About this Author
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe
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February 26, 2009
Posted by Derek
Metformin, now there’s a drug story for you. It’s a startlingly small molecule, the sort of thing that chemists look and and say “That’s a real drug?” It kicked around in the literature and the labs in the 1960s, was marketed in Europe in the 1980s but was shopped around in the US for quite a while, partly because a lot of people had just that reaction. (It didn't help that a couple of other drugs in the same structural class turned out to cause lactic acidosis and had to be pulled from use). Bristol-Myers Squibb finally took metformin up, though, and did extremely well with it in the end under the brand name Glucophage. It’s now generic, and continues to be widely prescribed for Type II diabetes.
But for many years, no one had a clue how it worked. It not only went all the way through clinical trials and FDA approval without a mechanism, it was nearly to the end of its patent lifetime before a plausible mechanism became clear. It’s now generally accepted that metformin is an activator (somehow, maybe through another enzyme called LKB1) of adenosine monophosphate kinase (AMPK), and that many (most?) of its effects are probably driven through that pathway. AMPK’s a central player in a lot of metabolic processes, so this proposal is certainly plausible.
But never think that you completely understand these things (and, as a corollary, never trust anyone who tries to convince you that they do). A new paper in PNAS advances the potentially alarming hypothesis that metformin may actually exacerbate the pathology of Alzheimer’s disease. This hasn’t been proven in humans yet, but the evidence that the authors present makes a strong case that someone should check this out quickly.
There’s a strong connection between insulin, diabetes, and brain function. Actually, there are a lot of strong connections, and we definitely haven’t figured them all out yet. Some of them make immediate sense – the brain pretty much has to run on glucose, as opposed to the rest of the body, which can largely switch to fatty acids as an energy source if need be. So blood sugar regulation is a very large concern up there in the skull. But insulin has many, many more effects than its instant actions on glucose uptake. It’s also tied into powerful growth factor pathways, cell development, lifespan, and other things, so its interactions with brain function are surely rather tangled.
And there’s some sort of connection between diabetes and Alzheimer’s. Type II diabetes is considered to be a risk factor for AD, and there’s some evidence that insulin can improve cognition in patients with the disease. There’s also some evidence that the marketed PPAR-gamma drugs (the thiazolidinediones rosiglitazone and pioglitazone) have some benefit for patients with early-stage Alzheimer’s. (Nothing, as far as I’m aware, is of much benefit for people with late-stage Alzheimer’s). Just in the past month, more work has appeared in this area. The authors of this latest paper wanted to take a look at metformin from this angle, since it’s so widely used in the older diabetic population.
What came out was a surprise. In cell culture, metformin seems to increase the amount of beta-amyloid generated by neurons. If you buy into the beta-amyloid hypothesis of Alzheimer’s, that’s very bad news indeed. (And even people that don’t think that amyloid is the proximate cause of the disease don’t think it’s good for you.) It seems to be doing this by upregulating beta-secretase (BACE), one of the key enzymes involved in producing beta-amyloid from the larger amyloid precursor protein (APP). And that upregulation seems to be driven by AMPK, but independent of glucose and insulin effects.
The paper takes this pretty thoroughly through cell culture models, and at the end all the way to live rats. They showed small but significant increases in beta-secretase activity in rat brain after six days of metformin treatment. And the authors conclude that:
Our finding that metformin increases A-beta generation and secretion raises the concern of potential side-effects, of accelerating AD clinical manifestation in patients with type 2 diabetes, especially in the aged population. This concern needs to be addressed by direct testing of the drug in animal models, in conjunction with learning, memory and behavioral tests.
Unfortunately, I think they’re quite right. Update - in response to questions, it appears that metformin may well cross into the brain, presumably at least partly by some sort of active transport. There's some evidence both ways, but it's certainly possible that relevant levels make it in. With any luck, this will be found not to translate to humans, or not with any real clinical effect, but someone’s going to have to make sure of that. For those of us back in the early stages of drug discovery, the lesson is (once again): never, never think we completely understand what a drug is doing. We don’t.
Comments (19)
+ TrackBacks (0) | Category: Alzheimer's Disease | Diabetes and Obesity | Drug Industry History | Toxicology
January 8, 2009
Posted by Derek
I have a few short links for everyone today. One series of posts that you might not have seen from Xconomy is a tour of the technological hot spots of India by Boston University's Vinit Nijhawan. It's interesting stuff for people like me who haven't been to the country, and he isn't shy about pointing out both the good and the bad about India's current situation. He's not focusing on the chemistry/pharmaceutical sector, but it's an interesting read in general. I would very much enjoy seeing a similar series written from China - perhaps the Xconomy folks are working on that one?
Next: if Sanjay Gupta really is going to be surgeon general (and why not?), it's worth watching his exchange with Michael Moore when Moore's movie "Sicko" came out. This is a 17-minute YouTube clip, and you may not make it through if you can't stand Michael Moore, but it has some good moments. Gupta is a *lot* more reasonable dealing the Moore than I would have been, but gets hammered on for his pains anyway.
And here's an interesting one, from a financial standpoint. Raising money for startup companies has, in the last few months, gone from the usual state of “not so easy” to “nearly impossible”. Everyone’s hoping for that to improve, but for now, this is a nasty time to try to float a new startup. That goes for follow-on financing, too, naturally, and that can hurt even more than troubles with start-up money. You can potentially delay the launch of your new venture – after all, no one else is getting anything off the ground, either – but if you’re already got a company going, the funds need to keep flowing. Companies that lined up more money in the middle of 2007 are shivering over the narrowness of their escape.
So it's impressive that an outfit called Satori Pharmaceuticals has made it through a full round of venture funding, and for Alzheimer's therapies, no less. That's a notorious graveyard for good ideas, but (at the same time) it's equally notorious for being hugely under-served. Good luck to them - they'll need it (and don't we all?)
Comments (20)
+ TrackBacks (0) | Category: Alzheimer's Disease | Current Events | Press Coverage
October 15, 2008
Posted by Derek
A recent correspondence on the topic of “Why aren’t there more drugs for the big CNS disorders” got me thinking about the topic. My take, having worked in the field, is that there is still so much unmet need in that area because we just don’t understand what's going on. It’s hard to come up with disease-altering therapies when you don’t really understand a single disease in the whole field.
Does amyloid cause Alzheimer’s, or does Alzheimer’s give you amyloid, or is amyloid just a sideshow? What sets off the chain of events that ends up killing off cells in the substantia nigra in Parkinson’s? What are the detailed molecular mechanisms of depression, or schizophrenia? Why don’t neurons remyelinate in multiple sclerosis? We don’t know. We know a lot more than we used to; we know more every year. But we don't know enough to cure anyone yet. Even in the areas where we know more than average, we still don’t know enough to step in with therapies that can do what people really want them to do.
By that, I mean do for these diseases what insulin does to Type I diabetes, or what antibiotics do to infections. To any working CNS researcher, such results in their field would be hard to distinguish from magic. We can’t even touch the surrogate endpoints, and do what statins do for LDL levels, or the various antihypertensives do for blood pressure. We understand those areas a lot better than we understand the brain. Even so, we still get surprised, as witness the controversy over Vytorin, and the various ongoing attempts to find something that will raise HDL – you push a bit beyond the mechanisms that you’ve worked out, and all sorts of things start to happen.
The best way I can illustrate how difficult it is to find a disease-stopping therapy for something like Alzheimer’s is to point out the incentives for one. Any drug company that came out with such a therapy would immediately have one of the most profitable drugs on the market, and they would go on to reap more and more money every year. Think of the sensation that a treatment that stopped – just plain stopped – schizophrenia. As I said, indistinguishable from magic. But the success that such a thing would have would be immense. The incentives are there; it’s just that the barriers are very, very high.
Of course, it may not be possible to do some of these things. I’d be very careful to rule anything out, at our current stage of ignorance, but schizophrenia may well be one of these things where a dozen (or a hundred) different pathways lead to the same roughly similar disease state. (Cancer, as I’ve said here before, is the best example of something like this). And even if it’s not quite that bad, it may be that the tangle of the disease just doesn’t lend itself to a single agent – that, I’d say, is quite likely. I strongly doubt if just stepping in and adjusting the D-whatever dopamine receptor a bit will turn out to do the trick. This doesn’t mean that it’ll be impossible to treat, it just means that it’ll be very complex.
