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: email@example.com
August 28, 2009
I wrote years ago on this blog about REACH, the European program to (as the acronym has it) Register, Evaluate, Authorize and Restrict Chemical substances. (I'm not sure where that second R got off to in there). This is a massive effort to do a sort of catch-up for chemicals that were introduced before modern regulatory regimes, and it involves fresh toxicological investigations and an absolute blizzard of paperwork. This program was launched in 2006, after years of wrangling, and the last few years have been spent in yet more wrangling about its implementation.
The worried voices are getting louder. Thomas Hartung (a toxicologist at Johns Hopkins and the University of Konstanz) and his co-author, Italian chemist Costanza Rovida, now say that the program is heading off the cliff. (Their full report is here as a PDF). In Nature, the authors have a commentary that summarizes their findings. They estimate that around 68,000 chemical substances will fall under the program, and when they run the numbers on how those will need to be tested, well. . .
"Our results suggest that generating data to comply with REACH will require 54 million vertebrate animals and cost 9.5 billion Euros over the next 10 years. This is 20 times more animals and 6 times the costs of the official estimates. By comparison, some 90,000 animals are currently used every year for testing new chemicals in Europe, costing the industry some 60 million Euros per year. Without a major investment into high-throughput methodologies, the feasibility of the programme is under threat — especially given that our calculations represent a best-case scenario. In 15 months' time, industry has to submit existing toxicity data and animal-testing plans for the first of three groups of old chemicals."
These are staggering numbers. There are not enough labs, not enough toxicologists, and not enough rats (well, usable rats) in Europe to even come close to realizing such an effort. It turns out that the biggest expense, on both the animal and money counts, is reproductive toxicity testing, which is apparently being mandated into the second generation of rodents. That works out to an average of 3,200 rats sacrificed per chemical evaluated, so you can see how things get out of hand. The authors are calling for an immediate re-evaluation of the reproductive toxicity testing protocols, arguing that the cost/benefit ratio is wildly out of whack, and that the rate of false positives (especially involving second-generation studies) is high enough to end up scaring a lot of people for no sound reason at all.
I'm absolutely with them on this. The program seems like one of these "No cost is too high for absolute safety" ideas that make politicians and regulators happy, but don't do nearly as much good for society as you'd think. (It's worth noting that Hartung and Rovida actually support the idea of REACH, but think that its implementation has gone off the rails). One beneficial side effect, as the authors mention, is that the whole mess will probably end up advancing the state of the art in toxicology a good deal, partly in ways to figure out how to avoid the coming debacle.
Not suprisingly, the European Chemicals Agency is disputing the study, saying that they don't anticipate the numbers of chemicals registered (or the costs associated with studying them) to differ much from their estimates. If I can suggest it, though, I would like to mention that the history of large regulatory programs in general does not provide much support for that optimistic forecast. At all. To put it in the mildest possible terms. We'll see who's right, though, won't we?
+ TrackBacks (0) | Category: Regulatory Affairs | Toxicology
August 27, 2009
Here's an interesting paper that some of you may have seen in J. Med. Chem.: "Heteroaromatic Rings of the Future". That's an odd title, but an appropriate one.
For the non-chemists in the crowd who made it to this paragraph, heteroaromatic rings are a very wide class of organic compounds. They're flat cyclic structures with one or more nitrogen, oxygen, or sulfur atoms in the ring - I'll leave out explaining the concept of "aromaticity" for now, but suffice it to say that it makes them flat and gives them some other distinct properties. These structures are especially important in medicinal chemistry. If you stripped out all the drugs that contain something from this class, you'd lose a bit under half of the current pharmacopoeia, and that share has lately been increasing.
The authors have sat down and attempted to work out computationally all the possible heteroaromatic systems. If you include a carbonyl group as a component of the ring, you get 23,895 different scaffolds (and only 2986 if you leave the carbonyl out of it). Their methods to define and predict that adjective "possible" are extensive and worth reading if you're curious; they did put a lot of effort into that question, and their assumptions seem realistic to me. (For example, right off, they only considered mono- and bicyclic systems, 5- and 6-membered only, C, H, N, O and S).
At any rate, only 1701 of those 23,985 have ever been reported in the literature. And it looks as if reports of new ring systems reached a peak in the late 1970s, and have either dropped off or (at the very least) never exceeded those heights since then. The authors estimate that perhaps 3,000 of their list are synthetically feasible, with a few hundred of them being notably more likely than the rest. Their paper, in fact, seems to be a brief to alter that publication trend by explicitly pointing out unexplored synthetic territory. It wouldn't surprise me if they go back in a few years to see if they were able to cause an inflection point.
I hope they do. I'm a great believer in the idea that we medicinal chemists need all the help we can get, and if there are reasonable ring systems out there that we're not exploiting, then we should get to them. Adventurous chemists should have a look.
+ TrackBacks (0) | Category: Chemical News | Drug Industry History | The Scientific Literature
August 26, 2009
So, if you're a patient with a rare disease (or a relative of a patient with one), and you have an idea for repurposing an old drug for treatment. . .and you get a company interested, and it actually works. . .works to the point that the company takes in a billion or two dollars a year. . .what then?
Some readers will have guessed that I'm talking about thalidomide and Celgene, and right they are. Beth Jacobsen is the person involved - her husband died of multiple myeloma, but her medical sleuthing had turned up the idea of using thalidomide as a therapy for the disease, and she kept up the pressure to have the idea tried out. Celgene's mentioned her in annual reports, and she's been thanked by name in a publication on the clinical results.
But now she's suing Celgene, saying that they misappropriated her idea. Complicating the issue is the question of whether the late Judah Folkman was really the source of the inspiration, in a phone conversation with Jacobsen (earlier versions of the story have it that way, but the lawsuit apparently tells it differently). Which way did it happen? Is Jacobsen indeed owed compensation? And whether she is or not, will she be able to convince a court? Matt Herper has the story at Forbes.
I'll defer my own comments until I know a bit more about the case, but this is definitely an interesting one. I can add something that might be of relevance, though: a search in PubMed for "thalidomide myeloma" turns up 64 pages of references, almost all of them post-1999. But there is this one, from Italy in 1963. Has the idea been around for that long? Someone who can track down that journal can tell us. . .
+ TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History | Patents and IP
Ariad's trek through the legal system has not yet ended! This story has been running for years now - I think the original lawsuit was filed in 2002. Back in the spring, a decision by the Court of Appeals for the Federal Circuit reversed a Massachusetts District Court ruling in Ariad v. Eli Lilly. That decision invalidated a lot of Ariad's key patent claims regarding the Nf-kB signaling pathway, and some of us thought (well, I did) that this would be the end of the story.
But no, Ariad filed a petition in June (PDF) for a rehearing, and that has now been granted. So this fall, the decision will be revisited. It looks like this time, though, the question will not be decided so much on the science and history of Nf-kB, but on a question of patentability.
There are several requirements to get a patent, of course, novelty and utility being the first big ones. You also have to have a complete written description of the invention, and (if you want your claims to stand up) you're going to want to enable them - that is, actually show that you can do what you say, and prove that you have. For pharmaceuticals, that means you need to make real compounds, show physical data for them sufficient to prove that you've made them, and (if you're claiming their effects) show that they do what you're claiming they can do.
