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
Twitter: Dereklowe
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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.
Comments (14)
+ TrackBacks (0) | Category: "Me Too" Drugs | Drug Development | The Central Nervous System | Why Everyone Loves Us
February 4, 2008
Posted by Derek
The topic of “me too” drugs has come up quite a bit around here over the years. For the most part, I’m a defender, although there are some places I draw the line (Clarinex for Claritin comes to mind as a particularly useless advance). A reader pointed out the amount of advertising he’s seeing for Aciphex (rabeprazole), another proton pump inhibitor for gastrointestinal reflux and general stomach acid problems, and wonders what side of the line this one is on.
I’m already on record as wondering just how much of an advance Nexium (esomeprazole) was over its racemic form, Prilosec (omeprazole), so the bar is set pretty high in this area already. Looking through PubMed, I find numerous comparisons between the drugs, which suggest some small differences in PK. Some earlier studies suggested that rabeprazole works more quickly over a course of therapy, but this is in dispute. There do seem to be differences in drug interactions between the various drugs in this category, which could be important in older patients who are already taking other medications. (Protonix (pantoprazole) may also be in this category). Perhaps reflecting this, this study found that rabeprazole was "significantly more effective" in elderly patients.
So, overall, there do seem to be some differences between the various drugs in this category (summarized here, among other places). In most cases, though, they're pretty much the same. This looks like a fight among near-equals, with the occasional tiebreaker going to one compound or another. This would explain why the ads for the various compounds are pretty interchangeable as well, featuring people holding their stomachs when confronted with a plate of barbecue. (Living in the Boston area, I can understand that reaction to some of the local stuff, but that's another topic).
As I say, I generally defend the idea of several drugs entering the same therapeutic space. In theory, and for the most part in practice, each new entrant provides something that the previous ones didn’t, and can thus carve out a space for itself. In this case, though, the differences between these drugs, though real, are comparatively small and subtle. There are patients who benefit from the number of choices in this category, but not as many as the advertising dollars would suggest. The whole proton-pump inhibitor market seems to be a fight among near-equals to carve up a large and lucrative market. The parallels that occur to me are the markets for SUVs and laundry detergent.
That means that it's a fight made for the big companies, for one thing. A smaller outfit would have been crazy to get into the PPI arena without a big partner. Given the current state of the art, it would seem crazy for anyone else to be contemplating an entry at all, unless they have some huge advance that they can demonstrate clinically. The existence of so many PPIs is not a scandal - yet - but it's not a glorious chapter in the history of drug research, either.
Comments (4)
+ TrackBacks (0) | Category: "Me Too" Drugs | Business and Markets
November 28, 2007
Posted by Derek
Novartis must wonder what they did to deserve this one. A few years ago, it looked as if they ruled the potentially lucrative world of dipeptidylylpeptidase-IV (DPP-IV) inhibitors for diabetes. (Note - name of enzyme corrected after brain hiccup - DBL). Novartis seemed to be the first big company to come up with good chemical matter in the area, and they published a whole string of papers while their lead compound went through the clinic.
Then came trouble. Merck turned out to have a big program of their own in the area, which in Merckian fashion they’d kept very quiet about, and they actually beat Novartis to the FDA. And then they beat them to market, because the agency had some questions about the Novartis compound. Those questions have done nothing but multiply. Now the problem appears to be liver tox, one of the last things the diabetic population needs. It’s looking very likely that Novartis’s compound may never get to the market in the US at all.
So here’s a question: if both compounds had made it to market, wouldn’t the people who tally up lists of “me-too” drugs have considered the first compound (from Merck) to be the original, and the Novartis one to be the copycat? After all, they target the same enzyme for the same disease in the same way. (I should mention that a DPP-IV inhibitor itself is just the sort of thing the industry is supposed to be turning out, a completely new way to treat a major and growing public health problem, but we'll pass over that for now).
But these compounds were developed more or less simultaneously, with the two companies racing each other to the market. It’s not like either company sat back and watched the big profits roll in, and said “I need to latch on to some of that – let’s make one of those, too.” The whole thing was done on a risk basis, because while the biochemical rationale behind DPP-IV inhibition makes sense, a lot of things make sense and still go nowhere. No one really knew how the drugs would perform, either in the clinic or in the marketplace.
And take a look at the problems that the Novartis compound has. Like so many other toxicology hits, these came out of the cloudless sky. Well, actually, it’s more accurate to say that the sky over the toxicologists is never cloudless, because you never know what’s going to happen. In this case, Novartis has taken an especially painful and expensive beating, since the drug had advanced so far before the problems began to make themselves clear.
I’d like to ask some of the critics of the industry what they think about this situation. Me-too drugs are a particular arguing point with many of these people, so here we go: does that term apply in this case? If not, then why not? Should companies go after the same target in the same way at the same time? If not, then why not? How do we deal with the fact that any compound can fail at any time, other than turning companies loose to compete with each other and take as many shots at a target as possible? Do you have a better solution – and if not, well, then, why not?
Comments (34)
+ TrackBacks (0) | Category: "Me Too" Drugs | Diabetes and Obesity | Drug Development
July 24, 2007
Posted by Derek
Arnold Relman is back. The co-author, with Marcia Angell, of The Truth About The Drug Companies , has a long review in The New Republic of Richard Epstein's new book on the industry, Overdose.