And so it is, and so are most of the other big CNS conditions. I find it hard to explain to people outside the field just how complex these things are, and why progress has been so painfully slow for the patients who need these things now. It’s not that there’s no explanation. It’s that actually finding a drug that works for anything is ridiculously hard and expensive, a very difficult task by anyone’s standards. And CNS drugs are fiendishly difficult even by the standards of drug discovery.
Comments (14)
+ TrackBacks (0) | Category: Alzheimer's Disease | Drug Development | Drug Industry History | The Central Nervous System
July 31, 2008
Posted by Derek
Today we take up the extremely interesting story of Rember, hailed in this week’s press as a potential wonder drug for Alzheimer’s. There are a lot of unusual features to this one.
To take the most obvious first, the Phase II data seem to have been impressive. It’s hard to show decent efficacy in an Alzheimer’s trial – you can ask Wyeth and Elan about that, although it’s a sore subject with them. But Rember, according to reports (this is the best I've seen), was significantly more effective than the current standard of care (Aricept/donezepil, a cholinesterase inhibitor). In light of some of the more breathless news stories, though, it’s worth keeping in mind that this was efficacy in slowing the rate of decline – not stopping it, and certainly not reversing it. Especially in the later stages of the disease, it’s extremely hard to imagine reversing the sort of damage that Alzheimer’s does to the brain (and yes, I know about the TNF-alpha reports – that subject is coming in a post next week). If Rember is twice as effective as Aricept, that's great - except Aricept's efficacy has never been all that impressive.
But that's still something, considering how the drug is supposed to work. Its target is different than the usual Alzheimer’s therapy. Accumulation of amyloid protein has long been suspected as the cause of the disease, but there have always been partisans for another pathology, the neurofibrillary tangles associated with tau protein. Arguments have been going on for years – decades – about which of these has more to do with the underlying cause(s) of Alzheimer’s. Rember is the first clinical shot (that I’m aware of) at targeting tau. If the first attempt manages to show such interesting results, it’s a strong argument that tau must be important. (Other people are working in this area, too, of course, but my impression is that it's nowhere near as many as work on amyloid).
That’s food for thought, considering the amount of time and effort that’s been expending on amyloid. It may be that both pathologies are worth targeting, or it may even be that these results with Rember are a fluke. But it’s also possible that tau is really the place to be, in which case the amyloid hypothesis will take its place in the medical histories as a gigantic dead end. I’m not quite ready to bet that way myself, but it’s definitely not something that can be ruled out. I wouldn’t put all my money on amyloid either, at this point. (Boy, am I glad I'm not still working in Alzheimer's: this sort of stuff is wonderful to watch from the outside, but from the inside it's hard to deal with).
Now, what about the drug itself? It’s coming from a small company called TauRx, whose unimpressive web site just went up recently. The underlying science (and the clinical data) all come from Dr. Claude Wischik of the University of Aberdeen, who has so far not published anything on the drug. The presentation this week has, by far, been the most that anyone’s seen of it (papers are said to be in the works).
And Rember itself is. . .well, it’s methylene blue. Now there’s an interesting development. Methylene blue has been around forever, used for urinary tract infections, malaria, and all sorts of things, up to treating protozoal infections in fish tanks. (For that matter, it’s turned up over the years as a surreptitious additive to blueberry pies and the like, turning the unsuspecting consumer’s urine greenish/blue, generally to their great alarm: a storied med school prank from the old days). What on earth is it doing for tau protein?
According to TauRx, the problem is that the aggregation of tau protein is autocatalytic: once it gets going, it's a cascade. They believe that methylene blue disrupts the aggregation, and even helps to dissociate existing aggregates. Once they're out in their monomeric forms, the helical tau fragments are degraded normally again, and the whole tau backup starts to clear out.
Now for another issue: there's been some commentary to the effect that Rember can't possibly make anyone any money, because it's a known compound. Au contraire. While we evil pharmaceutical folks would much rather have proprietary chemical matter, there are plenty of other inventive steps worth a patent. For one thing, I suspect that formulation will be a challenge here (and that Medpage story seems to bear this out). I doubt if methylene blue crosses the blood-brain barrier so wonderfully, and I also believe that it's cleared pretty well (thus that green urine). So TauRx had to dose three times a day, and their highest dose didn't seem to work, probably because of absorption issues. (That's also going to lead to gastrointestinal trouble). So formulating this ancient stuff so it'll actually work well could be a real challenge: t.i.d with diarrhea is not the ideal dosing profile for an Alzheimer's therapy, to put it mildly.
And for another, there's always mechanism of action. I deeply dislike patent claims that try to grab hold of an entire area, but there's so much prior art in tau that no one could try it. But use of a specific compound (or group of compounds) for a specific therapy: oh, yes indeed. It's a complicated area, and the law varies between Europe and the US, but it definitely can be done. The people who say that this can't be patented should check out the issued patents US7335505 or US6953794. Or patent applications US20070191352, WO2007110627, WO2007110629, and WO2007110630. There you go; that wasn't hard. Mind you, there might be some prior art for using such compounds as cognition-improving agents: I'd start here if I were in the business of looking into that sort of thing.
Finally, is methylene blue (or some derivative thereof) actually going to be a reasonable drug? There's that dosing problem, for one thing, but the long history in humans is encouraging (and is a key part of TauRx's hopes not to spend so much money on toxicity testing in the clinic - talks with the FDA should be starting soon). There have been contradictory reports (plus, minus) on the effects of the compound on the brain in general, though, so they may have to do more work than they're planning on. All in all, a fascinating story.
Comments (77)
+ TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Patents and IP | Regulatory Affairs
July 30, 2008
Posted by Derek
Note: I'm still working my way through the information on the much-hyped TauRx drug, Rember - a post on that is coming. Here's more from the same Alzheimer's meeting, though:
Elan and Wyeth unveiled the data on their widely anticipated Alzheimer’s drug bapineuzumab yesterday. This is another antibody from Elan’s shop, part of a long-running effort to induce an immune response to the amyloid protein which is thought to be a key player in the development of disease. And. . .well, this is an Alzheimer’s drug. That means it comes with all the standard baggage: it’s trying to treat an extremely difficult disease that we don’t understand very well, by a mechanism that no one can be sure will work or is even relevant. (Cue up this discussion from last week around here!)
This drug was always expected to have its best chance of working in patients without the APOE4 mutation, a lipoprotein which was identified in the 1990s as a significant risk factor for Alzheimer’s. Update: I shouldn't have used "always" there, since this was picked up during Phase II. But that shows that Wyeth and Elan did have it in mind as something to look for. The Phase III trials will, in fact, be stratified according to APOE4 status. And so it did – but not as dramatically as everyone had been hoping. About one-third of Alzheimer’s patients lack the APOE4 mutation, and this cohort showed slower decline in their brain functions with bapineuzumab treatment. But how much slower? The trial used a standard survey scale (ADAS-COG) – on that one, the existing Alzheimer’s drugs (Aricept, e.g.) show at most a 3-point effect, while bapineuzumab showed a five-point change.
That’s probably real, but I’m not sure how much that’s going to mean in the real world, and it’s certainly less than one would want. On top of that, the drug showed little or no benefit (and more side effects) in the two-thirds of the patients who have the APOE4 alleles, which meant that when all patients in the trial were taken together, improvement over placebo didn’t reach significance. And since this trial doesn’t seem to have been designed from the start to distinguish between those different patient groups, that’s the only number that you can take away with any certainty. All the other analyses are ex post facto, and thus carry less weight.
Investors, some of whom were clearly expecting a lot more than this, have not reacted well to the news: Elan’s drop has been taking the whole Irish stock exchange down along with it today. They have several other Alzheimer’s therapies in development, but the worries are starting to develop about the effectiveness of all the approaches that target amyloid. You can see some of those concerns being aired out in the latter half of the Forbes article. Some of the stronger statements are from people who are backing alternate hypotheses, which you should keep in mind, but there’s no doubt that the amyloid hypothesis for Alzheimer’s is still very much unproven. (Perhaps Lilly can shed some light today, but I doubt it, to tell you the truth). It’s going to be a long time before we can stop using that disclaimer that I had in the first paragraph.
Comments (2)
+ TrackBacks (0) | Category: Alzheimer's Disease
July 23, 2008
Posted by Derek
A longtime reader sent along a very interesting example that’s being used in a new book. The Gridlock Economy by Columbia economist Michael Heller is getting some good press, including this interview over at the Wall Street Journal>’s Law Blog. Heller’s thesis is:
“When too many owners control a single resource, cooperation breaks down, wealth disappears and everybody loses.” That is, the gridlock created by too much private ownership is wreaking havoc on our economy and lives. It’s keeping badly needed runways from being built, stifling high-tech innovation, and “costing lives” by keeping groundbreaking drugs from hitting the market.