The Ariad v. Eli Lilly decision in April turned on written description. Basically, the court held that the company had not described any molecules that could do the vast numbers of things the claims staked out. There was a 1997 case (also, oddly enough, involving Lilly) that raised the standard in that area, and the famous University of Rochester v. G. D. Searle case (COX-2 inhibitors) was decided by applying the same standard. There's been a lot of controversy about the 1997 ruling, though, with many people complaining that the court sort of superglued a tougher written description requirement onto the existing patent law. Ariad has invited the CAFC to take this opportunity to clear things up. That's probably a good thing, since this issue was going to have to be resolved at some point, but it pains me to see Ariad's ridiculous patent case be the means for this.
Personally, I think that Ariad's claims could be tossed by considering the enablement requirement, rather than just written description. (If you think that they didn't do a sufficient job of describing what they wanted to claim, you should see how they reduced it to practice). Here's a post that agrees with that view, and goes into much more detail. It appears, though, that the courts haven't yet come up with a good way to use enablement to chop humungous patent claims down to size. Perhaps this will eventually happen, and the whole written-description era will come to seem like a detour.
I suppose we'll be returning to this issue something this coming winter. Until then, Ariad's patent walks the earth still.
+ TrackBacks (0) | Category: Patents and IP
August 25, 2009
As some of you may know, there's a big patent dispute between Novartis and the government of India. The issue is Gleevec (imatinib, sold as Glivec in most of the rest of the world - Novartis must have figured that it would have been pronounced "Gly-veck" over here). The product is sold as a mesylate salt, and in fact, as a particular polymorph of that mesylate salt, and there's the problem.
For those outside the business, most drugs have either acidic or basic groups on them, and you can make a salt of them by combining them with a corresponding base or acid. Basic drugs - amines, mostly - are often sold as hydrochloride, mesylate, citrate, etc. salts, and acidic drugs are often sodium, potassium, calcium, etc. salts. These changes are usually done to make a compound absorb better when it's dosed and/or to make it easier to handle or more stable during manufacturing and storage.
Polymorphs, meanwhile, are different crystalline forms of the same compound. That's something that you don't encounter much outside a chemistry lab. The closest everyday analog is to think of table salt vs. kosher salt vs. sea salt, but those are still the same crystal-packing form when you get right down to it. A real polymorph is quite a different beast; it's as if you could dissolve up regular salt, cool it down in some tricky way, and have it crystallize out as needles or prisms instead of tiny cubes. And those needles or prisms might then, as it happens, refuse to dissolve if you added them to your soup. That's a polymorph, and it's a pretty common occurrence with drug substances. A key step in a real manufacturing process is making sure that you have the best one, and that you can always be sure that it's the one being produced. The wrong one will do things like refuse to dissolve into the bloodstream, which can be most unfortunate.
So Gleevec is a particular polymorph of a particular salt, and Novartis has patents on just that form in many countries. But not India, or not yet. As this post from a lawyer there details, the dispute is (to a large extent) about whether this form of the drug should be compared to another polymorph, to another salt, or to the original free base compound when time comes to judge its novelty and patentability. Another question is whether Novartis's previous patent filings disclose or anticipate the particular salt and polymorph form of the final compound. These arguments are complicated by the fact that India didn't even allow patents on pharmaceutical substances until a few years ago. For more on recent drug company patent disputes there, see this from the WSJ.
So I'd like to throw a question out to the readership: how many examples can people think of where a particular salt or polymorph was a key to getting good efficacy or properties for a drug? I realize that a lot of these stories never see the light of day - I've seen polymorph problems give people fits during development, as have many readers, I'm sure, but most of these things never get published. So I'm not asking for anything from the inside, just the publicly known examples.
Update: if you want a good indicator of how serious the IP issues are around these things, check out this conference. . .
+ TrackBacks (0) | Category: Drug Development | Patents and IP
August 24, 2009
Eli Lilly announced some bad news last week when they dropped arzoxifene, a once-promising osteoporosis treatment (and successor to Evista (raloxifene), which has been one of the company's big successes).
If this drug had been found ten or fifteen years ago, it might have made it though. But the trial data showed that while it made its primary endpoints (reducing vertebral fractures, for example), it missed several secondary ones (such as, well, non-vertebral fractures). And the side effect profile wasn't good, either. That combination meant that the drug was going to face at hard time at the FDA for starters, and even if it somehow got through, it would face a hard time competing with generic Fosamax (and Lilly's own Evista).
So down it went, and it sound like the right decision to make. Unfortunately, given the complexities of estrogen receptor signaling, the clinic is the only place that you can find out about such things. And there are no short, inexpensive clinical trials in osteoporosis, so the company had to run one of the big, expensive ones only to find out that arzoxifene didn't quite measure up. That's why this is a territory for the deep-pocketed, or (at the very least) for those who hope to do a deal with them at the first opportunity.
One more point is worth emphasizing. Take a look at the structures of the two compounds (from those Wikipedia links in the first paragraph). Pretty darn similar, aren't they? Arzoxifene is clearly a follow-up drug in every way - modified a bit here and there, but absolutely in the same family. A "me-too" drug, in other words, an attempt to come up with something that works similarly but sands off some of the rough edges of the previous compound. But anyone who thinks that development of a follow-up compound is easy - and a lot of people outside the industry do - should consider what happened to this one.
+ TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | Drug Development | Toxicology
August 21, 2009
Here's an interesting post at Chemiotics (a new addition to the blogroll): Something is Wrong With the Model
. . . The Center for Disease Control released new data for 2007 (based on 90% of all USA death certificiates) showing that mortality rates dropped again (by over 2%) to 760/100,000 population. It’s been dropping for the past 8 years, and viewed longer term is half of what it was 60 years ago. Interestingly death rates from heart disease dropped a staggering 5% and even cancer dropped 2%.
But the populace is fat and getting fatter. . .
The heart disease death rate is particularly interesting. One explanation, which we can't rule out, is that these improvements are due to other factors (which the post goes on to elaborate), and that the improvement would be even more impressive if everyone weren't packing on the pounds. Another possibility is that excess weight, up to a point, may not have as big an effect on mortality and morbidity as we've been thinking it does.
That's a real possibility, and it's been looked at in the context of these sorts of public heath figures. The current use of BMI, at the very least, doesn't seem to be that useful in that regard. Only the high end of the BMI envelope (>30) seems to show much of a meaningful health effect. Of course, there are other costs to being obese, but (up to a point) bad health may not be one of the major ones. As for what this means to the current health care proposals, you can go here for the arguing.
+ TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs
August 20, 2009
It's hard to think of a more important class of drug targets than the G-protein coupled receptors (GPCRS). And back about fifteen years ago, I thought I had a reasonable understanding of how they worked. I was quite wrong, even given the standards of knowledge at the time, but since then the GPCR world has become gradually crazier and crazier.
The classic way of thinking about these receptors is that they live up on the cell surface, with part of the protein on the outside and part on the inside. The inside face is associated with various G-proteins, and the outside face has a binding site for some sort of signaling molecule. If the right molecule shows up and slots in the correct way into this binding cavity, the transmembrane helices of the protein rearrange, sliding around to change the shape and binding properties down there at the G-protein interface. This sets off some intracellular messaging - often by affecting levels of the messenger molecule cyclic-AMP. Thus is a signal from outside the cell relayed through the membrane to the inside.
