Reasons to Forget About Pristiq”. From the way things look, I have to agree with them; at the moment it’s hard to see much need for the stuff.
But there’s a good point made there by an investigator on the clinical trials, Dr. Michael Liebowitz of Columbia. He, quite reasonably, is waiting for the market to settle whether the drug is of any use or not: “If it is useful, then it will make money for the company, and if it is not, it won’t.” Update: there's more from Liebowitz on this topic, and on follow-on CNS drugs in general.
Exactly. I’m very much in favor of letting drugs stand or fall on their merits, if any. My first guess is that Pristiq is not much of an addition to the pharmacopeia – and if it isn’t, Wyeth deserves to lose the money they’ve put into it, since that, frankly, would have been the presumption from very early in the drug’s development. They took this drug forward at their own risk, and should profit or lose by it accordingly.
One thing I’ll say for the company, though: they actually seem to be running a head-to-head study between the two drugs. That’s good to see, and it’ll be quite interesting to see what case Wyeth can make, if any, after the data come in. At least they’re not just banging on tin cans and shouting “Now with the great taste of fish!” or something. Interestingly, as a comment on the Carlat blog points out, the company has already published data on one unimpressive trial with Pristiq, and I have to thank them for doing that, too. If there was ever a head-to-head efficacy study run between Claritin and Clarinex, I definitely missed it – I’m willing to be corrected, of course, but I’m pretty sure that there never was one).
So one-and-a-half cheers for Wyeth. I wish, in most cases, that companies would avoid the metabolite-drug idea. Alternatively, I wish that everyone’s drug pipeline was well stocked enough that such follow-ups didn’t look financially appealing. But if you’re going to have them, taking an honest look at their benefits is the only way to go.
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+ TrackBacks (0) | Category: "Me Too" Drugs | Drug Development | The Central Nervous System | Why Everyone Loves Us
March 18, 2008
Posted by Derek
Do drug discovery and drug marketing belong in the same company or not? That question’s been asked in several forms, but two MIT professors are taking it about as far as it can go. Stan Finkelstein and Peter Temin have a book coming out (“Reasonable Rx: Solving the Drug Price Crisis”) which proposes decoupling the two by force.
By analogy to the way the electrical power industry was divided into generation and distribution sectors, they propose splitting up the pharmaceutical business into drug discovery firms and drug marketing firms. But wait, there’s more: they also would like to have an “independent, public, non-profit Drug Development Corporation” formed to act as an intermediary between the two:
“It is a two-level program in which scientists and other experts would recommend to decision-makers which kinds of drugs to fund the most. This would insulate development decisions from the political winds," (Finkelstein) said.
The MIT press release also talks up the other putative benefits of this plan, such as how it would “insulate drug development from the blockbuster mentality, which drives companies to invest in discovering a billion-dollar drug to offset their costs”. There’s a lot to talk about in this idea, but here are some of my first impressions:
1. The electric power analogy is probably specious. Generating electricity is, for the most part, a sure thing. If you build a big coal-fired generating plant, which we most certainly know how to do, it will generate electricity for you. And its output will be proportional to how fast the turbines spin. Research is most profoundly different, as many executives from other industries have found to their sorrow. You can turn the crank like crazy and have hardly anything come out the other end at all – ask Pfizer – and that’s because we do not have a very clear idea of how to discover drugs.
Another problem is that electricity is fungible. The electric power coming from one plant is exactly the same as that coming from another, and can be pooled and distributed in exactly the same way. Every drug, however, is different. The electric power industry would be rather changed in appearance if some kilowatts were ten times as profitable as the others, but only for a few years after the generating plant came on line, or if particular kilowatts were only of benefit to certain homes or businesses and had to be routed there specifically.
2. Where are these experts, exactly? I have an instinctive distrust of plans that call for a board of dispassionate technocrats to step in and do things that the market is supposedly doing by itself. It’s not that such things absolutely can’t work, but my default belief is that they won’t work as well as their planners hope. Finkelstein and Termin’s “DDC” proposal is just the sort of thing I worry about. I can see establishing something to make sure that less immediately profitable diseases get R&D directed to them, but running the whole industry like an NIH grant review board sound like a recipe for disaster.