It’s that last example that caught the eye of my correspondent, and I wanted more details. Fortunately, Heller went on the in the interview to talk about that very case, and I’m going to just quote him on it:
”Here’s a life or death example that’s happening right now: A drug company executive tells me he may have a better Alzheimer’s treatment. But to get FDA approval and bring it to market, he has to license dozens and dozens of patents relevant to testing for safety and side effects. So negotiations fail and the Alzheimer’s drug sits on a shelf, even though my informant is confident it could save countless lives and earn billions of dollars.”
Now, here’s the problem: I’ve actually worked on Alzheimer’s disease myself, and this story does not ring true. I don’t know if Heller’s “informant” is talking about animal testing or clinical trials in humans, but the same points hold in both cases. For one thing, I’m not aware of any patents that have to be licensed to do the standard testing for safety and side effects. There could conceivably be a couple for faster or more convenient tests, but I don’t even know of those. Otherwise, safety testing, in both animals and humans, is (to the best of my knowledge) done pretty much outside the realm of patent considerations. That “dozens and dozens of patents” line seems wildly off to me. I have never heard of a drug (for any disease) that has not advanced due to patent considerations related to safety testing.
Update - and that's partly for a very good legal reason: the safe harbor provisions of the 1984 Hatch-Waxman Act, as reaffirmed in the 2005 Merck v. Integra decision by the Supreme Court. There is specific protection from infringement in the use of a patented compound for purposes of submitting regulatory filings. And the language of the ruling makes it look like it's intended to cover all sorts of patented technologies as well.
Second, it’s important to remember that efficacy testing comes after safety, at least when you get to humans. So this contact of Heller’s is talking about a drug that has not been evaluated in humans for either quality, but he’s still “confident it could save countless lives and earn billions of dollars”. Right – for Alzheimer’s, where you have to worry about human brain levels, where we’re still arguing about what even causes the whole disease, where the clinical trials take years because the deterioration is so slow. Professor Heller is being had.
And let’s stipulate that there are, somehow, enough convincing data to make a reasonable observer confident that said drug would go on to earn billions of dollars. (There is never enough information to completely convince anyone of that in this industry before a drug hits the market, but let’s pretend that there is). In that case, those mysterious patent negotiations would not fail. Some sort of agreement would be reached, with money like that on the table.
The problem with Heller using this example is that there are indeed a lot of problems and potential problems with intellectual property in the drug industry. (I’ve talked about a few of them here). It’s a big, important, complicated, topic – and for all I know, it gets a good treatment in Heller’s book. (I’ll read it and find out). But this cartoon of an example is going to confuse anyone outside the field, and irritate anyone inside it.
Comments (24)
+ TrackBacks (0) | Category: Alzheimer's Disease | Patents and IP
June 30, 2008
Posted by Derek
I was mentioning the gamma secretase enzyme around here just the other day as a longstanding target for Alzheimer's therapy. I remember the periodduring the 1990s when the enzyme hadn't been identified yet, and frankly, it was a lot easier to get excited about it then. That's because when it was finally worked out, the protease turned out to be a big multifunctional multiprotein complex, and among its many functions was affecting Notch signaling.
That's worrisome, because a lot of important cellular development pathways go through the Notch receptor, and these are things that you'd really rather not mess with. (Just run the word "notch" through PubMed to see what I mean). Indeed, some of the toxic effects of the earlier gamma secretase inhibitors seem to have been mediated through just those side effects. So for some years now in the gamma secretase field, the hunt has been on for compounds that will shut down beta-amyloid production without messing with the other functions of the enzyme complex.
Myriad Genetics took such a compound of theirs, Flurizan, into the clinic, after licensing it out to the Danish CNS drug company Lundbeck. They claim that these aren't straight inhibitors, but rather change the activity of the protease in some way that relatively less amyloid is produced. The drug showed some effects in Phase II studies - nothing to jump up and down about, but enough for Lundbeck to pony up for Phase III.
They wish now that they hadn't. As of this morning, the drug appears to have missed all its clinical endpoints in the Phase III trial: no improvement in cognition, no improvement in quality of life. There's no way to spin this kind of result, and the company announced at the same time that they're discontinuing any further work on the compound. (Interestingly, this news seems to have actually made some of its investors happier). It's Lundbeck, though, that seems to be left holding the bag, and their stock is getting hammered to multiyear lows. They have a monstrous patent expiration coming up in 2012 (Lexapro, by far their biggest drug ever), which might explain why they took a flier on the Myriad compound in the first place. The whole effort looks like something of a Hail Mary throw on their part - and most of those go down as incomplete. . .
Comments (9)
+ TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials
June 17, 2008
Posted by Derek
Let’s start from first principles: most drugs mess something up. More elegantly, most drugs inhibit some enzyme’s activity or block some receptor’s binding site. Proteins are generally pretty well optimized at what they do, so it’s a lot easier to block their activities than it is to speed them up. (There are rare exceptions).
And if you’re going to target an enzyme with a small molecule inhibitor, you’ll do just that – find a small molecule that fits into the active site of the enzyme and gums up the works. In a few cases, we know of drugs that bind to other sites on the protein and mess up the active site indirectly, by altering the whole conformation of the protein, but most inhibitors are in or near the site where the natural substrates bind.
This background is what makes a paper in the latest Nature so odd. A large multicenter academic team has been studying inhibition of beta-amyloid formation by some known anti-inflammatory drugs. Beta-amyloid is cleaved out of a larger protein called APP, and the proteases that do the chopping have long been drug discovery targets. (Mind you, when I was working on Alzheimer’s disease in the early 1990s, we still didn’t know which enzymes those were, which made things rather difficult).
The key enzymes in that process are known as beta-secretase (or BACE) and gamma-secretase. The effect of the various known drugs has seemed to be more tied to the latter, although no one’s been sure just what the mechanism is, since none of them seem to be actual gamma-secretase inhibitors when you study them in isolated systems. The current work has turned some of these drugs into photoaffinity probes to try to find out what they’re really targeting.
(For those outside the field, photoaffinity probes are derivatives of some compound of interest, where some special UV-light-absorbing group has been attached off the back end. These photoaffinity groups are innocuous under normal conditions, but they turn into crazily reactive intermediates when they’re irradiated, and will then form a bond with the first thing they see. The idea is that you let your photoaffinity-modified compound find its usual protein targets, then you turn on the ultraviolet lamp. The reactive group does its werewolf thing and forms a permanent bond to the protein its next to. You can then search for the strangely labeled proteins, and you’ve found what the drug of interest was binding to. When it works, it works, although it’s a lot harder than I’ve made it sound).
When they labeled various gamma-secretase systems, all the way up to whole cell extracts, they found that the anti-inflammatories did not actually seem to bind to gamma-secretase at all: it wasn’t labeled. Based on earlier enzyme studies, that’s probably what they expected. But what was labeled was a real surprise: the APP protein, the substrate of the enzyme. Looking more closely, it appears that the compounds bind right to the part of APP that gets cleaved into beta-amyloid, and inhibit the enzyme’s action that way.
That, as far as I know, is pretty much a first. Update: the closest thing might be the mechanism of the antibiotic vancomycin, which binds to the weird D-Ala-D-Ala section of two of the components of the gram-positive bacterial cell wall and prevents them from being used.). This isn’t something that most drug discovery programs would try a priori, that’s for sure. For one thing, we have a hard time getting small molecule to bind to protein surfaces. Active sites inside proteins are our usual speed, because those are more defined cavities which are optimized to hold reasonably small substrates. But sticking to some outer part of a protein, while it does happen, is very hard to do in a targeted fashion. (We’d love to learn the trick, if there’s a trick to be learned – inhibiting protein-protein interactions with small molecules would open up a whole new world of drug targets).
Another reason that no one targets substrates instead of enzymes is that there’s generally a whole lot more substrate floating around than there is enzyme. Imagine someone throwing a hungry piranha into a pond full of goldfish. Which is the more efficient way to defuse the situation - armoring each goldfish, or disabling the piranha? That metaphor just occurred to me, and while a bit weird, it’s actually reasonably close to the situation you have with a protease enzyme and its substrates - if you want to get fancy, you can imagine that the piranha only likes certain types of goldfish, and only bites them in select spots.