Pretty nearly makes sense, doesn't it? Well, take a look at this new report from PLoS Biology. The authors rigged up living cells with a built-in fluorescent sensor system to monitor cAMP, and then studied the behavior of the thyroid-stimulating-hormone (TSH) receptor. That's a perfectly reasonable protein-ligand GPCR, but it turns out that it does things that are not (to us) perfectly reasonable.
This paper shows that when a TSH molecule binds, that the receptor gets taken back down through the membrane into the cell. That's certainly a known process (internalization), and was thought to be a regulatory process, a standard method for taking a specific GPCR out of the signaling business. Some receptors seem to do this right after they're used, and of those, some of them later resurface and some are broken up. (Other types hang around for many cycles until they're somehow worn out). But the ones that internalize quickly still set off their intracellular message before they get pulled back down. That's their purpose in life.
TSH does that. But the weird part is that the authors saw the receptor internalize along with its G-protein partners, and then continue signaling from inside the cell. Not only that, this extra signaling behavior set off somewhat different responses as compared to the first "normal" burst, and seems to be a necessary part of the usual TSH signaling pathway. It's a very odd thought, if you're used to thinking about GPCRs - it's like finding out that your cell phone works when it's turned off.
Now this sort of behavior has been demonstrated for a different class of signaling proteins (the tyrosine kinase receptors). And even GPCRs have been found, over the last few years, to be capable of setting off a different signaling regime (the MAP kinase pathway) after they've been internalized. (That's one of the weird findings of recent years that I mentioned in the introductory paragraph, and we still don't know what to do with that one as far as drug discovery goes). But everyone agreed that at least the good ol' cyclic AMP pathway worked the way we thought it did, through signaling at the cell surface, and thank goodness there was something you could still count on in this world.
Hah. Now we're going to have to see how many other GPCRs show this kind of behavior, and under what circumstances, and why. It may well turn out to be different for different cells or for different signaling ligands, or only occur under certain conditions. And we'll have to see how this relates to the other strange things that are being unraveled about GPCR behavior - they way that they can dimerize, with themselves or even other receptors, out on the cell surface, and the way that some of them seem to work in an opposite-sign signaling regime (always on, until something turns them off). Do these things still signal from beneath the waves, too?
Oh, this will keep the receptor folks busy, as if they weren't already. And, as usual when something like this shows up, it should serve as a reminder to anyone who thinks that we understand even the well-worked-out parts of cell biology. Hah!
+ TrackBacks (0) | Category: Biological News
August 19, 2009
Many of you may have looked at the short bio on the left-hand side of the site and wondered where the heck Hendrix College is. To my surprise, I opened up the New York Times today and found this article, which is surely the most coverage the school has ever received from them. (No science or chemistry connection in the article, though).
Last year I saluted Warfield Teague, my now-retired inorganic chem professor there, and I've mentioned the school's (in)famous organic professor, Tom Goodwin, several times (most recently here).
+ TrackBacks (0) | Category: Blog Housekeeping
There's an interesting article up over at InVivoBlog, and I wanted to see what the readership here thought of its main premise. Subtracting out the cute ecological analogies (Big Pharma as polar bears, for example), you get to this:
. . .For example, AstraZeneca, Novartis, and Bristol-Myers, all operate in the fields of neuroscience, oncology, and cardiovascular health. While some pharmas involve themselves in nutritionals, animal health, infectious disease, and other fields, all of these companies also engage with a mixing pot of therapeutic areas.
The relative strategic uniformity isn’t generally the case with the leading companies in other industries. In the high-tech industry, for example, there is a much higher level of specialization. Google is mainly in the advertising business; Microsoft, software; Research in Motion, in wireless solutions. You aren’t likely to see Facebook manufacturing semiconductors any time soon. (Yes we are aware of Microsoft’s Bing search engine and the new Google Chrome OS, but still.)
It is likely that health care businesses will evolve in a similar fashion. The leaders of the future will be those with unique and complex models which sub-speciate into differentiated forms. Companies will focus nearly all of their efforts on a single therapeutic area, becoming “immunology companies” or “cancer companies”. These companies will also become more integrated across sectors. A cardiology company will sell diagnostics, devices, and therapeutics pertaining to cardiovascular health.
I'm not so sure, myself. I can see reasons for this to happen, but I can also see forces that will pull in other directions. For one thing, I'm not sure if there are enough targets in some of these therapeutic areas to keep even a medium-sized company running. The host-of-smaller-companies model, each of them trying to hit it big, seems like a better fit, as long as they can share an ecosystem (there I go, too) with the larger deep-pocketed multi-area players.
Another problem is that I think the barriers to, say, a cardiovascular drug company becoming also a cardiovascular device company are higher than the ones to it becoming a cardiovascular-and-diabetes drug company. Moving into another drug discovery area at least lets you use some of your existing staff and resources, while heading out into diagnostics or devices will probably take you into territory that you don't know so well.
And besides, I think that the analogy with other industries doesn't hold up very well. The authors list off a few software and hardware companies, but don't Google and Microsoft have their hands in a lot of different areas? And have car makers (domestic or foreign) settled down into making only SUVs, only pickup trucks, or only sedans? Not that I've seen. Know of any movie studios making nothing but adventures or romantic comedies? Or any grocery chains that only sell vegetables, but not fruit?
In all those cases, the existing infrastructure lets such companies expand, at relatively lower cost, into related areas that will diversify their customer base. Medical devices and diagnostics may look like a similar situation, but I really don't think it is.
+ TrackBacks (0) | Category: Business and Markets | Drug Industry History
I'm not always a fan of John Boehner, but I think he's on the right track with his letter to Billy Tauzin (PDF here from NPR's health care site). I understand that line about how in Washington, if you're not at the table you're on the menu. And I understand how the industry wants to get into the middle of the whole process to try to protect its interests. I just don't think that cutting this kind of deal is, in the end, doing that. And apparently Boehner agrees:
The Obama Administration tacitly acknowledged last week that the President will not be bound by the $80 billion limit PhRMA and its board of directors were led to believe had been secured in exchange for your organization's support of the Administration's health care takeover, and key Democrats in Congress, including Speaker Nancy Pelosi (D-CA) and Energy & Commerce Committee Chairman Henry Waxman (D-CA) have said explicitly they will not honor the agreement. In other words, now that the deal is publicly known and would be messy for your to reverse, Big Government is now changing the terms. . .because it can.
Boehner goes on to say that Tauzin will surely "object to this letter and quarrel with its premise", which I think is a pretty sure bet. But stripped of the boilerplate that's found in the rest of it, I find that I agree with its key point very much, as stated above. I don't think that it's possible to do a PhRMA-style deal with an entity like the federal government. Because, you know, they can always change their minds, and what possible recourse do you have then?
Update: Yes, of course Boehner is a political opponent of President Obama, and has interests beyond purely philosophical ones in scuppering some of his grander plans. Both Boehner and Obama make me grit my teeth when I hear them talk about this issue, to tell you the truth, and boy howdy, there are plenty of other people in that category with them. And I realize that when I start talking politics, that many readers start to grit their own teeth in response.
Fear not, this is not going to turn into a political blog. But it's always been concerned with the drug industry, how it does what it does, and what its future might be. The current efforts at health care reform could well have an impact on these things, to put it delicately, so the topic has to come up. My free-market biases are pretty well known, though, so some readers may be able to save time by just skipping over what I write about it on the grounds that they probably have a good idea of what I'll have to say. I wouldn't blame anyone for doing that; vita brevis est. And I promise to not have the issue take over the site - I don't want to be a political blogger, either, really. . .