Not everything in Epstein's book is right, and not everything in Relman's review of it is wrong. But when Relman misses, he misses big. Take, for example, this:
"Indeed, the industry's greatest enemy is itself. Innovation by the major pharmaceutical firms has certainly fallen off sharply in recent years, but there is good evidence that the cause lies with the industry's own policies rather than with government regulation. The drug companies are being driven more by financial ambition and marketing considerations than by scientific or public health objectives, and that is the root of their current problems."
That must be why we plowed all that money into genomics, among other technologies: marketing made us do it. I knew we'd track down the culprits eventually! OK, Relman's targets here are the "me-too" drugs, which I've written about many times on this site. I get the strong impression that he underestimates the cost and difficulty of developing these - he seems to think that it's pretty much a breeze once the first drug in a class has hit the market. Actually, to my mind, one of the main advantages companies are seeking in a me-too is that the first drug has proven that a market exists, and that its mechanism actually works. The development costs for the later drugs, though, aren't hugely cheaper than for the first one. And, I might add, they still don't always work.
Inside the industry, people spend a lot of time talking about why productivity has gone down (we're in agreement on that point). But you don't hear many people advancing Relman's pet thesis, that we're spending too much time chasing each other. That's because I think he's confusing cause and effect a bit: we're not unproductive because of the me-too drugs - we're making me-too drugs because a lot of our other stuff doesn't work.
Believe me, companies would love to come up with new therapies for underserved markets - Alzheimer's, say - or to come up with anticancer compounds that would do for the many what the likes of Gleevec do for the few. And we'd certainly make money at these, too - if we could find a way to do them. Saying that it's for lack of trying just doesn't ring true.
That mention of making money brings up another favorite part of Relman's review:
"Regardless of the disease it targets, and whatever the benefit, no one has ever adequately explained exactly how the "value" of any new drug can be translated into dollars. It seems more likely that the price of newly approved patented drugs is simply set at whatever the manufacturer believes the market will bear. "
Good Lord! Where will it end, if companies price things according to what they think that people will pay for them? I look forward to the establishment of the Relman Board, which will determine, by means doubtless beyond my abilities to understand, the True Price (trademark applied for) of all drugs. Problem is, Relman himself probably looks forward to that, too. . .
Comments (23)
+ TrackBacks (0) | Category: "Me Too" Drugs | Drug Industry History | Drug Prices
September 22, 2005
Posted by Derek
One of the other incorrect lessons that people might take away from the press accounts of the antipsychotic trial is that drug companies have been comparing their medications to placebo too often. And why would you do that unless you were scared that you wouldn't be better than the competition? What's with these people, anyway?
Well, there are fields where placebo-controlled trials take place, and fields where they don't. It depends on the disease and options available to treat it. Cancer trials, for example, are very rarely run against placebo, unless there's just nothing left to do. (You'll see this with drugs that are meant for late-stage patients or those who have failed existing therapies.)
Antipsychotics are generally compared to an existing standard of care, because it's unethical to leave someone untreated when they've already been diagnosed as schizophrenic. The problem that the CATIE trial uncovered, though, is that many trials are run against haloperidol (known as Haldol). That's a typical older drug, and companies have been showing that they have better efficacy and fewer side effects than it does. (It's known to have significant problems with tardive dyskinesia, among other things).
But now we know that perphenazine is a better standard among the older drugs, mostly because of fewer side effects. I don't think that anyone is going to be able to run a haloperidol-controlled trial for a new antipsychotic. Now you're going to have to beat perphenazine, which will be a higher standard. The newer drugs have been able to get rid of the so-called extrapyramidal side effects, like tardive dyskinesia, but they haven't been able to increase their efficacy that much. That's not going to be enough any more - the ante has gone up in the field of schizophrenia therapy.
Now, if you think that your new drug is really going to cream the competition, running a trial against them is a smart move. There's no better way to persuade people to prescribe your drug than to show that it's clearly better than what's out there now. Another time you see head-to-head trials is when a company is making a run at the leader in a given category. The various attempts to out-do Lipitor are good examples, not that any of them have succeeded. But there really wasn't a clear leader in the antipsychotic area, and thus no real target to try to knock down. I'd bet that the companies involved strongly suspected that their own drugs weren't head and shoulders above everything else, either. This is the perfect situation for an outside agency like the NIH to do a comparison study, because if you're waiting for the companies involved to do it, you're going to have a pretty long wait.
Comments (4)
+ TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | The Central Nervous System
September 21, 2005
Posted by Derek
You've probably seen the headlines about the recent NIH-sponsored "CATIE" study comparing five anti-psychotic medications. The result, which is what made the whole thing newsworthy to the popular press, was that it was hard to distinguish among them, with the oldest generic working as well as (or better than) the newer drugs.
But I think that people outside of the medical world are going to learn the wrong lessons from all this. Does this study mean that everyone taking anti-schizophrenia medication should switch to the old generic? Not at all, although if they need to try a different medication, they should definitely consider it. Does it mean that all these newer drugs are unnecessary? No, again. There's an awful lot of patient-to-patient variation in central nervous system drugs. Says the study's principal investigator, Dr. Jeffrey Lieberman of Columbia:
"There is considerable variation in the therapeutic and side effects of antipsychotic medications. Doctors and patients must carefully evaluate the tradeoffs between efficacy and side effects in choosing an appropriate medication. What works for one person may not work for another."