But on the other side, there's also a reason why protecting the substrate might actually help out in some situations. Proteases tend to have multiple targets, so inhibiting them can also disrupt pathways that you didn't want to touch. Binding to the one substrate you care about might give you a much cleaner profile, compared to shutting down everything.
So you have to wonder what this result means. Have we been missing a whole range of potential enzyme inhibitors by ignoring things that bind to the substrates? I'm not convinced of that yet, but I am interested. I still have a hard time believing that we can do a good job targeting particular protein surfaces, at least at present, and I can't help wondering if there's something odd about that beta-amyloid sequence that makes it more likely to pick up small molecule interactions. (It certainly excels at picking up interactions with itself if it gets a chance, which is the whole problem). It's still going to be a lot easier to inhibit enzymes directly rather than bind to their targets, but it's worth exploring. We need all the ideas we can get.
Comments (7)
+ TrackBacks (0) | Category: Alzheimer's Disease
June 13, 2008
Posted by Derek
The long-running saga of Elan's attempt to come up with a vaccine for Alzheimer's disease continues. There have been bold attempts, setbacks, rethinks, more setbacks, and now they're starting up again. Dosing of the latest version of their vaccine against the beta-amyloid protein, known as ACC-001, was suddenly halted in April when one patient came down with a skin lesion which was thought to be possibly autoimmune-linked vasculitis.
Biopsy results didn't confirm that, though, and the Elan/Wyeth partnership is resuming clinical studies. I'm not sure what that couple of months has done to their trial design; I assume that they've just started enrolling new patients and will continue with them, while continuing to monitor the former dosage groups. Maybe, though, there's a way to continue with some of those people and not lose all the time, effort, and data.
The idea of an amyloid vaccine has always excited and alarmed me in equal measure. But that's how I feel about the immune system in general, come to think of it. We have enough cellular firepower to completely destroy ourselves from the inside out - keeping that on a leash to where it (mostly) only goes after what it's supposed to is extremely impressive.
Now, I think that the usual sorts of vaccines are one of the great public health advances of civilization, but they work so well because they're targeted to outside agents (viral coat proteins and the like). Even so, there's a disturbingly large part of the population that remain suspicious of all vaccinations - I say "disturbing" not least because if that population gets too large, the efficacy of vaccination in general could be crippled. But what will these people think about a vaccine that's targeted to an endogenous protein? My immunology may need brushing up, but I can't think of any other example of such.
One thing that may keep this from becoming a huge issue, though, is that an amyloid vaccine, if it succeeds, will be targeted at the elderly rather than at children. And it'll be something that will have an effect against a disease that everyone can see right in front of them, rather than preventing diseases that most people have only read about in books. We'll be back at the situation that prevailed when the polio vaccine was introduced: no one had much doubt that the vaccine was better than the disease.
But even a vaccine fan like me still has room to admire, from a distance, the nerve of this approach. The brain is a special case, immunologically, and letting slip the dogs of war in there is not an intrinsically safe idea. But Alzheimer's is an intrinsically nasty disease. . .
Comments (2)
+ TrackBacks (0) | Category: Alzheimer's Disease
May 13, 2008
Posted by Derek
Schering-Plough has had its share of troubles over the years, but the company has also seen itself saved by some pretty unlikely compounds. Vytorin (ezetimibe) is the example I’ve spoken about here, and if the drug doesn’t seem like a savior at the moment, well, you have to keep in mind that it was the biggest thing for them since Claritin went off-patent ten years ago.
Now there’s another one potentially coming up. Expectations are building for a thrombin receptor antagonist compound, SCH 530348. And I have a history with this one, too: while the labs down one hallway from me were discovering ezetimibe, down the other hallway they were laying the foundation for this one. There’s a big difference, though, in the way I saw the two.
This thrombin antagonist is an unlikely drug for several reasons. For one thing, its structure is not the sort of thing most medicinal chemists would go out of their way to make. But there’s a good reason for that: to a first approximation, it wasn’t made with medicinal chemistry in mind. 530348 is based on a natural product called himbacine, whose fame, such as it is, rests on its properties as a semi-selective muscarinic antagonist. And that’s how Schering-Plough got interested in this class of compounds; thrombin had nothing to do with it.
At the time (early to mid 1990s) the company had a team working on Alzheimer’s disease, and I’ll go ahead and mention again that I was one of the people involved. (Five minutes on SciFinder would tell you that, anyway). We were quite interested in selective muscarinic antagonists, particularly for the m2 subtype, and himbacine was at the time one of the more selective compounds with that profile. So one of the group leaders at the company, Sam Chackalamannil, decided to synthesize it and do some SAR around the structure.
That was no small undertaking. Himbacine’s not one of the most complex natural products by any means, but it’s no stroll to the beach, either, especially when compared to the usual sorts of drug structures. It took a lot of time, a lot of ingenuity, and (most importantly) a lot of effort to do it. And I. . .well, I thought this was a terrible idea.
I really did. By the time himbacine itself got made, the project team had muscarinic compounds that were more selective and more potent (and a lot easier to make, to boot). I would listen to Chackalamannil’s people presenting their long, difficult routes during meetings, and I’d sit there imagining the company going slowly bankrupt if everyone adopted this approach, the revenue slowly sinking as the number of JACS communications rose. I couldn’t see the point, and although I don’t think I ever quite had the nerve to say so to Chackalamannil himself (hi, Sam!), I said it to plenty of other people.
So, is it time for me to eat crow? Well, one plateful, at least. Some of the himbacine analogs hit in the high-throughput screen for thrombin activity, to everyone’s surprise, and some further compounds (now shed of their muscarinic activity) were even better. The drug discovery effort culminated in 530548, which now might be about to benefit a huge number of people and make the company a ton of money, if everything goes well.
Of course, if these things hadn’t hit in the thrombin assay, I could have remained secure in my opinion. After all, they were never worth very much as muscarinics, as far as I know. (Of course, our muscarinic compounds, in the end, never were worth very much as Alzheimer’s drugs, which is something to keep in mind). So that’s the question: how likely is it for molecules like this to work? It’s very hard to answer that, but given this data point, I guess the answer is “at least a little more likely than I thought”. The very fact that they didn’t look like most other things in the screening deck was probably in their favor. I still think that these compounds were a long shot, but this is a business that lives on long shots. This one came through, and congratulations to everyone involved.
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+ TrackBacks (0) | Category: Alzheimer's Disease | Cardiovascular Disease | Drug Development
May 6, 2008
Posted by Derek
Several recent papers in Neurology offer some interesting ideas on Alzheimer's disease. The one that's getting some headlines today suggests that long-term use of ibuprofen has a protective effect against the disease. Actually, the authors looked at all sorts of non-steroidal antiinflammatory drugs, but the correlation was strongest for ibuprofen. (That may be just because it's used so much, however, and not some intrinsic property of that specific drug). Interestingly, although some NSAIDs have been shown to inhibit formation of beta-amyloid (the protein fragment implicated for many years in Alzheimer's), no particular effect was seen for that class of drugs versus the other NSAIDs.
There's long been a suspicion that a lot of Alzheimer's pathology is driven by inflammation cascades, and although evidence has been mixed to date, this would seem to be good evidence for that idea. (More on this in another post). This wasn't a prospective study - they didn't enroll people just to test this idea - but a huge number of VA patients were studied retrospectively, and the authors appear to have done as much as possible to control for other variables. Of course, in an observational study like this one, you can't control for the biggest possible confounding factor: what if there's something about patients who end up taking NSAIDs more often that also keeps them from developing Alzheimer's? That certainly can't be ruled out, but I don't think there's room for that in most of the headlines. It's going to be tempting for worried patients to start taking ibuprofen to prevent dementia - and that just might work, still - but we really can't be sure without plenty of prospective trial data.
Of course, not everything is good for preventing Alzheimer's. You can apparently add statins to that list. An examination of aging Catholic clergy (mostly nuns) showed no correlation at all between statin use and the development of the disease. This is one of those long-running studies that ends with death and subsequent brain histopathology, too, so it's pretty hard to argue with. Intellectually demanding work, though, does perhaps show a protective effect. Interestingly, this effect was even stronger in the cohort of patients that scored lower in assessment of overall intelligence, which makes sense in a way. (Cue the arguments about whether general intelligence exists, whether it can be measured, and if so, whether it's being measured in the correct way).