+ TrackBacks (0) | Category: Current Events | Drug Prices | Regulatory Affairs
August 18, 2009
I was going to put up another post here at lunchtime, but they've been tearing up the street or something right outside my building all morning. It's like a gigantic dental drill is trying to break in here - my desk vibrates. I've hardly had two sequential thoughts all morning - any more of this, and I'll be fit to be a managerial consultant.
+ TrackBacks (0) | Category: Blog Housekeeping
I see that there's a serious effort underway to standardize biochemical diagrams. About time! As a chemist, I don't mind admitting that I've been confused by many of these things over the years. As the current task force points out, one reason for that is that there are too many processes that all get drawn the same way: with a curved arrow. Enzymatic cleavage? Allosteric regulation? Product inhibition? Nucleic acid splicing? Enzyme activation? A curvy arrow should do nicely. And if the same scheme includes several of those phenomena at once, then we'll just use more arrows, making sure, of course, that they're all exactly the same size and style.
The new proposal seems to be based on the ideas behind electrical circuit diagrams and flow-chart conventions, and will attempt to convey information through several means (box shapes, arrow styles, etc.) I hope it, or something like it, actually catches on, although it'll take me a while to get used to translating it. Actually, what will take a while is getting used to the idea that biological diagrams are supposed to be imparting information at all. I've been trained in the other direction for too long.
+ TrackBacks (0) | Category: Biological News
August 17, 2009
Now for a bit on the pharma industry and the current fight over health care legislation. Does the industry want a new system to come into force, or not?
Depends on what that new system is, of course. But the industry is naturally trying to make sure that it has a hand in whatever passes. And here we come to a meeting of political interests. The administration would also prefer not to have the drug industry actively working against it, since drug companies have a lot of money to use for such purposes. Therefore, as anyone who knows politics could have predicted, a deal has been struck.
Or has it? As everyone has heard by now, Billy Tauzin, head of the industry's largest association (PhRMA), said that an understanding had been reached with Max Baucus of the Senate Finance Committee, with the approval of the White House. The industry would agree to come up with 80 billion dollars of savings, and the administration would then consider them to have done their part. More specifically, there would be no more talk of price negotiations for Medicare-approved drugs, of drug reimportation, or rebates for drugs prescribed to joint Medicare/Medicaid patients. The industry would also agree to support the new health plan by running ads (and, no doubt, by lobbying behind the scenes). Come, let us reason together.
It doesn't surprise me at all that such a quid pro quo would be worked out in advance - that's exactly how politics gets done. But what amazed me was that Tauzin would go around telling people. Predictably, many of the other players are now complaining, and PhRMA is reduced to saying that it's "counterproductive" to keep on talking about it.
Tauzin and PhRMA are also taking flak from their right - the Wall Street Journal blasted the whole idea of a deal the other day, calling it short-sighted. Congress could, after all, change the terms any time they can round up the votes, which would be any time it's convenient to blame the drug companies for something. I find myself more in this camp. I understand that PhRMA can't afford to stay out of this process (in which case the carving knives would come out sooner rather than later), but I think it's a sad business all the same, trading the threat of price controls now for the threat of price controls a little later on. Here's more complaining from National Review.
But that brings us back to Tauzin. I will work under the assumption that he's not an idiot, although I'm willing to listen to evidence for either side on that one. But if he isn't, why did he go around boasting of this wonderful backroom deal? All it seems to have done is endanger whatever agreement was reached. If my not-an-idiot stipulation is justified, though, the only reason I can see for doing this is as a tactic to get something even better. Did PhRMA look at the polls and decide the time was right to help torpedo everything? (And yes, I know the Rasmussen polls lean right, but I think they're picking up something real). Is that the game here?
Well, I get e-mails from people at PhRMA once in a while, and I'll probably get another one after I put this post up. Something tells me that I'm not going to get to hear what's really going on, but that doesn't stop a person from wondering.
+ TrackBacks (0) | Category: Current Events | Drug Prices | Regulatory Affairs
August 14, 2009
I do a lot of talking around here about how the general public doesn't really have a good idea of what goes on inside a drug company. But a conversation with a colleague has put me to thinking that this might be largely our own fault.
Consider the public face that our industry projects. Look at the press releases and the advertisements - what's the impression that you get? That there is a defined process for discovering drugs, for one thing, and what's more, that we are the master of it. Now, I know that we don't always send out that message. There are attempts to tell people about how many compounds have to be made, how many projects end up failing. But for the most part, we don't press-release that stuff.
No, the press releases are for the investors, and for them, we want to project that we're productive, confident, resourceful. . .in short, that we've got things under control. The last thing Wall Street wants to hear about is that you don't always know which drug targets are the right ones to work on, that you're not quite sure of the best way to prosecute them, and that (despite continuing efforts) these conditions look to obtain for quite a while to come.
And this attitude is one of the things that seeps out into the general public consciousness. That, I think, is why you get people who are convinced that we could cure a lot of these diseases, but that we just don't - you know, for all sorts of evil and profitable reasons. They've bought into our hype. If we haven't cured the common cold, that must be because we make a lot more money selling people stuff for it, not because antiviral drug development is flippin' difficult. (Especially for something like the common cold, but that's another story).
Now, to some extent, there is a defined process for discovering drugs - well, several defined processes. It's just that it doesn't work all that well, not on the absolute scale. No one could look at clinical failure rates of around 90% and say that we've got everything covered. Weirdly, that's one of the things that gives me hope for the industry, that even small improvements would make a big difference. What if only 80% of all the compounds we took into the clinic crashed and burned? That would be great! It would double our success rate!
But when I mention that 90% problem to people outside the drug industry, they usually have no idea. All they hear about are the successes. Perhaps it would do us some good to mention the failures once in a while?
+ TrackBacks (0) | Category: Drug Development | Drug Industry History | Why Everyone Loves Us
August 13, 2009
Why do we test drugs on animals, anyway? This question showed up in the comments section from a lay reader. It's definitely a fair thing to ask, and you'd expect that we in the business would have a good answer. So here it is: because for all we know about biochemistry, about physiology and about biology in general, living systems are still far too complex for us to model. We're more ignorant than we seem to be. The only way we can find out what will happen if we give a new compound to a living creature is to give it to some of them and watch carefully.
That sounds primitive, and I suppose it is. We don't do it in a primitive manner, though. We watch with all the tools of our trade - remote-control physiological radio transmitters, motion-sensing software hooked up to video cameras, sensitive mass spectrometry analysis of blood, of urine, and whatever else, painstaking microscopic inspection of tissue samples, whatever we can bring to bear. But in the end, it all comes down to dosing animals and waiting to see what happens. That principle hasn't changed in decades, just the technology we use to do it.
No isolated enzymes can yet serve as a model for what can happen in a single real cell. And no culture of cells can recapitulate what goes on in a real organism. The signaling, the feedback loops, the interconnectedness of these systems is (so far) too much for us to handle. We keep discovering new pathways all the time, things that no model would have included because we didn't even know that they were there. The end is not yet in sight, occasional newspaper headlines to the contrary.