But I think that this study does make clear that the newer antipsychotics aren't as good as they should be. The field is a tough one, as I know from personal experience, having played a small role in helping a company spend I've-no-idea-how-many millions of dollars to find out that a potential schizophrenia medication didn't do squat. There's a lot of room for improvement, and we haven't been able to improve things very much.
It's important to emphasize that this was a surprising result. No one expected the side effect profiles of the four "second-generation" drugs to be so similar to the older one (perphenazine), and so similar to each other. That's one reason that a study like this is so valuable - huge clinical trials that tell you something that you already knew aren't too wonderful. I think that this is an excellent thing for the NIH to be doing. Tomorrow: what this says about head-to-head trials in general.
Comments (4)
+ TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | The Central Nervous System
August 23, 2005
Posted by Derek
I'll tell you a company that's been watching what's happened to Merck and thinking hard about it: Sanofi. Well, OK, everyone in the industry has been looking at Merck's situation and shuddering, but I suspect the people at Sanofi(-Aventis) are especially jumpy. Why? Rimonabant.
Rimonabant, which will come to the market next year (most likely) under the name Acomplia, is one everyone's short list of potential multibillion dollar drugs. It'll be the first new drug treatment for obesity in years, and it's the first one ever with its mechanism of action (antagonism of the CB(1) receptor). It has potential for many sorts of addiction therapy as well. Although there's room to argue about just how effective it is compared to existing therapies, and there's some concern about how many HMOs will pay for it, there's little doubt that it's going to sell like crazy.
And there's the worry. There is absolutely no way that large enough clinical trials could be run on a drug like this to predict everything that might happen when millions of people start taking it. Can't be done. You can get down to a margin of safety that will get you past the FDA, but that isn't enough, now is it? No, if one person out of a hundred thousand has a nasty side effect, that's enough to bring the sky down on your head. And we can't test down to the level of one-per-hundred-thousand effects.
A fine situation, isn't it? This same argument applies to every new drug, naturally, but especially to a groundbreaking compound like rimonabant. That's just what we needed, an incentive not to be first in class with a new drug. What, exactly, are we doing to ourselves?
Comments (3)
+ TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | Diabetes and Obesity
December 10, 2004
Posted by Derek
Alex Tabarrok has finished up his short series on me-too drugs, and he's done a fine job of hitting the nail on the head. It's gratifying to see people from outside the field who really know what they're talking about:
"(Marcia) Angell is also skeptical that me-too drugs can have different effects in different people. Frankly, I was shocked at this argument. Every clinical trial that has ever been run demonstrates that the same drugs have different effects in different people - it's hardly a surprise that different drugs have different effects. And me-toos are different - different enough not to violate the patent on the innovator drug almost certainly means different enough to have different effects in some people. My local supermarket carries at least a dozen different styles of peanut butter, a fact of which I approve, but Angell thinks two angiotensin-converting-enzyme (ACE) inhibitors may be one too many (p.90). Give me a break.
Finally, it's important to recognize that small changes can actually make for important improvements. What could be more me-too than a once-a-day pill replacing a twice-a-day pill? Yet, to dismiss this change is to overlook the people factor. A once-a-day regime that people stick to is much better than a twice-a-day regime that people fail to follow. Forget the chemical structure the economics says a drug that people actually take is a better drug."
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+ TrackBacks (0) | Category: "Me Too" Drugs
December 7, 2004
Posted by Derek
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+ TrackBacks (0) | Category: "Me Too" Drugs | Blink ›
December 2, 2004
Posted by Derek
Via Tyler Cowen at Marginal Revolution, I came across this editorial by John Gapper in the Financial Times on me-too drugs. Its points will be familiar to readers of this blog:
"If there is one product that annoys people, it is the me-too drug. Pharmaceuticals companies should take advantage of the genetics revolution to find cures for intractable diseases such as cancer and cystic fibrosis, the critics moan. Instead, they spend billions trying to match the pills already made by others."
Ay-yep, that they do, and that we do, too. But this piece goes a bit further than usual, pointing out to Financial Times readers that:
". . .drugs can make it through clinical trials only for side-effects to be discovered when they are prescribed to millions of patients. If all drugs in each therapeutic class were identical, Celebrex would now be off the market along with Vioxx. In fact, one pill can turn out to be safer than another. Indeed, without going into details about Levitra and Viagra, their effects can also vary. . ."
The author goes on to point how how head-to-head trials of drugs are becoming more common, and how in the post-Vioxx world they're likely be even more widely conducted:
"From the perspective of drugs companies, this makes life trickier. Not only is the least safe drug in any class liable to be knocked out in the same way as Vioxx, but even safe ones will have to face off against each other to establish the best of all.
This may all sound terribly wasteful to a doctor, but it is the same thing that is good for consumers in other markets: open competition. The problem until now has not been too much of it, but too little. The last thing that a patient should want is a choice of only one drug. As the Vioxx withdrawal shows, me-too pills may inspire little affection, but they would be missed if they were not there."