On the ever-profitable herbal front, you see all sorts of claims made for Gingko biloba extract and cognitive function, and there are a lot of contradictory studies (many of which, unfortunately, aren't worth much). This latest one won't help much - in the intent-to-treat analysis, no effect was seen. When they controlled for how well patients stuck to the treatment, then some correlations emerged between taking the extract and slower rates of memory loss. Unfortunately, a correlation (at the same level of significance) emerged with stroke and associated TIAs. My prediction: the ginkgo biloba sellers will trumpet the first set of statistics, assuming they need recourse to any data at all, and ignore the second one completely.
Such is the current state of Alzheimer's. To be honest, none of these studies (or most of the others in the same issue) would have been out of place back when I was working in the field in the early 1990s. The field awaits its breakthrough, and has been waiting for a long time. . .
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+ TrackBacks (0) | Category: Alzheimer's Disease
February 28, 2008
Posted by Derek
Science has coverage of a diagnostic test for the APOE gene that’s coming into the market. For about $400, you can find out what form of the protein you have. The problem is, the main thing this test is good for is telling you that you have a greater-than-average chance of developing Alzheimer’s disease, which raises the question of whether it’s good for anything at all.
Most of the people quoted in the article have their doubts, which I share. Since we really don’t have any decent therapies for Alzheimer’s, what’s the good of knowing that you’re at greater risk for it? The only exception I can think of is mentioned by law professor Henry Greely of Stanford: if you’re homozygous for APOE4, you’re about 15 times more likely to develop Alzheimer’s. That gets into the range where you might want to make some long-term plans. Still, yikes – think of getting those results back.
About 2% of the population could potentially open that envelope. A further 25% are heterozygous for the gene, which corresponds to maybe 3 times the usual risk. That combination of a large number of people with a smaller level of risk seems to me to put it in the “not worth it” category. The psychological distress would seem to outweigh any benefit. Personally, as someone who makes his living with his memory and his brain, I’d be horrified, and to no good end. (And I’m a pretty even-keeled person, as my wife, who does the worrying in the family, will testify). It’s to the point that there’s even been a study following up the psychological reaction to the news of the test. It didn’t show anything alarming, apparently, but the sample was from people with a family history of Alzheimer’s.
No, I think that I’d have to be at least twenty years older to consider taking such a test at all, and even then I’d only want to know if I turned out to be homozygous, which I suppose I could be. (My kids, being Arkansas-Iranian hybrids, have a decreased chance of being homozygous for much of anything). I was going to say that I’d also like to know if I turned out to have no APOE4 allele at all, but quickly realized that those stipulations would end up telling me my status no matter what.
Anyway, here’s hoping that in twenty years we have something more useful to offer to people in that position. And here’s hoping that Smart Genetics, the company that has licensed the test and is bringing it to market, handles it responsibly and resists the temptation to sell fear and uncertainly for a profit. But the article’s quote from the company’s CEO, Julian Awad, isn’t encouraging: “We saw there was a big growth" in genetic testing and believed "there was something there for adding value to what people wanted," he says. I’m still working out what that sentence might actually mean, but I’m not sure I like it. Perhaps it’s just my aversion to business-speak.
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+ TrackBacks (0) | Category: Alzheimer's Disease
February 11, 2008
Posted by Derek
One of the first projects I ever worked on when I started in industry was targeting Alzheimer's disease. Things could have easily worked out to find me still targeting Alzheimer's disease, nearly twenty years later, because the standard of care really hasn't advanced all that much in the intervening years.
It's a hard, hard area to work in. CNS programs are always difficult, since we understand less about the brain's workings than those of any other organ, and since the brain's own blood supply is another barrier to getting a drug through to do anything. And Alzheimer's has tough features on top of that, since (for one thing) we're the only animal that gets the disease, and (for another) the clinical trials needed to show efficacy can be hideously long, large, and expensive. And the underlying biochemistry has been a tangle, too: I've said for years that if you'd told me back in 1990 that people would still be arguing in 1999 (or 2002, or 2007. . .) about whether amyloid caused Alzheimer's or not, that I probably would have buried my head in my hands.
Well, it's 2008, and the arguments may finally get settled. There's a report in Nature from a group at Harvard who did an experiment that's simultaneously brute-force and elegant. The elegant part was the monitoring live brain cells in mutant mice as amyloid protein deposited among them - and the brute force part was that this monitoring involved surgically implanting a small window into their skulls to do it.
What they found was that the characteristic amyloid plaques of Alzheimer's can form startlingly quickly - on a time scale of hours. This is beyond what anyone had suspected, for sure. And the further pathologies (microglia, etc.) that form around the plaques definitely come later, settling a long-standing dispute. There's always the worry that the mouse model (which was engineered to develop amyloid within the brain) might not reflect the human disease, but this is pretty compelling (and alarming) stuff.
If this is even close to what's going on in humans, a therapy that tries to prevent amyloid formation or deposition is going to have some real work to do. We'll be finding that out, though, and good luck to everyone involved. . .
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+ TrackBacks (0) | Category: Alzheimer's Disease | The Central Nervous System
October 15, 2007
Posted by Derek
The news of a possible diagnostic test for Alzheimer’s disease is very interesting, although there’s always room to wonder about the utility of a diagnosis of a disease for which there is little effective therapy. The sample size for this study is smaller than I’d like to see, but the protein markers that they’re finding seem pretty plausible, and I’m sure that many of them will turn out to have some association with the disease.
But let’s run some numbers. The test was 91% accurate when run on stored blood samples of people who were later checked for development of Alzheimer’s, which compared to the existing techniques is pretty good. Is it good enough for a diagnostic test, though? We’ll concentrate on the younger elderly, who would be most in the market for this test.The NIH estimates that about 5% of people from 65 to 74 have AD. According to the Census Bureau (pdf), we had 17.3 million people between those ages in 2000, and that’s expected to grow to almost 38 million in 2030. Let’s call it 20 million as a nice round number.
What if all 20 million had been tested with this new method? We’ll break that down into the two groups – the 1 million who are really going to get the disease and the 19 million who aren’t. When that latter group gets their results back, 17,290,000 people are going to be told, correctly, that they don’t seem to be on track to get Alzheimer’s. Unfortunately, because of that 91% accuracy rate, 1,710,000 people are going to be told, incorrectly, that they are. You can guess what this will do for their peace of mind. Note, also, that almost twice as many people have just been wrongly told that they’re getting Alzheimer’s than the total number of people who really will.
Meanwhile, the million people who really are in trouble are opening their envelopes, and 910,000 of them are getting the bad news. But 90,000 of them are being told, incorrectly, that they’re in good shape, and are in for a cruel time of it in the coming years.
The people who got the hard news are likely to want to know if that’s real or not, and many of them will take the test again just to be sure. But that’s not going to help; in fact, it’ll confuse things even more. If that whole cohort of 1.7 million people who were wrongly diagnosed as being at risk get re-tested, about 1.556 million of them will get a clean test this time. Now they have a dilemma – they’ve got one up and one down, and which one do you believe? Meanwhile, nearly 154,000 of them will get a second wrong diagnosis, and will be more sure than ever that they’re on the list for Alzheimer’s.
Meanwhile, if that list of 910,000 people who were correctly diagnosed as being at risk get re-tested, 828 thousand of them will hear the bad news again and will (correctly) assume that they’re in trouble. But we’ve just added to the mixed-diagnosis crowd, because almost 82,000 people will be incorrectly given a clean result and won’t know what to believe.
I’ll assume that the people who got the clean test the first time will not be motivated to check again. So after two rounds of testing, we have 17.3 million people who’ve been correctly given a clean ticket, and 828,000 who’ve been correctly been given the red flag. But we also have 154,000 people who aren’t going to get the disease but have been told twice that they will, 90,000 people who are going to get it but have been told that they aren’t, and over 1.6 million people who have been through a blender and don’t know anything more than when they started.
Sad but true: 91% is just not good enough for a diagnostic test. And getting back to that key point in the first paragraph, would 100% be enough for a disease that we can't do anything about? Wait for an effective therapy, is my advice, and for a better test.
Update: See the comments for more, because there's more to it than this. For one thing, are the false positive and false negative rates for this test the same? (That'll naturally make a big difference). And how about differential diagnosis, using other tests to rule out similar conditions? On the should-you-know question, what about the financial and estate planning implications of a positive test - shouldn't those be worth something? (And there's another topic that no one's brought up yet: suicide, which you'd have to think would be statistically noticeable. . .)