We do use all those things as filters before a compound even sees its first rodent. In a target-driven approach, which is the great majority of the industry, if a compound doesn't work on an isolated protein, it doesn't go on to the cell assay. If it doesn't work on the cells, it doesn't go on to animals. (And if it kills cells, it most certainly doesn't go on to the animals, unless it's some blunderbuss oncology agent of the old school). The great majority of compounds made in this business have never been given to so much as one mouse, and never will.
So what are we looking for when we finally do dose animals? We're waiting to see if the compound has the effect we're hoping for, first off. Does it lower blood pressure, slow or stop the growth of tumors, or cure viral infections? Doing these things requires having sick animals, of course. But we also give the drug candidates to healthy ones, at higher doses and for longer periods of time, in order to see what else the compounds might do that we don't expect. Most of those effects are bad - I'd casually estimate 99% of the time, anyway - and many of them will stop a drug candidate from ever being developed. The more severe the toxic effect, the greater the chance that it's based on some fundamental mechanism that will be common to all animals. In some cases we can identify what's causing the trouble, once we've seen it, and once in a great while we can use that information to argue that we can keep going, that humans wouldn't be at the same risk. But this is very rare - we generally don't know enough to make a persuasive case. If your compound kills mice or kills rats, your compound is dead, too.
I've lost count of the number of compounds I've worked on that have been pulled due to toxicity concerns; suffice it to say that it's a very common thing. Every time it's been something different, and it's often not for any of the reasons I feared beforehand. I've often said here that if you don't hold your breath when your drug candidate goes into its first two-week tox testing, then you haven't been doing this stuff long enough.
Here's the problem: giving new chemicals to animals to see if they get sick (and making animals sick so that we can see if they get better) are not things that are directly compatible with trying to keep animals from suffering. Ideally, we would want to do neither of those things. Fortunately, several factors all line up in the same direction to keep things moving toward that.
For one thing, animal testing is quite expensive. Only human testing is costlier. In this case, ethical concerns and capitalist principles manage to line up very well indeed. Doing assays in vitro is almost invariably faster and cheaper, so whenever we can confidently replace a direct animal observation with an assay on a dish, plate, or chip, we do. All that equipment I mentioned above has also cut down on the number of animals needed, and that trend is expected to continue as our measurements become more sensitive.
So things are lined up in the right direction. Any company that found a reliable way to eliminate any significant part of its animal testing would immediately find itself in a better competitive position.
And for the existing tests, it's also fortunate that unhappy animals give poor data. We want to observe them under the most normal conditions possible, not with stress hormones running through their systems, and a great deal of time and trouble (and money) goes toward that end. (In this case, it's scientific principles that line up with ethical ones). Diseased animals are clearly going to be in worse shape than normal ones, but in these situation, too, we try to minimize all the other factors so we're getting as clear a read as possible on changes in the disease itself.
So that's my answer: we use animals because we have (as yet) no alternative. And our animal assays prove that to us over and over by surprising us with things we didn't know, and that we would have had no other opportunity to learn. We'd very much like to be able to do things differently, since "differently" would surely mean "faster and more cheaply". None of us enjoy it when our compounds sicken healthy animals, or have no effect on sick ones. Just the wasted time and effort alone is enough to make any drug discoverer think so. There are billions of dollars waiting to be picked up by anyone who finds a better way.
+ TrackBacks (0) | Category: Animal Testing | Pharma 101
August 12, 2009
Let us now praise sulfur. Well, some kinds of sulfur, anyway. The +2 oxidation state (earlier typo fixed, aargh) is a bit hard to handle, what with all those angry-skunk, burnt-tire overtones. But move up the ladder to +4, and you've got some possibilities.
Those do not include the hideous thioacetone, but bring some oxygen into the picture and you get a sulfoxide. And these guys I like, probably because one of the best compounds I've made in my career had one as a prominent feature.
Not every medicinal chemist shares my enthusiasm, that's for sure. Sulfoxides have a reputation for being potentially metabolically unstable - and they can go either way, being oxidized up to sulfones or reduced back to the parent sulfide. (I believe the former is more common, and is the clearance mechanism for DMSO, among other members of the tribe). But there are some out there in the market, chief among them esomeprazole (Nexium). Then there's armodafinil (Nuvigil), Cephalon's follow-up to Provigil, like Nexium another single-enantiomer-of-a-racemate drug.
But sulfoxides aren't just for extending your patent life and raking in the money. They can make a big difference in activity. The group has a strange character to it, because that oxygen atom is about as close to a naked O-minus as you're going to find. And the tetrahedral geometry of the sulfur means that this electronegative group is held is a very specific orientation relative to the other parts of your molecule. Like a nitrile, a sulfoxide is sui generis: there's nothing else that will do what it does.
And they're chiral. That can either be a bug or a feature, depending on your project and on your view of the world. If your target protein recognizes that chirality, it's probably really going to recognize it, because of that strong character. But that chirality is yet another reason that people avoid the sulfoxide, because that means chiral synthesis, which is a pain. All sorts of methods have shown up - chiral oxidation of sulfides, displacement with inversion at the sulfoxide sulfur - but there's no good general solution. The existence of the commercial drugs shows that this problem can be overcome, but there's no use denying that it's a problem.
All these problems can, at times, blend together. I was told some years ago about a Merck clinical compound that had a chiral sulfoxide. When they checked for metabolites, they found what looked like unchanged drug substance coming back out. A closer look, though showed that this was actually the enantiomer of the starting drug! What happened, as I heard it, was that the sulfoxide was first getting reduced, then oxidized back up to the opposite sulfoxide, when then passed out unchanged. Eating your starting material and collecting your own urine has yet to catch on as a sulfoxide inversion method, though. . .
+ TrackBacks (0) | Category: Life in the Drug Labs
August 11, 2009
I was looking over a paper in PNAS, where a group at Stanford describes finding several small molecules that inhibit Hedgehog signaling. That's a very interesting (and ferociously complex) area, and the more tools that are available to study it, the better.
But let me throw something out to those who have read (or will read) the paper. (Here's the PDF, which is open access). The researchers seem to have done a screen against about 125,000 compounds, and come up with four single-digit micromolar hits. Characterizing these against a list of downstream assays showed that each of these acts in a somewhat different manner on the Hedgehog pathway.
And that's fine - the original screen would have picked up a variety of mechanisms, and there certainly are a variety out there to be picked up. I can believe that a list of compounds would differentiate on closer inspection. What I keep looking for, though, is (first) a mention that these compounds were run through some sort of general screening panel for other enzyme and/or receptor activities. They did look for three different kinase activities that had been shown to interfere (and didn't see them), but I'd feel much better about using some new structures as probes if I'd run them through a big panel of secondary assays first.
Second, I've been looking for some indication that there might have been some structure-activity relationships observed. I assume that each of these compounds might well have been part of a series - so how did the related structures fare? Having a one-off compound doesn't negate the data, naturally, although it certainly does make it harder to build anything from the hit you've found. But SAR is another factor that I'd immediately look for after a screen, and it seems strange to me that I can't find any mention of it.
Have I missed these things, or are they just not there? If they aren't, is that a big deal, or not? Thoughts?
+ TrackBacks (0) | Category: Biological News | Drug Assays
Novartis has had trouble for years with animal rights activists, and now things are getting nastier than ever:
Novartis CEO Daniel Vasella says the people who burned down his holiday home and defiled his family's graves are not criminals but "terrorists" beyond dialogue.
