About this Author
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: firstname.lastname@example.org
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