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+ TrackBacks (0) | Category: Alzheimer's Disease | Biological News
May 17, 2007
Posted by Derek
(My apologies for no update today - it's been hectic around here, for reasons that I hope to be able to reveal soon).
Some of the first work I did in the industry was on Alzheimer's disease. It's hard stuff to deal with, and it was even hard seventeen years ago, I can tell you. You may have noticed that there isn't much that anyone can do about AD, even now, and there's most definitely a reason for that: it's a hard disease in a hard field.
One of the most promising areas (for an unnervingly long time) has been the inhibition of the formation of beta-amyloid, long thought (though not by everyone) to be a primary cause of Alzheimer's pathology. (There's no doubt that AD patients show abundant deposits of beta-amyloid plaques in their brain tissue - the argument has been about whether amyloid gives you Alzheimer's, or if Alzheimer's gives you amyloid). The protein is clipped off a larger precursor protein (APP, which is an acronym for just what you think), and back when I started in the field, the major race was on to find out which proteases did the clipping.
That's been worked out in the intervening years. One of them, the beta-secretase enzyme BACE1, has been a target of a lot of work for quite a while now. Getting good, selective, non-peptidic inhibitors hasn't been easy, though, but here's some from Merck, and there have been other reports. Will one of these be the Alzheimer's drug that everyone's been waiting for?
Well. . .maybe not. A recent PNAS paper from a large academic/industrial collaboration has raised a disturbing possibility. They found that mice that produced extra APP (but did not show beta-amyloid pathology) had improved spatial memory. Disrupting their beta-secretase was downright harmful to their performance, as well, suggesting that some of the beta-secretase cleavage products might actually be beneficial. It would be just like the natural world to have beta-amyloid turn out to be memory-enhancing in smaller quantities, but no one's sure if it's the player here - it could also be the intracellular hunk of APP that's also liberated by the secretase.
The authors finish the paper with an unmissable warning:
"A practical implication of this work involves safety considerations for experimental therapies of AD. To ensure that experimental therapies do not prevent BACE1-mediated facilitation of memory by APP, preclinical studies of experimental beta-secretase inhibitors should be done not only in animal models of AD, but also in natural animals to evaluate their effects on normal cognitive function."
One wonders what GlaxoSmithKline has made of this, in light of their recent paper on in vivo dosing of a BACE1 inhibitor. And there may be others. . .
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+ TrackBacks (0) | Category: Alzheimer's Disease
April 2, 2007
Posted by Derek
Here's something that you don't see discussed very often, but it's worth some thought: what kind of personality do you need to have to do drug discovery research? Clearly, any conclusions are going to carry over well to other fields, but drug work has some peculiarities that can't be ignored.
The most obvious one is that the huge, horrible, overwhelming majority of projects never lead to a marketed drug. Many readers will have seen the sobering statistics of 85 to 95% failure rates in the clinic, but (bad as that is) it doesn't get across the number of times that projects get nowhere near the clinic at all. Take it from the top: the majority of targets that are screened for chemical matter don't turn up anything useful (it's not even close). The majority of the ones that do still die on their way to clinical trials. And then a solid 90% of those don't make it to market.
So, if you define yourself as a success by whether or not you've put something on a pharmacy shelf, you've set a very high bar, one that many people in basic research don't reach. It's different for people further down the line, where the field has already narrowed. But if you're working on early med-chem, for example, you're likely to go years between realistic shots at a drug you can claim part of the credit for.
That'll vary by your company's culture, too. Some companies bang out projects like a sawmill spitting out boards - or try to, anyway - while others carefully take their time for years and years. There's no certain advantage to either method, as far as I can see (else the companies doing the best one would have taken over by now and driven other modes out of existence). But you'll certainly have more shots on goal at the first type of company, which might keep your spirits up. Of course, the fact that you're largely going to be getting more chances to fail in the clinic might just depress them again, so you have to take that into account.
It'll also vary by therapeutic area. Central nervous system projects are going to run slower than oncology ones, by and large. In cancer, the clinical goals are comparatively clear, and where the disease is often (and most terribly) progressing at such a pace to give you solid numbers in a reasonably short period. Contrast that to Alzheimer's disease, for example, whose ruinous clinical trials could take years to tell you anything useful. Cancer will also give you more shots per compound, since a drug that does zilch for pancreatic cancer (and most do just that) might be useful in the lung or liver. While what we call cancer is several hundred diseases, what we call Alzheimer's might only be one. Depression and schizophrenia are clearly more complicated and split up, but (as opposed to cancer), there's no easy way to tell how many types there are or what particular one a patient might be presenting with, so the clinical work is correspondingly more difficult.
So, this is the pharmaceutical world you're going to have to live in. If you take each drug project personally, as an indicator of your own worth, you're probably not going to make it. You'll be beaten down by the numbers. As an antidote, a bit of realistic fatalism is helpful, although too much of it will shade into ah-that'll-never-work cynicism, which is the ditch on the other side of the road from prideful optimism. I'd recommend learning to enjoy the upside surprises, and to not be surprised by the failures (while still looking them over to see if there's something you can avoid next time around). You really have to draw a line between the things you can affect through your own talent and hard work, and the things you can't. Most of the crucial stuff is in the second category. A sense of humor about your own abilities and limitations will serve you well. But that goes for a lot of other jobs besides the drug business, doesn't it?
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+ TrackBacks (0) | Category: Alzheimer's Disease | Cancer | Drug Development | The Central Nervous System | Who Discovers and Why
April 14, 2005
Posted by Derek
Pfizer and Eisai picked up some headlines on the news that their Alzheimer's drug, Aricept (donezipil) showed some effectiveness in delaying the onset of Alzheimer's. That used to be my field of work, although I've got no competing interest in that therapeutic area now. I make that disclaimer up front, because I'm not all that impressed by this new study.
Aricept is a cholinesterase inhibitor, part of the first wave of compounds that were brought in as Alzheimer's therapies. Inhibiting cholinesterase increases the amount of a key neurotransmitter (acetylcholine) that hangs around in the synapse, which should, in theory, lead to stronger signaling between neurons. But this is and always has been a brute-force mechanism, real back-of-the-envelope stuff, which I realized even when I used to work on something pretty similar.
We don't understand neurotransmission well enough to be sure that we're doing much good just by turning up synaptic signaling. To add to the problem, the relevant cholinergic neurons are among those being damaged by Alzheimer's itself, so the drug's therapeutic target is slowly disappearing. That's why the cholinesterase inhibitors are recommended for very early stages of Alzheimer's, and are considered useless for late stages of the disease.
And that's why Pfizer went out as early as possible, out to before patients had even shown signs of Alzheimer's at all. It appears that Aricept therapy helped slow the onset of the disease, among those who developed it at all. Problem is, the effect wasn't large, and after three years any benefit had completely disappeared. The placebo-treated Alzheimer's patients were in the same shape as the ones who had been getting Aricept all along. (Note that Aricept has been studied in non-Alzheimer populations before.)
You wouldn't know all this from a quick look at most of the popular press, though, which went with New Breakthrough headlines like "Drug is First to Delay Onslaught of Alzheimer's." (Science, on the other hand, went with "Study Questions Efficacy of Popular Alzheimer's Treatments", which is more like it.) I'm in the same camp, and it's the same one as the editorial from the issue of the New England Journal of Medicine where the study appeared. Aricept, the journal said, "may offer some benefit, but any such benefit is quite limited and apparently transient" Try turning that into something that'll make you sit past the commercial break. . .
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January 23, 2005
Posted by Derek
So Johnson and Johnson is the latest company to try to broaden their market for a drug and run into cardiovascular side effects. Their Alzheimer's drug Reminyl (galantamine), makes some money, but is hardly a blockbuster. It's a natural product (derived from daffodil bulbs, of all things), and it's a cholinesterase inhibitor, the same mechanism as the two other Alzheimer's drugs on the market. None of them are gigantic sellers, because they don't do all that much for people, especially once they have serious symptoms. But if you could show beneficial effects in the pre-Alzheimer's population, then the potential number of patient could be much larger. I should, in fairness, point out that the potential benefits to the patients could be larger, too: earlier treatment before the disease has had more time to do irreversible damage.
Cholinesterase inhibition is a pretty crude tool to help Alzheimer's, but it's all that we have at the moment. The idea is the turn up the volume of neuronal signals that use acetylcholine as a transmitter molecule, by inhibiting the enzyme that would break it down and sweep it out of the synapse. I don't see an obvious connection between this mechanism and the cardiovascular effects that showed up in J&J's trial.