3. To some extent, the industry is already divided in the manner proposed. But it's not done through review boards, it's done through business dealings. Many small firms don't have the resources to develop their own drug candidates, so they shop them to larger firms who can handle the clinical, regulatory, and marketing aspects of the process. This goes on all the time. It's been proposed (many times) that one or more large companies might shut their own research down completely and serve as a clearinghouse for the smaller ones in just this way, but no one has been willing to take the plunge. My guess is that there aren't enough good ideas out there for sale to keep a company going without having some of its own research in the game; I feel sure that the numbers have been run on this idea more than once.
Of course, these deals are made on the basis of who will make money, rather than how much society will benefit. But you'd be surprised at how often those two can overlap.
Where do the costs go? I suppose I'll have to read the book to get the details, but I'm not sure how money is supposed to be saved here. The cost of developing drugs doesn't look like it'll be changed much, since Temin and Finkelstein aren't coming in with any insights into human biochemistry or any new ways for us to predict efficacy or side effects. Profits, however, would surely be reduced: the the DDC that they propose would seem to exist to recommend that less profitable drugs be developed, for the good of society, rather than the ones that companies believe that they can make the most money from.
I note that the press release makes much of climate change and globalization, probably because in many circles these days you can't be taken seriously unless you mention those somewhere. This is done in the context of tropical diseases possibly making inroads into the US and other industrialized countries. But if that were to happen, research on these diseases would become much more profitable - which I realize is a crude way of looking at it, but the market doesn't have to be pretty to work. And I think the process would be slow enough to fit the timelines for drug discovery as it's practiced today - an example would be the burst of work on avian influenza in the last few years. A sudden epidemic would be bad news indeed, and might well catch the industry flat-footed, but that's going to be hard to avoid under any drug development regime.
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March 7, 2008
Posted by Derek
Hang around any drug discovery organization and you’ll hear complaints about how the drug candidates don’t dissolve well. The people who test the compounds on cells and proteins complain a bit about this, and the ones who test on mice and rats complain even more. Traditionally, the problem eventually lands on the lab benches of the people who work out formulations, who complain that by the time it gets to them that there’s only so much than can be done. So over the years, it’s become more of a concern for the chemists who make the things in the first place, as I guess it should.
Solubility isn’t the single most important factor in making drug candidates, but you can’t ignore it, either. Having a drug that dissolves well frees you up during development. Whenever you get low or variable blood levels while testing a new compound in animals, you always wonder if the compound was dissolving in the gut properly. If the answer is already known to be “Yes”, then you can concentrate on the other potential problems. (That said, solubility doesn’t correlate with good blood levels as well as you might imagine, because of those other factors. Awful solubility correlates pretty well with awful blood levels, though).
There are other virtues: a soluble compound is also a lot easier to dose i.v., which is a valuable stage in figuring out how it’s being distributed in whole animals. And getting into the clinic is hard enough without having to worry about how you’re going to dose the first human volunteers, and whether a temporary fix for the problem (a “service formulation”) will provide relevant data or hold up at all as you go on into Phase II. There are, to be sure, some valuable drugs with absolutely horrible solubility problems (taxol comes immediately to mind), but you'd rather not find yourself competing with it for the title.
But solubility, as a word, conceals several different behaviors. It comes down to how much the compound likes to associate with itself versus how much it likes to associate with solvent. Those two values can vary pretty independently, and you get different situations as they slide up and down. In the case of a drug formulation, that solvent is going to be as watery as feasible, so here’s how things break down:
Low self-affinity and low aqueous affinity: the first value will give you an oil or a low-melting solid, and the second will give you trouble going into solution. We try to avoid this category if possible, although you can always formuate as some sort of oil-filled gel cap if you’re really up for it, as with Vitamin E.
Lower self-affinity and higher aqueous affinity: Depending on the absolute values here, this could be low-melting again. But this time it’ll hop right into water, because it’s actually happier there than it is in its own crystal form. Formulation should be a breeze, but the problem with these guys is that they’ll soak water right out of the air and turn into goo if you don’t watch out.