Reading this, Tyler wonders:
"Why have me-too drugs been so prevalent? Are they an inefficient form of product mimicry? An artifact of bad patent or FDA policies? The long-run path to affordable medical care?"
I've talked about this before (see the category over on the right), but here's the short answer: that the first drug in a category proves that the mechanism is a viable one in the market. ACE inhibitors really do lower blood pressure, HMG CoA reductase inhibitors really do lower cholesterol, and so on, and to a degree that people are willing to pay for. That's a big hurdle, one that not every new first-in-class drug makes it over. There are numerous new-mechanism drugs that few people have heard of, because they didn't work well enough to attract a market. No me-toos follow them.
But when something takes off, later drugs in the category are attracted by the proven mechanism and sales potential. Then they try to go a bit better, to take market share - more convenient dosing, better efficacy, fewer side effects - whatever we can come up with. There are also situations like Vioxx and Celebrex, where the two drugs were developed at roughly the same time. In those cases, we don't know much about your competition while the development is going on. We just have to try to get to the market first and hope for the best.
So there's some product mimicry, but real mimicry is impossible. No two drugs are, or even can be, completely identical. That gives new ones a shot at being better, or at just being better in some situations, or, likewise, a shot at being worse in some (or all) of them, too. But not the same.
Comments (1)
+ TrackBacks (0) | Category: "Me Too" Drugs
September 2, 2004
Posted by Derek
What sort of markets breed multiple therapies? The ones with the largest number of potential (paying) patients, for one thing, which shouldn't surprise anyone. Fortunately, that also corresponds pretty well with the markets that could be better served with another drug. The success of the first compound in a new market shows that it can be done, and proves that there's money to be made, and that attracts more companies to the field. The path has been cleared, up to a point - but remember, all the following compounds have to go through the same degree of efficacy and safety testing as the first one did, although the later entries at least know, broadly, how to set up their clinical trials.
But entering an existing market is no guarantee of riches. There are no guarantees of riches. Look at Bristol-Meyers Squibb and their statin, Pravachor, which has been weighed in the balance against Lipitor and been found wanting (with BMS paying for the whole process). Now what? You can be sure that AstraZeneca is beavering away, trying to show that their big statin hope (Crestor) has even more of the effects that Lipitor has shown. It'll need to.
Or look at the erectile dysfunction field. Pfizer showed that it could be a moneymaker with Viagra, and don't believe for a minute that this was obvious beforehand. There were plenty of sceptics, doubtless some of them within Pfizer itself. But Viagra's success attracted a lot of interest around the industry, since many companies had a stable of potential PDE inhibitor leads. Now Bayer (partnered with Glaxo SmithKline) and Icos (partnered with Lilly) are in the field with Levitra and Cialis, respectively. A glance at your e-mail spam will have already familiarized you with both compounds, in case you've somehow missed the massive advertising campaigns.
The hope was the the new compounds, which differ from Viagra (and each other) in side effects, onset, and duration of action, would expand the market even more to people who had never tried Viagra. But as far as anyone can see, neither of them has been the as big a hit as the companies involved might have hoped for. It looks like the size of the market is still roughly the same, only now there are three compounds beating each other up inside the same box. The promotional costs for everyone involved are not trivial, and they would have been a lot easier to bear if a lot more patients had decided to try the therapies for the first time. It doesn't seem to have happened, at least not yet. Those are the breaks. We make money in this business, true, but if you think it comes easy, well, come on down with your leaf blower and scoop some up.
Comments (3)
+ TrackBacks (0) | Category: "Me Too" Drugs | Cardiovascular Disease
August 31, 2004
Posted by Derek
As came up in the comments to the previous post, there's not as much price competition inside a given drug category as you'd think. That's not because we're Evil Price Gougers, at least not necessarily. As I was pointed out yesterday, "me-too" type drugs aren't as equivalent as some people think. The main reason we go ahead with a drug in a category where there's already competition is because we think we have some advantage that we can use to gain market share.
This is a constant worry in every drug development effort where there's already a compound out there. I've personally, many times, been in drug project meetings where we've looked at the best competing compound (one that's either already marketed or well into clinical trials) and said "We haven't beaten them yet. We're not going to make it without some kind of unique selling point." The best of those, naturally, would be superior efficacy or a superior safety profile. Then you have easier dosing, fewer interactions with other drugs, and so on. I need to emphasize this: I have seen drug projects killed because no case for an advantage could be made.
Now, there's room to argue about how much better efficacy a drug needs to be a real advance in the field, or at least a bigger seller. You can argue about any of those possible advantages I listed, and it's true that drug companies push some compounds that aren't exactly huge leaps over the previous state of the art. (You see more of that when there's a case of shriveled pipeline in progress.) But there has to be something, and the bigger the difference, the better it is for us. We're motivated, by market forces, to come up with the biggest advances we can. The sales force would much, much rather be out there with data to show that the new drug beats the competition in a clean fight, as opposed to saying that it beats the old one on points, in a subset of patients, if you massage the data enough and squint hard, and besides it tastes better, too. . .