This is another illustration of the same thing that's bringing down the COX-2 inhibitors. The larger the population that takes your drug, and the more clinical trials you run, the better your chance of finding the side effects. All drugs have side effects, and if you turn over enough rocks you'll see them. But without expanding the patient population, you won't be helping all the people you could help, and you won't be making all the money you could make. It's like walking through a minefield. It's what we do for a living over here. What a business!
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+ TrackBacks (0) | Category: Alzheimer's Disease | Toxicology
November 9, 2004
Posted by Derek
The October 29th issue of Science has an interesting article from a team at Stanford on a possible approach for Alzheimer's therapy. The dominant Alzheimer's hypothesis, as everyone will probably have heard, is that the aggregation of amyloid protein into plaques in the brain is the driving force of the disease. There's some well-thought-out dissent from that view, but there's a lot of evidence on its side, too.
So you'd figure that keeping the amyloid from clumping up would be a good way to treat Alzheimer's, and in theory you'd be correct. In practice, though, amyloid is extremely prone to aggregation - you could pick a lot of easier protein-protein interactions to try to disrupt, for sure. And protein-protein targets are tough ones to work on in general, because it's so hard to find a reasonable-sized molecule that can disrupt them. It's been done, in a few well-publicized cases, but it's still a long shot. Proteins are just too big, and in most cases so are the surfaces that they're interacting with.
The Stanford team tried a useful bounce-shot approach. Instead of keeping the amyloid strands off each other directly, they found a molecule that will cause another unrelated protein to stick to them. This damps down the tendency of the amyloid to self-aggregate. The way they did this was, by medicinal chemistry standards, simplicity itself. There's a well-known dye, the exotically named Congo Red, that stains amyloid very powerfully - which must mean that it has a strong molecular interaction with the protein. They took the dye structure and attached a spacer group coming off one end of it, and at the other end they put a synthetic ligand which is known to have high affinity for the FK506 binding protein (FKBP). That one is expressed in just about all cell types, and there are a number of small molecules that are known to bind to it.
The hybrid molecule does just what you'd expect: the Congo Red end of it sticks to amyloid, and the other end sticks to FKBP, which brings the two proteins together. And this does indeed seem to inhibit amyloid's powerful tendency for self-aggregation. And what's more the aggregates that do form appear to be less toxic when cells are exposed to them. It's a fine result, although I'd caution the folks involved not to expect things to make this much sense very often. That stich-em-together technique works sometimes, but it's not a sure thing.
So. . .(and you knew that there was going to be a paragraph like this one coming). . .do we have a drug here? The authors suggest that "Analogs based on (this) model may have potential as therapeutics for Alzheimer's disease." I hate to say it, but I'd be very surprised if that were true. All the work in this paper was done in vitro, and it's a big leap into an animal. For one thing, I'm about ready to eat my own socks if this hybrid compound can cross the blood-brain barrier. Actually, I'm about ready to sit down for a plateful of hosiery if the compound even shows reasonable blood levels after oral dosing.
It's just too huge. Congo Red isn't a particularly small molecule, and by the time you add the linking group and the FKBP ligand end, the hybrid is a real whopper - two or three times the size of a reasonable drug candidate. The dye part of the structure has some very polar sulfonate groups on it, as many dyes do, and they're vital to the amyloid binding. But they're just the sort of thing you want to avoid when you need to get a compound into the brain. No, if this structure came up in a random screen in the drug industry, we'd have to be pretty desperate to use it as a starting point.
Science's commentary on the paper quotes a molecular biologist as saying that this approach shows how ". . .a small drug becomes a large drug that can push away the protein. . ." But that's wrong. You can tell he's from a university, just by that statement. I'm not trying to be offensive about it, but neither Congo Red nor the new hybrid molecule are drugs. Drugs are effective against a disease, and this molecule isn't going to work against Alzheimer's unless it's administered with a drill press. If that's a drug, then I must have single-handedly made a thousand of them. The distance between this thing and a drug is a good illustration of the distance between academia and industry.
To be fair, this general approach could have value against other protein-protein interaction targets. I think that it's worth pursuing. But I'd attack something other than a CNS disease, and I'd pick some other molecule than Congo Red as a starting point.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Alzheimer's Disease
August 3, 2004
Posted by Derek
One of the comments in my post on animal models prompts me to write a bit more on mutations. I stated that the mutant animal models that we use all have something wrong with them, but I didn't mean to imply that all mutations will do that. There are plenty of so-called "silent" mutations out there, single amino-acid changes in large proteins that basically make no difference. If you switch, say, valine for isoleucine, most of the time it's not going to hurt much (or help much.) (The reason our mutant animals have something wrong with them is that we're trying to mimic a diseased human; if they weren't defective, we wouldn't be interested.)
Billions of years of evolution have honed things down pretty well. If a protein gets altered, it's a lot easier to have a sudden loss of function than it is to have a sudden gain. It's like popping your hood and throwing rocks at your car engine - you have a better chance of damaging the thing than you have of whacking it in a way that increases your gas mileage.
I wrote about a particularly vivid example of this a couple of years ago on my old Lagniappe site. (That material seems to be succumbing to bit-rot when I try to pull it out via Google, so I'm going to rescue some of it every so often.) Here's a slightly reworked version of what I had to say about a famous Alzheimer's mutation:
One of the things that gives me the willies about biochemistry is the nonlinearity. If anyone were to ever come up with a set of equations to model all the ins and outs ofa living organism, there would be all these terms - way out in the boonies of the expression - with things to the eighth and tenth powers in them.
Of course, the coefficients in front of those terms would usually be zero, or close to it, so you'd hardly know they were out there. But if anything tips over and gives a little weight to that part of the equation. . .suddenly something unexpected wakes up, and a buried biological effect comes roaring to life out of nowhere.
Here's the real-world example that got me thinking in that direction. When I used to work on Alzheimer's disease, I first learned the canonical Amyloid Hypothesis of the disease. Briefly put, at autopsy, the brains of Alzheimer's patients always show plaques of precipitated protein, surrounded by dying neurons. It's always the same protein, a 42-amino-acid number called beta-amyloid. A good deal of work went into finding out where it came from, namely, from a much larger protein (751 amino acids) called APP. That stands for "amyloid precursor protein," in case you thought that acronym was going to tell you something useful
The ever-tempting hypothesis has been that an abnormal accumulation of beta-amyloid is the cause of Alzheimer's. This isn't the time to get into the competing hypotheses, but amyloid has always led the pack, notwithstanding a vocal group of detractors who've claimed that Alzheimer's gives you amyloid deposits, not the other way around. (Note from 2004: I wrote recently about developments in the amyloid field here and here.)
So what's APP, and what's it good for? It took all of the 1990s to answer that one, and the answers are still coming in. It's found all over the place, and seems to have a role in cellular (and nuclear) signaling. Normally, it's cleaved to give smaller protein fragments other than the 42-mer that causes all the trouble.
One of the stronger arguments for amyloid as an Alzheimer's cause came from the so-called "Dutch mutation," which is what got me to thinking. As was worked out in 1990, there's a family in Holland with a slightly different version of APP. One of the 751 amino acids is changed - where the rest of the world has glutamic acid, they have glutamine - almost the same size and shape, but lacking the acidic side chain.
So. . .there's one amino acid out of 751 that's been altered. And that's in one protein out of. . .how many? A few hundred thousand seems like the right order of magnitude for the proteome, maybe more. And what happens if you kick over that particular grain of sand on the beach? Well, what happens is, you die - with rampaging early-onset Alzheimer's (and a high likelihood of cerebral hemorrhage) before you're well into your 40s.
As it happens, that amino acid is right in the section of the protein that becomes beta-amyloid. Altering it makes it much easier for proteases to come and break the amide bond in the protein backbone, so you start accumulating beta-amyloid plaques early. Much too early. Bad luck - the change of just a few atoms - snowballs into metabolic disaster. Since then, many other mutations have been found in APP, and many of them are bad news for similar reasons.
But it's not like every amino acid substitution in some random protein causes death, of course. There are any number of silent mutations, and plenty that are relatively benign. Most of the time, those high-exponent terms out there in the mathematics sleep on undisturbed. And it's better that way.
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December 30, 2002
Posted by Derek
After a (reasonably) refreshing holiday break, Lagniappe is back. Thanks to everyone who kept doggedly hitting this site during the last few days - I admire your persistance.