In an interview with the SonntagsBlick newspaper, the 55-year-old chief executive said the attacks have changed his life and that more needs to be done to rein in the animal-rights extremists believed responsible for the "wicked" acts.
Last week Vasella's home in Austria was set on fire. In July his mother's urn was stolen and his dead 19-year-old sister's grave was desecrated. Crosses bearing his name and that of his wife were placed in a Chur cemetery. Workers' cars have been torched and angry graffiti sprayed on walls. . .
"How far do things have to go before you can speak of terrorism?" Vasella told the newspaper.
I'd say that's far enough, definitely. If that's not being done with intent to terrorize, then what? One idiotic part of the whole business is that the protesters seem to be trying to get Novartis to stop working with Huntingdon Life Sciences, the British animal testing company. (Similar tactics have been used elsewhere). But Novartis says that they currently have no relationship at all with HLS, and haven't for several years.
Mere statements of dull fact, though, won't make a dent in the self-righteousness of the sorts of people who think that spray-painting gravestones is a blow for justice.
+ TrackBacks (0) | Category: Animal Testing | Why Everyone Loves Us
August 10, 2009
+ TrackBacks (0) | Category: Blog Housekeeping
There's a recent article in Nature Reviews Drug Discovery that has some alarming figures in it. This is yet another look at the industry from McKinsey, and we'll get to their McKinseyish solutions in a moment. But first, some numbers:
They calculate that the return on investment (ROI) from small-molecule drug research was nearly 12% during the late 1990s, but since 2001 it's been more like 7.5%. If true, that's not a very nice number at all, because their data indicate that most companies assume a capitalization rate of between 8.5 and 11% - in other words, internal industry estimates of what it costs to develop a drug over time now run higher, on average, than the actual returns from developing one.
Another alarming bit of news is their analysis of Phase III failures. From 1990 to 2007 there were 106 of those nasty, expensive events. But the McKinsey figures are that 45% of those failures were due to insufficient efficacy versus placebo - which, in theory, is the sort of thing you're supposed to be rather more sure about by that point, what with having run Phase II trials for efficacy and all. (I'd like to know how many Phase III trials succeeded over that time period as well - what's the overall percentage of failure at that point?) Another 24% of the failures were due to insufficient efficacy versus the standard of care, which is at least a bit more understandable. But together, nearly 70% of all Phase III failures aren't due to tox, they're because the drugs just didn't work as well as their developers thought.
Back to those ROI figures, though. Either those numbers are wrong, or we're in quite a fix. (Of course, since the authors are consultants, their viewpoint is likely that those numbers are the best available, that all of us are indeed in a fix, and that if we pay them money they'll help us out of it). The paper does have some recommendations, to wit:
1. Cut costs, but not the obvious stuff that companies have been doing. Instead, they suggest broader strategies such as considering whether a company's clinical trials are consistently over-powered, and to not do quite as much "planning for success", since most development programs fail. That is, don't automatically gear up for a full overlapping development workup for every compound in the pipeline, but consider staging things so you won't waste as much effort if (or when) they crash out. And naturally, they also suggest outsourcing whatever "non-core" functions there are available.
2. Work faster. I have to say, though, that if I got paid every time I heard this one, I wouldn't have to work. The authors point out, correctly, that delays in getting a compound to market are indeed hideously costly, but on-the-other-hand it by saying that "Of course, gains in speed cannot come from short cuts: the key to capturing value from programme acceleration is choosing the right programmes to accelerate". And that leads into their third category, which is. . .
3. Make better decisions. This isn't quite a much of an eye-roller as it might seem, because this is where they bring in those Phase III numbers above. Such failures suggest some deeper problems:
"In our experience, many organizations still advance compounds for the wrong reasons: because of momentum, 'numbers-focused' incentive systems or through waiting too long to have tough conversations about the required level of product differentiation."
And I have to say, they have a point. People who've been in the industry for some years will have seen all of those mistakes made. for sure. But figuring how to stop those things from happening is the tough part, and presumably that's one of the things that McKinsey is selling.
+ TrackBacks (0) | Category: Business and Markets | Drug Development | Drug Industry History
August 7, 2009
For those who don't work in the industry, and wonder what goes on behind the closed doors of the research buildings, allow me to give you a fly-on-the-wall view of a typical meeting of a drug discovery project team. There are no huge revelations here, and I'm not going to try to reproduce 45 minutes worth of talk, but I think that my industrial readers will find this to be a pretty accurate depiction:
(Camera view of the inside of a small conference room, with six or eight people seated around a table)
CHEMIST A: OK, is this everyone that's going to show up? We have to stop this thing of starting all the meetings fifteen minutes late. (Slide goes up on screen from laptop). All right, here are the two scaffolds, and here's where we were last time with them. You guys should know that at the last Senior Review Meeting everyone kept asking when we were going to narrow down on just one of these, and I kept having to tell them that we're not ready to do it yet. But they're getting tired of hearing that.
CHEMIST B: Not as tired as we are of them asking the question. But I guess you probably didn't say that? OK, I'll do Scaffold 1; my lab's been working on that one the whole time. (New slide goes up). As usual, these things are potent out the wazoo, but we can't shake that Other Enzyme activity, and none of these compounds have the plasma stability that we want.
Last time we said that we were going to hang a bunch of stuff off the 4-position to try to fix that metabolic problem, but we only got a few of the things made. Every time you try to put anything useful out there, you get this side product, and most of the time you can't separate the stuff, you can just see it in the NMR and maybe on the LC/MS trace.
But we've made these four analogs - the potency isn't getting any better, but it isn't getting any worse, and we've put 'em in for PK. If they work, though, we're going to have to find another way to do this stuff.
CHEMIST C: Why don't you try to put in those groups via (obscure name reaction)?
CHEMIST B: Because (obscure name reaction) doesn't flippin' work on this system - we tried that, too, and all we get back is starting material. At least the route we've got gives us something. Sometimes. Sort of.
CHEMIST A: What are we going to do if those come back from PK with the same short half-life?
CHEMIST B: Well. . .work on something else, I guess, because if the problem is out here in the 4-position, you'd think that these changes would fix it. Unless we suddenly made some other part of the molecule more likely to be metabolized by messing with this end of it. But you can assume stuff like that all day, and it doesn't get you anywhere. Keep thinking like that, and you'll never make anything.
CHEMIST A: OK, we'll wait for the numbers. My group's been doing the second scaffold, so I'll take that one. (New slide goes up). These have always been the most selective compounds we've got against That Other Enzyme, and they have pretty good PK numbers, but we keep trying to get more potency. We made this series of amines, trying to pick up a hydrogen bond out there in the far binding pocket, but. . .well, most of them don't seem to work. They're really soluble, though. Every time we make something that's really soluble, it doesn't bind.
BIOLOGIST A: Yeah, those things were nice. Should have known.
CHEMIST A: The outlier is that third one, the piperazine. That looks like it might be picking up something, so we're going to make another series off of that one. What we really need is the piperazine with this funky group on it, and you're supposed to be able to buy it from insert name of fly-by-night supplier, but I don't want to depend on those guys.
CHEMIST D: So how long are we going to keep beating on these things? Have you guys ever made anything that's below, like, fifty or a hundred nanomolar?