And as I've pointed out before, we often find out things about compounds long after they've reached the market. Lipitor, as discussed yesterday, is a case in point. I have not been a Lipitor fan in the past. The statin field seemed already pretty well served to me (as it did to a number of people inside Warner-Lambert during the drug's development, frankly.) The drug made its way forward based on efficacy in the clinic: it seemed to do a better job lowering cholesterol and improving the LDL/HDL ratio. How much advantage that is in the long term is another question, but those are the best markers we have.
The whole antiinflammatory c-reactive-protein story about the drug only came up after it was already on the market. The marked differences between it and the other statins, which I have to assume at this point are real, are a pleasant surprise to everyone involved. Warner-Lambert (and then Pfizer) thought it was a better compound, but not to this degree or for these reasons, I'l bet. I'd say that this is another argument for having multiple drugs in the same category. We don't, and can't, know everything that they'll do.
Comments (2)
+ TrackBacks (0) | Category: "Me Too" Drugs | Cardiovascular Disease | Clinical Trials | Drug Development | Drug Prices
Posted by Derek
Allow me to get a little defensive. If I understand some of the critics of my industry, we spend most of our time making "me-too" ripoff drugs rather than doing something that provides any clinical benefit to patients. And, if I have this right, here's how we determine efficacy: we run clinical studies until we get the answer we want, and then we bury all the other ones. (Mind you, we bury the data by giving it to the FDA, but stay with me here.)
OK, now let's try to explain this. Merck has just released a study on its statin drug, Zocor. Following in the footsteps of two other studies with Pfizer's statin, the market-leading Lipitor, Merck dosed patients who had just suffered heart attacks. Lipitor treatment seemed to show a real benefit in these situations, lowering the rate of later cardiovascular trouble, and Merck was hoping for (and no doubt expecting) the same thing.
But they were rudely surprised. At the lower doses of Zocor, they failed to show any benefit at all. And at the highest dose, while they managed to show a lower rate of second heart attacks, they still didn't reach significance versus the placebo group. Worst of all, several of the high-doses patients showed the muscle-weakening condition rhabdomyolosis. That's the bane of statin drugs, and the reason why Bayer pulled their compound (Baycol) from the market. (Just to complicate things, one of Merck's placebo patients showed rhabdomyolosis, too, which is food for thought and should give you an idea of how much fun it is to interpret clinical trial data.)
So what's going on here? Zocor and Lipitor both work by inhibiting HMG-CoA reductase. They hit the same mechanism. Were the patients different? The study's authors say it's possible. The patients in the Lipitor studies seem to have been receiving more aggressive therapy in addition to the drug. Are the drugs different? That's possible, too. Lipitor, as it turns out, seems to lower the inflammation marker C-reactive protein much more than Zocor, and that could potentially make a difference.
But if the drugs are really different, what happens to the idea that Lipitor is just a me-too, yet another statin piling on the profits? If we in the industry hadn't kept banging away at these drugs, we wouldn't have ever known that better ones could be found. Would we? As I've pointed out in the past, if you're going to market a drug in a category where the competition is ahead of you, you'd better have some improvement to point at or set about finding one. Lipitor came into the market under the banner of "lower dose / higher efficacy", and it may be picking up more advantages as time goes on.
Now, if we believe that the drugs aren't different, which will be an interesting thing to try to prove at this point, then we have to figure out how much weight to put on this study. How does it go into the Great Clinical Trial Repository? With an asterisk? Then shouldn't the earlier two studies with Lipitor have one, too? This is the same situation I spoke of before.
And what about this clinical trial data in general? Isn't this the sort of bad news that we're supposed to be sweeping under the rug over here? A full article in JAMA complete with vigorous editorial commentary. . .some rug. Oh, and one other thing: those two earlier Lipitor studies that showed a benefit. One of them was from Pfizer(/Pharmacia), as you'd expect. But the other one was from their competition. Bristol-Meyers Squibb has been trying to prove that their statin, Pravachor, is better than Lipitor, and failing. Where's that damn rug when you need it?
Comments (5)
+ TrackBacks (0) | Category: "Me Too" Drugs | Cardiovascular Disease | Clinical Trials
December 18, 2002
Posted by Derek
There were plenty of stories in the press today about the ALLHAT study, which showed that diuretics are still the most effective way to treat hypertension in most people. Let me say right off that I really like this kind of study, and I think that there should be more of them (more on this tomorrow - the Wall Street Journal did the best job covering this angle today.) And I don't disagree with these findings, either - the study seems, as much as I've seen of it, to have been done very well and I think the data speak pretty clearly.
Most of the press coverage has been heavy on the "if not for drug company greed" angle. The New York Times gave this aspect its own story and headline. The critics have a point: pharma companies have aggressively marketed the newer mechanisms as they've come along, both by saying the new ones are good and that the old ones aren't.
But if there's any business that works differently, then I'd like the Times to tell me what it is. Some of the coverage makes it sound like Big Pharma is one large company, and Big Pharma abandoned diuretics in order to blow the horn for its more expensive drugs. But these were individual companies, and the first companies with, say, ACE inhibitors (like Merck) naturally came into the market talking about how great their new drug with the new mechanism of action was. This wasn't Big Pharma talking, this was Merck trying to gain advantage over its competition. Nobody sent around an industry memo saying Drop Diuretics, Push ACE Inhibitors.