High self-affinity and lower aqueous affinity: here’s where you run into trouble, and here, unfortunately, is where a lot of med-chem drug candidates land. The first value will give you a high melting point – the crystal’s very happy the way it is, thanks, and would rather not give up its structure. And water has a hard time competing. This is where the formulations people really get a workout – in a future post we’ll talk about some of the tricks used in this situation. Sometimes the chemists can fix things by making one part of the molecule lumpier – literally – so that the structure doesn’t pack so well into a crystal form.
High self-affinity and high aqueous affinity: depending on the absolute values again, this could be tricky. There are some high-melting solids that dissolve in water just fine: ionic substances like table salt make great crystals, but their interactions with water are even more favorable. But you can also end up with a compound that will stay in water, but has trouble going into water. Once the molecules are surrounded by water, they’re happy, but those first few water molecules have a tough time pulling each drug molecule out of the crystal surface. If you grind one of these guys up really fine and stir it for three days, you’ll probably get a reasonable solution, but at first glance you’d take it for a compound from the previous class. All the more reason to make sure you're at equilibrium before drawing any conclusions.
So that’s a quick look at solubility, and a quick look at the range that a medicinal chemist has to think about: from picturing molecules stacking one by one into a crystal, to picturing a drug candidate gumming up a syringe held by a muttering, red-faced pharmacologist.
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+ TrackBacks (0) | Category: Drug Development
March 4, 2008
Posted by Derek
Here's a snapshot for you, to illustrate how little we know about what many of our compounds can do. I was browsing the latest issue of the British Journal of Pharmacology, which is one of many perfectly respectable journals in that field, and was struck by the table of contents.
Here, for example, is a paper on Celebrex (celecoxib), but not about its role in pain or inflammation. No, this one, from a group in Turin, is studying the drug's effects on a colon cancer cell line, and finding that it affects the ability of the cells to stick to surfaces. This appears to be driven by downregulation of adhesion proteins such as ICAM-1 and VCAM-1, and that seems to have nothing particular to do with COX-2 inhibition, which is, of course, the whole reason that Celebrex exists.
This is a story that's been going on for a few years now. There's been quite a bit of study on the use of COX-2 drugs in cancer (particularly colon cancer), but that was driven by their actual COX-2 effects. Now it's to the point that people are looking at close analogs of the drugs that don't have any COX-2 effects at all, but still seem to have promise in oncology. You never know.
Moving down the list of papers, there's this one, which studies a well-known model of diabetes in rats. Cardiovascular complications are among the worst features of chronic diabetes, so these folks are looking at the effect of vascular relaxing compounds to see if they might provide some therapeutic effect. And they found that giving these diabetic rats sildenafil, better known as Viagra, seems to have helped quite a bit. They suggest that smaller chronic doses might well be beneficial in human patients, which is definitely not something that the drug was targeted for, but could actually work.
And further down, here's another paper looking at a known drug. In this case, it's another piece of the puzzle about the effects of Acomplia (rimonabant), Sanofi-Aventis's one-time wonder drug candidate for obesity. It's become clear that it (and perhaps all CB-1 compounds) may also have effects on inflammation and the immune system, and these researchers confirm that with one subtype of blood cells. It appears that rimonabant is also a novel immune modulator, which is most definitely not one of the things it was envisioned as. Do the other CB-1 compounds (such as Merck's taranabant) have such effects? No one knows, but it wouldn't come as a complete surprise, would it?
These are not unusual examples. They just serve to show how little we understand about human physiology, and how important it is to study drugs in whole living systems. You might never learn about such things by studying the biochemical pathways in isolation, as valuable as that is in other contexts. But our context in the drug industry is the real world, with real human patients, and they're going to be surprising us for a long time to come. Good surprises, and bad ones, too.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Drug Development | Toxicology
February 20, 2008
Posted by Derek
A recent item from InVivoBlog about Merck which brought up some interesting points. They aren’t cheerful ones. The article is largely about Merck’s reputation, which has taken some dents in recent years, to put it lightly. The Vioxx debacle is the main reason for this, but the hits have kept on coming, such as the latest controversy over the release of the disappointing Vytorin study data.