CHEMIST A: Well, that thiophene compound was the best, and that's what got us excited, you know, but none of the other aryls seemed to work as well. So we've still got the three-position to try out there, and I think we've got some intermediates that we can use to get some analogs. I don't want to pull the plug until we've made those. And we need to make that piperazine series that's up there.
CHEMIST D: But last time you didn't want to pull the plug until you'd made these compounds. Does the plug ever actually come out, or not?
CHEMIST A: Well, not yet, partly because, hey, when you get down to it, this is probably the best series we have to work on. Nothing else gives us those plasma levels.
CHEMIST B: But there's only so much that blood levels can do for you if the potency isn't there. Would you put a hundred nanomolar compound into the animal model?
BIOLOGIST B: I hope not, because as you guys know, that model is a pain in the neck to run, and we'd rather not spend three or four weeks on it unless you've got something that you think is going to actually work.
CHEMIST C: What if you try to mimic that right-hand part of the first scaffold with some sort of cyclic amine goes to screen and waves hands like over here? Piperidine, pyrrolidine - would that hit the same part? It looks like there's space in the X-ray structure to get over there.
CHEMIST A: You want to try it?
CHEMIST C: Well. . .OK. I'll take a look, see if we can get something like that. You guys have any of the ester left, or did you burn it all up already?
(camera pulls back out of the conference room)
. . .and that's how it goes. In fact, that's almost exactly how it goes, most of the time. That's science as it's being done.
+ TrackBacks (0) | Category: Life in the Drug Labs
August 6, 2009
As much as I defend the industry I work in, I have to talk about things that we do that I don't think are so defensible. Another one of those has come up thanks to the New York Times and PLoS Medicine, who obtained a pile of records from a current court case.
This article has the details. Wyeth seems to have contracted with a medical writing outfit (DesignWrite) to produce and place a number of review articles covering hormone therapy for menopausal women. (Wyeth, of course, was the main player in that market). The articles seem to have been entirely written by the staff at DesignWrite - authors are listed as "TBD", and then academics were recruited to serve as lead authors and to submit the papers to journals.
No mention was ever made in the published papers of the medical writing group's role, nor of Wyeth's (who were paying them for this service). As far as the readers could see, these were the standard sorts of review articles that show up in the medical literature all the time. And that's the part that bothers me. For all I know, these articles were reasonable reviews of the field - I'm no great expert in the field, so I can't judge if they're truly fair summaries. But even if they are, the readership of a journal is entitled to know that a drug company was the impetus behind them, and they're also most certainly entitled to know the actual authors (as opposed to the people who would appear to have been the authors, but just signed off on the stuff).
I think that drug companies are entitled to promote their products. But full disclosure should be the the standard to try to reach in any market: put it all out on the table, and let physicians make their own decisions. It doesn't help, not one bit, to get papers into the journals this way - because when a company goes to such lengths to hide its participation, it almost looks as if it has something to hide. . .
+ TrackBacks (0) | Category: Business and Markets | The Dark Side | The Scientific Literature | Why Everyone Loves Us
August 5, 2009
I know that many people are getting tired of this topic. But many people who work in the industry have never met someone who's convinced that drug companies are just standing in the way of innovation, and that all the good stuff comes from the NIH, anyway. So allow me a couple of quick quotes from Dr. Jerry Avorn, chief of pharmacoepidemiology at Boston's Brigham and Women's Hospital, and (thus) a person who should know better:
". . .Virtually every progressive recommendation about health policy for the last 20 or 30 years that the drug industry felt might harm its bottom line has been met by the threat that if they don't make as much money before, innovation will cease and there will be no cures for new diseases. It came up around Medicare drug pricing and generic drugs. It's not a surprise to see it come up around health-care reform.
There are a couple reasons that this is a specious argument. One is that according to their filings with the SEC, the drug companies only spend about 15 cents of every dollar on research and development. That's compared to more than 30 cents in administration and marketing and more than 20 cents on shareholder equity. As an investment in R&D, I think any venture capitalist would say a company spending 15 percent on research is not a robust innovation engine.
The second issue is that if one looks at the new pipeline of drugs that Pharma has been generating in recent years, it's been puny. Wall Street has noticed this as well. There have been 20 or fewer drugs approved by FDA in recent years, which is lower than in past periods. It's sort of an open secret that innovation isn't working that efficiently.
The third leg of the stool is that if you really trace back where the seminal discoveries come from on which new drugs are based, it is federally supported research, usually funded by the National Institute of Health, and frequently conducted at universities or academic medical centers. The drug companies will then identify these discoveries and do hard, costly, and important work commercializing them. And they deserve compensation for that work. But it's disingenuous for them to imply that all the discoveries occur in their walls.. . ."
Read the rest of the interview if you want to hear how we'd all be better off if everything turned into biotech start-ups. But you say that you thought those were companies, too, and weren't funded by NIH money, but rather by investors who are often hoping for a deal with a big drug company? Adjust your thinking! This last quote should help you:
". . .if we want innovation and scientific discovery we should fund innovation and scientific discovery, not go after it bass-ackwards by paying too much for overpriced drugs and hoping that some of the excess profit will trickle down into innovative research. If I'm right that a lot of the important and useful innovation comes from NIH studies, then the way to get more innovation is to fund innovation. It frankly would be a far more interesting use of any given dollar one wanted to spend. . ."
Megan McArdle has done the work of attacking this at greater length than I can right now, and her post is a good palate-cleaning read after the Avorn interview. One tiny point she brings up that Dr. Avorn might want to internalize is that 15% is actually quite a large percentage of R&D spending. Apple spends 3%, and Google, 10%. Intel manages to get all the way up to 15%. At any rate, the whole post is worth reading, and was clearly written in a mood of complete exasperation. Which I share.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Prices
Patent applications are no fun to write. You have to figure out just what you're trying to cover (and how wide a space around it you want to try to clear), and the lawyers have to whip up language that casts just the right legal spell. The chemists have to write up detailed experimental procedures for all the important compounds and procedures, gather the matching analytical data, and make sure that it all fits together. Just getting the numbers assigned to the compounds right (and keeping them right through all the revisions) is a tedious job in itself. You always have to go through more drafts than you thought. No one enjoys it.
So maybe it's not surprising that things sometimes, well, slip a little. But how about when they slip a lot? Take this morning's example from Merck (a company that pitchforks out patent applications by the pile). Their WO2009091856 just published recently, directed at bicyclic beta-lactamase inhibitors. And everything looks normal for quite a while - 120 pages or so, in fact. Then the text suddenly snaps into bold face, and an authorial voice makes itself heard:
It appears that the data in Table 3 were generated in the same manner using the same enzymes as in Table 2 (Table 2 is unchanged from the provisional filing. I plan to DELETE the entries in Table 3 for Ex. 2,6,7 and 8 because this data duplicates the data in Table 2. . .Also, the entries in Table 2 for Ex.8 are both "1.6", not "16" as shown in Table 3. Please clarify these differences. . .
Is the data shown for Ex 1A data generated in a separate run, or is it supposed to be the same as for Ex. 1?. . .You don't want to include synergy data for these compouds (sic). It would be helpful to include it, at least for some of the examples (could put in a separate table). Recommend we include it for Ex. 14, since this is a likely backup candidate.