And as the ACE inhibitors became wildly successful, other companies got into the field, or decided that they needed to come up with new mechanisms of their own. That's part of the free market, too - we in the pharmaceutical business get forced to come up with new stuff, because the me-too business can only go on so long. (In the case of the ACE inhibitors, it went on longer than usual, because the first generation of them had a dry cough side effect that made people stop taking them.)
You don't hear about many of those other hypertension projects, because they didn't live up to their potential: endothelin converting enzyme, anyone? Renin inhibitors? There were quotes today about all the excess money spent by patients over the years (by not taking diuretics.) The various drug companies who chased these (and other) mechanisms during the 1980s and 1990s would like to have some of that money back, too.
So, once we got them to work, did the drug companies push the newer hypertension medications? Well, yeah, like crazy. That's what we do. But what we do includes the "new" part as well as the "push" part of that sentence. (The "crazy" part is another subject!)
A couple of other points: the main Times story waits until paragraph 26 to mention that there were other factors other than the Greed of Big Pharma for the move away from diuretics:
A factor in the switch from use of diuretics to newer drugs was a Swedish study reported in The New England Journal of Medicine in 1989. It found that diuretics could cause biochemical changes that were thought to increase susceptibility to heart attacks.
The other thing I'd like to mention is that some of the figures given for market share of diuretics make them seem more ignored than they are. The Wall Street Journal ran a pie chart, but it's done by dollar sales. Because the diuretics are cheaper, they don't make nearly as much impact in that sort of presentation. The Times ran a better graphic showing total number of prescriptions, and there's some interesting stuff there:
While it's true that diuretics only have about 27% of the total number of prescriptions for hypertension, they outdid ACE inhibitors every year until 2001. And they've beaten calcium-channel blockers (another big part of the ALLHAT study) every year, because those drugs, heavily marketed though they are, have only grown 3% in prescription volume since 1997. ACE inhibitor scrips have been up 39% in that period - and diuretics, with virtually no advertising, have been up 29%. Maybe Big Pharma isn't getting as much bang-for-the-buck as it could with all those marketing campaigns (and maybe physicians are doing a better job exercising their judgment than today's coverage gives them credit for.)
(Post edited next morning for clarity, emphasis, and to correct late-night typos.)
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September 8, 2002
Posted by Derek
There's an interesting interview up at Business Week's site with Anthony Ford-Hutchinson, a Merck research honcho. Much of the interview is routine: "How's the new drug for XYZ coming along?" "Why, just fine!" But he does get in a few good cuts:
Q: How would you describe the culture of Merck's research and development?
A:" If you look at Pfizer's annual report and compare it to Merck's, theirs says something about wanting to be the most valued company in the world, whereas Merck's talks mainly about curing diseases."
That's the sound of a catapult in Rahway unloading a bag of overripe Jersey tomatoes in the direction of Groton. He goes on to say that "we don't go after the Nexiums and Clarinexes of the world." I have to applaud that sentiment, and I'm glad to hear someone say it out loud. But I have to note that Merck is coming along with a follow-up COX-2 inhibitor to bring up the slack behind Vioxx. . .I also note that that's a slam against Merck's current development buddy, Schering-Plough, which takes some nerve.
As for merging, he sticks with the Merck line of "no way." Some of his comments really make him sound like my soul brother:
" . . .every time you see a big drug merger, the research at those two companies grinds to a halt. Everybody starts worrying about their jobs. . . "
". . .the research can easily get screwed up when two companies merge. I think the effects of this may not be so apparent right away, but a decade from now the effects will undoubtedly be apparent."
All I can say to that is "Preach it!" Let's hope that we're all doing well enough in ten years to see who's right.
As an aside, if I ever form my own company, it's going to be hard to resist the temptation to have official titles like "research honcho" or "exalted pooh-bah." Maybe if one of my colleagues gets his drug company off the ground, he can use those. Right now, all he has is an evocative name, considering the genomics era. He wants to call it "InVivogen," and I can see the point!
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July 28, 2002
Posted by Derek
Another question I've had posed to me is whether the FDA standards for drug approval are too tight (no one who writes to me seems to worry that they might be too loose, although you can find groups who'd argue just that.)
Overall, I don't think so. There are really two sets of standards, for safety and for efficacy, and neither are really set in stone. From drug to drug and disease to disease, things can slide around - which is how it should be. Safety is an open-ended problem that has to be addressed by closed-ended regulatory solutions, and as time goes one, the bar is raised. We know a lot more that we used to about, say, QT-interval prolongation as a cardiac side effect, and that means that we have to test for it instead of crossing our fingers. If this weren't getting harder, neither the drug companies nor the FDA would be doing their jobs.
As for efficacy, I see the suggestion every so often that this requirement be done away with. I'm firmly opposed to that idea. It would open the door to even more Miraculous Herbal Tonics than we have already - all you'd need to do to get past the safety requirement is make sure your snake-oil doesn't have anything active in it. Honestly, you'd have people springing up selling powdered drink mix at $5 the glass to cleanse your liver, grow new hair, and make your genitalia go out in the morning and fetch the newspaper. What? You say we have that already? Well, now they'd be "FDA-approved" on top of it.