So, although this is a painful question, perhaps it needs to be asked: remember when Merck was above all that stuff? Maybe there should be a “seemed” in that sentence somewhere; that might take some of the sting away. But the company really did have a singular reputation at one time. Depending on your point of view, you could have used words like “insular” or “arrogant” to describe the culture over there, but they were distinctive.
Merck didn’t merge with anyone. They stuck with targets and projects for years and years if they thought something would come out of them. And (until Vioxx) they avoided the sorts of disasters that seemed to hit other companies. That’s gone. Not all gone – they still seem to run on longer timelines over there – but one of the most distinctive things about the company was how it guarded its reputation, and that seems to have slipped down the list. They didn't have to do ad campaigns like this one. The company's trying to convince people, or convince themselves, that things haven't changed, but they're wrong.
The other thing that struck me about the article was about the development of the company’s CB-1 antagonist. That’s the same mechanism as rimonabant, Sanofi-Aventis’s failed wonder drug for obesity. (OK, it’s on the market as Acomplia in several countries, but considering what people had thought it would do, it’s a failure, all right). I question Merck’s judgment in pushing another compound into that area, although these programs do take on a life of their own. And as the In Vivo post points out, Merck’s current reputation of pushing every drug as hard as possible won’t help it when it comes to getting the drug through the FDA.
The biggest problem with rimonabant was the comparison of its side effects to its efficacy. It does seem to help people lose weight, although not to any startling extent, but in a large patient population various psychiatric side effects showed up. Taranabant's side effect profile isn't yet clear. Merck is going to have to tread lightly, but can they? The situation is a bit too much like Vioxx, with a huge, lucrative market out there if you can just expand the patient population. And we can argue about just how bad Vioxx really was, and about its risk/benefit ratio, but that won't change the fact that it was a catastrophe for Merck. The last thing they need is another one. I don't think I would have picked this time to push another CB-1 antagonist forward, but I suppose we don't get to pick that sort of thing. . .
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+ TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Drug Industry History | The Dark Side
February 14, 2008
Posted by Derek
I’ve been reading an interesting paper from JACS with the catchy title of “Optimization of Activity-Based Probes for Proteomic Profiling of Histone Deacetylase Complexes”. This is work from Benjamin Cravatt's lab at Scripps, and it says something about me, I suppose, that I found that title of such interest that I immediately printed off a copy to study more closely. Now I’ll see if I can interest anyone who wasn’t already intruiged! First off, some discussion of protein tagging, so if you’re into that stuff already, you may want to skip ahead.
So, let’s say you have a molecule that has some interesting biological effect, but you’re not sure how it works. You have suspicions that it’s binding to some protein and altering its effects (always a good guess), but which protein? Protein folks love fluorescent assays, so if you could hang some fluorescent molecule off one end of yours, perhaps you could start the hunt: expose your cells to the tagged molecule, break them open, look for the proteins that glow. There are complications, though. You’d have to staple the fluorescent part on in a way that didn’t totally mess up that biological activity you care about, which isn’t always easy (or even possible). The fact that most of the good fluorescent tags are rather large and ugly doesn’t help. But there’s more trouble: even if you manage to do that, what’s to keep your molecule from drifting right back off of the protein while you’re cleaning things up for a look at the system? Odds are it will, unless it has a really amazing binding constant, and that’s not the way to bet.
One way around that problem is sticking yet another appendage on to the molecule, a so-called photoaffinity label. These groups turn into highly reactive species on exposure to particular wavelengths of light, ready to form a bond with the first thing they see. If your molecule is carrying one when it’s bound to your mystery protein, shining light on the system will likely cause a permanent bond to form between the two. Then you can do all your purifications and separations, and look at your leisure for which proteins fluoresce.
This is “activity-based protein profiling”, and it’s a hot field. There are a lot of different photoaffinity labels, and a lot of ways to attach them, and likewise with the fluorescent groups. The big problem, as mentioned above, is that it’s very hard to get both of those on your molecule of interest and still keep its biological activity – that’s an awful lot of tinsel to carry around. One slick solution is to use a small placeholder for the big fluorescent part. This, ideally, would be some little group that will hide out innocently during the whole protein-binding and photoaffinity-labeling steps, then react with a suitably decorated fluorescen |