Now that's not supposed to be in there! What you're reading are the comments of someone in Merck's legal department - the sorts of comments that every patent draft collects as it's written, the sorts of comments that are supposed to be excised before you send in the application. Not this time! So if you were wondering which compound in this application represents the real candidate, and which ones are the backups to it, well, wonder no more. That query about including synergy data, for example, is an attempt to make it harder to figure out the most preferred compound itself - in vain, as it turns out. Oh, and those corrections that the comments say should be made? They weren't. So you'll want to fill in the correct numbers yourself.
That sort of thing goes on all the time in patent writing. You have to disclose your best compound - and in fact, you have to "teach toward" it in the claims. But you don't have to spray-paint it orange, and there's no sense in making things easy for your competition to figure out. A careful analysis of a patent application's claim structure will narrow down what a patent's authors are really interested in protecting, but there's often still some doubt about which exact compound is the winner. There can be other clues. Sometimes it'll be the compound with the most extensive biological characterization, or sometimes, if you look through all the experimental procedures, you'll notice that everything's being done on 50-milligram scale until one prep jumps to twenty grams. Bingo! Careful preparation of an application can scrub most of this stuff out. But all is for naught if your legal team's strategy comments are included in the Special Bonus Director's Cut version of the application.
Oh well, bonus dormitat Homerus. Anyone who's interested in beta-lactamase inhibitors (which, I should add, I'm not) now has more data to work with. The patent analysts at Thomson-Reuters are the people who caught this mistake (a colleague forwarded their writeup on to me). As they note, the wayward legal paragraphs also mention the possibility of comparing compounds to "MK-8712". That MK designation is Merck's usual method of showing a compound that's been recommended for the clinic, but this is the first that anyone seems to have heard about this one. But we can be pretty sure of something: someone in Merck's legal department has had a very bad day of it within the past couple of weeks. . .
+ TrackBacks (0) | Category: How Not to Do It | Patents and IP
August 4, 2009
Now, while we've been talking about how much basic research is done in industry, or how much clinical research gets done in academia, here's something that might bear on the discussion. Too much of what looks like useful clinical research on the academic side is actually wasted effort. The New York Times has been running a series called "The Forty Year War", looking at the history of the "War on Cancer", and the latest installment is on clinical trials.
It's been a problem for some time now that there aren't enough patients to go around for many cancer trials. Breast cancer is an especially problematic area, last I heard. It's high-profile, fairly high-incidence, and a lot of investigational anticancer agents are lined up to take a whack at it. So many, in fact, that there aren't enough breast cancer patients available in the US, nowhere near, and the same situation obtains in a number of other areas.
Much of this problem comes from low recruitment rates. As the Times article makes clear, only three per cent of adult cancer patients are enrolled in any kind of trial at all. Many cancer patients want to stick with the best therapy that's currently known, and don't want to add any uncertainty to what they're already dealing with. It's hard to blame them, but that does make the state of the art advance more slowly.
Another factor that may come as a surprise is that many oncology practices find that they lose money by participating in trials. The reimbursement-to-paperwork ratio doesn't always come out very well, especially for centers that don't do a lot of clinical research and haven't been able to streamline the process as much as possible. When they look at the number of patients that they can serve, given the time that's taken up, the trials start to make less sense.
Finally, and this is the least excusable factor on the list, there are many trials that really shouldn't be run at all. The Times does work in a line about how some studies by drug companies are just "designed to persuade doctors to use their drugs." My take on that is that these studies usually are designed to do that by showing that their drug actually works better, which is not such a bad thing. But note this other problem:
There are more than 6,500 cancer clinical trials seeking adult patients, according to clinicaltrials.gov, a trials registry. But many will be abandoned along the way. More than one trial in five sponsored by the National Cancer Institute failed to enroll a single subject, and only half reached the minimum needed for a meaningful result, Dr. Ramsey and his colleague John Scoggins reported in a recent review in The Oncologist.
Even worse, many that do get under way are pretty much useless, even as they suck up the few patients willing to participate. These trials tend to be small ones, at single medical centers. They may be aimed at polishing a doctor’s résumé or making a center seem at the vanguard of cancer care. But they are designed only to be “exploratory,” meaning that there are too few patients to draw conclusions or that their design is less than rigorous.
“Unfortunately, many patients who are well intentioned are in trials that really don’t advance the field very much,” said Dr. Richard Schilsky, an oncologist at the University of Chicago and immediate past president of the American Society of Clinical Oncology.
I don't want to dump a bucket of tar on all academic and publicly funded clinical research, because there's a lot of good stuff that goes on as well. (And remember, the publicly basic research is very valuable indeed). But the next time someone tells you about the number of clinical trials run outside of the drug industry, you might want to keep those above figures in mind.
Not all trials are created equal, not by a long shot. But the ones that we run in industry, from what I can see, tend to have a better chance of relevance. That's partly because we're spending our own money on them, and with a goal of finding drugs that people will spend money on in turn. It focuses one's efforts. It's not like we never waste money in this business, but I'm very much willing to bet that we waste it less often than happens with public funds. Companies trying to get an agent through the clinic tend not to set up meaningless trials just to make everyone's resume look better. That I can tell you.
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August 3, 2009
Well, here's a nasty surprise for you: your new drug gets a 14 to 1 "Yes" vote from an FDA advisory committee, but the agency turns you down, anyway. That's what's just happened to Savient and their new biologic product for gout, Krystexxa (pegloticase).
The FDA isn't required to say why they do such things, at least not to anyone else other than the company that submitted the drug. And they're aren't talking this time, either, but it looks like there's a manufacturing issue involved. The process for making Krystexxa seems to have changed a bit since the clinical trial batches, and the agency apparently wants to make sure that this hasn't altered anything. If all goes well, then, you'd expect the company to get things straightened out sometime next year, but for Savient, that's an awful long time to wait.
People who follow the company (and the gout market) have been arguing for the last few years about its prospects. Krystexxa is a pegylated form form of an enzyme called uricase (urate oxidase) that clears out uric acid (crystals of which are the proximate source of trouble in gout). Interestingly, this is one of those enzymes that's found all over the various phyla, and in mammals up to primates - but it stops there. We have the gene for the enzyme, but it appears to have been mutated to an inactive form at some point (rather like our gene for the last step in endogenous Vitamin C synthesis - I always wonder what the Intelligent Design people have to say about such things, although I'm pretty sure that it's some variant of "Because it was Designed that way for some good reason that's not immediately clear to us right now").
Bringing in this enzyme, then, isn't a case of replacing something that we already have. This is adding a function that we lost back in the early primate days, so we're talking "foreign protein" here. The pegylation is partly there to help with that, and partly just to give the protein a chance to survive the usual metabolic processes. For those who don't know the term, "Peg" is short for "polyethylene glycol", so a pegylated protein has long polymer chains of this hanging off it at various points. The total effect is rather like spraying the thing down with a coat of clear varnish - it changes the solubility, slows down metabolism and clearance, and changes the immune response to the protein. Pegylation is useful indeed, but something of a black art, since it's difficult to predict just what'll happen each time you try it.
Well, I wish Savient luck in getting things straightened out. And I wish their shareholders luck today. The company's stock has not been a place for the easily alarmed over the last year or two, and I'll bet that a lot of people thought that the fear had been cleared by that 14-1 advisory committee meeting. But that's the thing about this whole industry: you can never quite breath easy. . .
+ TrackBacks (0) | Category: Business and Markets | Regulatory Affairs