No, I'm all for making companies show that their drugs actually do something. In fact, I'm all for making sure that any medicine entering a served market is tested head-to-head with the competition. Of course, this is often mandated already. And companies often do it themselves so they'll have an edge in marketing - exceptwhen it's a patent extension of one of their own drugs. As I mentioned a while back, I'd make Astra-Zeneca test Nexium against Prilosec, for example, and we'd see who's fooling whom.
There's no doubt that the FDA's gotten pickier in the last couple of years, and all of us in the industry are feeling it. But it hasn't gotten to the point where I think they're stepping over the line.
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June 6, 2002
Posted by Derek
As readers will have noted in my comments on drugs like Clarinex and Nexium, I certainly don't think the industry I work in is always a one-hundred-percent benefactor of humanity. Drug companies are here to make money, and (like any business) they're trying to make the most money they can, consistent with their tolerance for the chance of losing it.
The much-written-about report on innovation in the drug industry (PDF here) turned out, on inspection, to be much less confrontational than I had feared. The authors point out, correctly, that pharmaceutical companies are reacting rationally to their environment. Big, money-making drugs are coming off patent, and not enough new ones have been discovered in the last few years to take up the slack. Therefore, the companies will do whatever they can think of to keep the profits coming in for as long as possible.
That includes stepping up the marketing campaigns for what drugs they have. It includes ripping off their own expiring profit center drugs (as in the two mentioned above,) and doing whatever they can to get patients to ask for them and physicians to write for them. And that includes all sorts of schemes to delay generic competition. Some of them are bare-knuckled, but within the letter of the law (fighting patent claims.) Some are apparently legal, but have a certain shady aura around them (such as paying generic companies to go away.) And still others, like this accusation against Bristol-Meyers Squibb, are (if true) flat-out illegal.
It's capitalism in action, and it's not always - not even usually - a pretty sight. The same sorts of things go on in every other industry, in any number of variations. I think the same thing about individual economic competition, for that matter. One reason I like capitalism better than the other schemes that have sought to supplant it is that it seems to me to line up more closely with human nature. Not an original thought, but its validity is why it's so well known.
People are going to act in their own interest, to serve what they see as their needs and desires. You can't get rid of it, so you might as well set things up so they do some good while they're at it. Wouldn't it be more efficient if everyone worked that hard for the common good, though? Sure! Should some other zoological phylum develop intelligence, maybe they can give it a try. We, as far as I can tell, are wired for what we're doing.
And so are companies. Wouldn't it be more efficient if all of us in the drug industry just stopped trying to outdo each other? Open up the labs, put all our compounds in one gigantic screening file, pool our efforts? Well. . .it's a tempting idea, in some ways. But what keeps us going is the competition, the knowledge that (like the sharks we are,) that we have to keep moving or die. I fear that a Monolithic MegaPharm would become so bureaucratized and lethargic that whatever good came of getting larger would be more than canceled out. Some of the large merged companies we have now are showing signs of this disease as we speak.
Knowing that other people are working on the same targets keeps us moving. The ticking clock of patent expirations, the arm-wrestling with the regulatory agencies, the demands of shareholders keep us moving. I think the best thing to do would be to, again, arrange it so that the maximum amount of good gets done while we're out there pursuing our own agendas.
That means that I wouldn't, frankly, object to making it harder to put drugs like Clarinex, Nexium and so on on the market. If I were the FDA, I'd raise the bar in such cases for advantageous efficacy, and if I were an HMO, I'd raise it for what I'd reimburse. But at the same time, I'd make it easier to find and sell new drugs, so there would be less incentive for all these activities that don't lead to any real benefit. Faster regulatory approval, no method-of-treatment patent claims, more incentives like the orphan drug designation, some sort of tort reform: all these would help.
It boggles the mind, the amount of effort and ingenuity pulsing through a high-tech area like pharmaceuticals. But political grandstanding about the evil drug companies, schemes to clamp down good and hard on them: these could wipe out the crazy risk-taking that's at the heart of the industry. Whack the ones that get out of line, sure. But while you're doing that, set the system up so that we can whack on each other with even more ferocity than ever. That's where the good stuff comes from.
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May 30, 2002
Posted by Derek
Yesterday's report on pharmaceutical cost and innovation got a lot of play in the media, including the ABC special last night (which I didn't see much of.) I'm of two minds about it: there's some truth in it, but there are important things that it misses.
Companies will do everything they can think of to hold on to a lucrative market. It needs, as Shakespeare said, no ghost come from the grave to tell us this. Drug companies exist to make money, and this is a way to make money. Legal maneuvers to extend the patent life and make things difficult for generic companies are one strategy; internal me-too drugs are another.
As my May 2 post on Claritin and Clarinex shows, I believe that the industry does come up with drugs that have few (if any) advantages over their predecessors. Nexium vs. Prilosec is another example of this, as far as I can tell. Both these are largely designed to replace drugs that the companies already had which are going off-patent.
But the "me-too" label gets thrown around a bit too liberally when it comes to competition between companies. I can tell you, from personal experience, that for a serious R&D effort to be mounted, a project simply has to have some advantage versus the competition. I've never seen a project start off by saying "We're going to make the exact same thing as those guys did, and make up the difference with a huge ad campaign." Huge ad campaigns work better with something to hang them on.
The complexities of pharmacology give you plenty of chances to have differences between drugs that (in theory) might well work the same. Companies try to develop and promote those differences. If the combined size of the total market and the space for differentiation is large enough, you can have several companies piling into the same field, fighting it out.
That could be just plain old better efficacy, as Lipitor seems to have in the crowded field of cholesterol-lowering statins. It could be once-a-day dosing versus after-meals, fewer side effects, or fewer interactions with other drugs. It could be plain old lower price, too: the uncertainties of clinical development make it risky to start a project based on that alone, but it can come up by the end of the project. Ciba-Geigy (now Novartis) tried that with one of their statins a few years back, to pick one from the same area.
That's the free market, and may the best compounds win. Sometimes the differences that are promoted may not be enough to justify a new drug's existence, though. This happens (in my experience) along the way in the development process, when the plan for a bigger market advantage doesn't work out in the clinic. Ideally, such drugs wouldn't fly in the marketplace, but companies will sometimes try to make them take off anyway.
Physicians can feel stampeded when their patents come in asking for a new drug that they don't think is worth the cost. If they don't write for it, they think, someone else will. What we're seeing now, though, is a reluctance for managed-care plans to pay for some of these, a decision which is certainly their right to make. HMOs get to have their free-market fistfights, as well.
As for the general question of innovation, I can tell you that no company tries to make a living from just hopping into crowded fields where there's already competition. You have to innovate to survive. On the flip side, trying to break absolutely new ground every time out is a risky strategy, too, given the failure rate and the expenses involved. We can argue all day about just how much it takes to develop a new drug, but if you're the first-in-class in a new area, it's going to cost you more. But the potential payoff is bigger, too - you can have some real fun calculating the risk/reward, especially since some of the key numbers are impossible to truly quantify.
I'd also like to see a study like yesterday's address what happens to some of the groundbreaking drugs that they cite favorably. For example, they mention Avandia and Actos (rosiglitazone and pioglitazone) for diabetes in the category. Leave aside the fact that these two drugs work via almost identical mechanisms (with some slight differences, which the companies are, as per the above, trying to exploit.) And leave aside that they were developed at the same exact time, in sull knowledge that they'd be going head-to-head in the marketplace (which one was the me-too, if either one was?)
No, what I'd like to point out is that these innovative therapies weren't the first in that class. That would be Rezulin (troglitazone.) That was absolutely the first drug on the market to work by that mechanism, and the first to do what these compounds do for diabetes. Avandia and Actos were expected to have to go out and dethrone it; that's what the companies planned for. But Rezulin went down in flames due to toxicity, which only showed up when it got into a broad patient population. The lawsuits are still flying. If it had made it, then the other two drugs would surely be cited as more of those nasty, money-grubbing me-toos.
Where's that one in the sound bites about "nothing new in the drug industry"? The money spent to develop and market Rezulin is gone, and it's not coming back. Lots more is going to vanish, is vanishing right now, going to plaintiffs and lawyers. How do we make up for that?
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May 6, 2002
Posted by Derek
I get a lot of Google search hits about those two drugs, so I thought I'd give the public what it wants. I've mentioned that I still hold some Schering-Plough stock (dog though it's been recently,) and I'm about to do my holdings some minor amount of further harm.
That's because, frankly I don't think very much of Clarinex. I've already written (on March 10) about Sepracor and their role in its development. Fitting in with their business plan, Clarinex is another active-metabolite drug idea.
As I've been mentioning in connection with all the acrylamide business, the liver does a fine job ripping up organic compounds. Most of these altered compounds don't do much except go sluicing out the kidneys, but some of them are active. As it happens, Claritin has one main metabolite, and it still has the antihistamine effect that Claritin itself has. (This situation is becoming less frequent, by the way, since the FDA has come more and more to frown on active metabolites in general. Your regulatory path will be simpler now if you don't have any.)
And it's not an exotic transformation, either. For the organic chemists in the audience, it's loss of an ethyl N-carbamate group, down to the NH. Looking at the structure of Claritin, this is the absolute first thing that any competent medicinal chemist would predict as a main metabolite, and so it is.
That means that if you've taken Claritin, you've taken Clarinex. You starting taking it about twenty minutes after you swallowed the Claritin, when that dose started going through the hepatic portal vein and into your liver. It also means that the synthesis of the compound is essentially identical to Claritin, with really only a one-step difference to change the amine.
And, unfortunately, it also means that Clarinex is one of the more blatant me-too drugs out there, this time an internal one. I can't blame Schering, actually. It was clear for years that they'd need something to take up the slack of the Claritin franchise, and there have been some very good shots taken at that in several therapeutic areas. But none of them have paid off yet, and the company decided to do whatever it took to keep a revenue stream coming in. The other choice was virtuous penury, culminating in firing employees who are now occupied, instead, with finding something more useful. It's hard to see that as a better path.
But that still doesn't make Clarinex any better as a drug. I haven't gone over all the clinical data, but I find it hard to imagine that there's any particular advantage over Claritin. And if perchance there is, I find it hard to imagine that it's worth the price disparity versus (generic) Claritin. I may get some feedback setting me straight on this, but it'll have to be pretty convincing to change my mind.
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