I notice from my site's counter that I get a small but steady flow of Google hits for various miracle cures. I said some nasty things about the Budwig flaxseed-oil diet a while back, for example, and I still get Googled for that one. For those visitors, here's a post that (with any luck) will show up for a long time to come.
To put it in one sentence, distrust simple cures for complex diseases. Cancer is a complex disease, so are arthritis, MS, Alzheimer's and diabetes. What's a simple disease? An infectious one: there's a proximate cause, and a path to cure it. Get rid of the bacteria, and your septicemia goes with them. Clear out the parasites, and no more malaria. (You'll note that we don't have a universal malaria cure yet, which should say something about how hard even the simpler diseases are.)
The really tough ones, though, are all things that originate from some misfiring of the body's own systems. It's true that there are single-gene diseases, which would be simple to treat if we only knew how to get gene therapy to work. Most of them are rarities, diagnostic zebras that many physicians will never see. The ones that every physician sees are multifactorial and very hard to deal with.
I've spent a lot of time on this site talking about autism recently, and there's a common factor. I believe that many diseases only look like single conditions, which turn into dozens of other diseases on closer inspection. There's no such disease as "cancer," for example. Cancer is the name we sloppily apply to the end result of dozens, hundreds of metabolic or genetic defects and breakdowns, all of which end up as vaguely similar cell-differentiation diseases. It wouldn't surprise me if Alzheimer's ends up as something that can be caused several different ways, all of which end up in the same alternate low-energy state for the brain's metabolic order. (I speculated on this back in the first month of this blog's existence.)
And autism, too, could well be the name we're giving to several different diseases, distinguished by their time course, onset, and severity, caused by all sorts of intricate interplay - the wrong chord played on the instrument at just the wrong time.
You can, at times, find single factors that lead into these diseases - a compound called benzidine leads to bladder cancer, for example, although not in every person exposed, and at unpredictable exposures over unpredictable times. But that doesn't mean that everyone who has bladder cancer has been exposed to benzidine - not many people ever are these days. And stomach cancer, for example, has nothing to do with benzidine at all. Even the simple cases aren't too simple.
Remember the power line scare? How those electromagnetic fields from high-tension lines were messing up everyone's lives? You could see stories about how power-line exposure had been linked to brain cancer, to kidney cancer, to skin cancer. The problem was, one study would show a barely-there tenuous link to brain cancer - but not to anything else. Another would show the same wispy possible connection to kidney cancer - but not to anything else. And so on - after looking over all the data, the best conclusion was that this was all statistical noise. Beware statistical noise - that's another long-running theme around here.
Epidemiology hasn't been a simple field since the days of yellow fever, if it even was then. And medicine hasn't been a simple one since the first days that ever counted. As time goes on, we're clearing out more and more of the easy stuff. The really hard stuff is what's left, and it's going to be resistant to simple fixes.
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October 11, 2002
Posted by Derek
The Alzheimer's vaccine idea that I've covered every so often is back in the news. Two studies coming out in Nature Medicine give it a boost. One shows that the ill-fated Elan clinical trial (which came to a screeching halt when some patients developed brain inflammation) actually did lead to antibody production against the beta-amyloid protein. The antibodies recognized various types of amyloid deposits, and crossed into the brain. (That last part is what has amazed everyone since the first animal results - antibodies aren't supposed to be big players across the blood-brain barrier.)
The other paper reports that a very similar response in rodents can be achieved using a much smaller variant of the amyloid protein. That should lower the chance of inflammatory side-effects considerably, and gives new hope to human studies. This is looking like one of the crazy ideas that just might work - stipulating, for the moment, that amyloid really is the cause of Alzheimer's. . .
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September 22, 2002
Posted by Derek
One of the things that gives me the willies about biochemistry is the nonlinearity. If anyone were to ever come up with a set of equations to model all the ins and outs ofa living organism, there would be all these terms - way out in the boonies of the expression - with things to the eighth and tenth powers in them.
Of course, the coefficients in front of those terms would usually be zero, or close to it, so you'd hardly know they were out there. But if anything tips over and gives a little weight to that part of the equation. . .suddenly something unexpected wakes up, and a buried biological effect comes roaring to life out of nowhere.
Here's the real-world example that got me thinking in that direction. When I used to work on Alzheimer's disease, I first learned the canonical Amyloid Hypothesis of the disease. Briefly put, at autopsy, the brains of Alzheimer's patients always show plaques of precipitated protein, surrounded by dying neurons. It's always the same protein, a 42-amino-acid number called beta-amyloid. A good deal of work went into finding out where it came from, namely, from a much larger protein (751 amino acids) called APP. That stands for "amyloid precursor protein," in case you thought that acronym was going to tell you something useful
The ever-tempting hypothesis has been that an abnormal accumulation of beta-amyloid is the cause of Alzheimer's. This isn't the time to get into the competing hypotheses, but amyloid has always led the pack, notwithstanding a vocal group of detractors who've claimed that Alzheimer's gives you amyloid deposits, not the other way around.
So what's APP, and what's it good for? It took all of the 1990s to answer that one, and the answers are still coming in. It's found all over the place, and seems to have a role in cellular (and nuclear) signaling. Normally, it's cleaved to give smaller protein fragments other than the 42-mer that causes all the trouble.
(To get away from my main point, whether beta-amyloid has any normal biochemical use is a question that can still start some major arguments. Vast amounts of money and time (a very tiny percentage of it mine) have gone into trying to find the proteases that clip it out of APP, and to finding small drug-like molecules to inhibit them. We're finally to the point of having those, and the amyloid hypothesis is getting the acid test in the clinic. That'll all be a topic for another day.)
At any rate, one of the stronger arguments for amyloid as an Alzheimer's cause came from the so-called "Dutch mutation," which is what got me to thinking. As was worked out in 1990, there's a family in Holland with a slightly different version of APP. One of the 751 amino acids is changed - where the rest of the world has glutamic acid, they have glutamine - almost the same size and shape, but lacking the acidic side chain.
So. . .there's one amino acid out of 751 that's been altered. And that's in one protein out of. . .how many? A few hundred thousand seems like the right order of magnitude for the proteome, maybe more. And what happens if you kick over that particular grain of sand on the beach? Wll, what happens is, you die - with rampaging early-onset Alzheimer's (and a high likelihood of cerebral hemorrhage) before you're well into your 40s.
As it happens, that amino acid is right in the section of the protein that becomes beta-amyloid. Altering it makes it much easier for proteases to come and break the amide bond in the protein backbone, so you start accumulating beta-amyloid plaques early. Much too early. Bad luck - the change of just a few atoms - snowballs into metabolic disaster. Since then, a href="http://web.utk.edu/~saydin/omimab.html">many other mutations have been found in APP, and many of them are bad news for similar reasons.
But it's not like every amino acid substitution in some random protein causes death, of course. There are any number of silent mutations, and plenty that are relatively benign. Most of the time, those high-exponent terms out there in the mathematics sleep on undisturbed. And it's better that way.
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July 9, 2002
Posted by Derek
There's a report today that an Alzheimer's medication seems to help memory function even in people who don't have the disease. As reported in Neurology, pilots using a flight simulator performed better when repeating tasks learned while taking Pfizer's drug donepezil (Aricept - it's actually an Eisai drug that Pfizer licensed.)
Before anyone gets too excited, the changes, although statistically meaningful, were small. A quote in the NY Times science section today compared the size of the enhancement to that of the deficit imposed by, say, a hangover. For some people's hangovers that's probably an impressive yardstick, but it was meant to suggest a modest improvement. Still, there's an interesting concept here, and it's been much on the minds of researchers over the years.
Some background: Aricept is a cholinesterase inhibitor, which basically replaced the first such compound on the market, Tacrine (which had sporadically nasty liver toxicity.) As far as I know, it has most of the market for that mechanism. Other companies (such as Bayer) have tried to bring compounds to market, but getting them right can be difficult. After all, a good example of a truly effective, fast-acting cholinesterase inhibitor is nerve gas. You want to back away from that kind of activity for Alzheimer's patients, of course, but side effects are still possible.
And even if the compound is clean, there's only so much a cholinesterase inhibitor can do for someone with Alzheimer's. At best, you can hope to slow the progression of the disease a bit, and response rates vary. Some patients probably show improved quality-of-life, but others are likely wasting their time and money. The whole basis of cholinergic therapy for Alzheimer's (a field I've worked in,) is fairly crude: jacking up the levels of the neurotransmitter acetylcholine across the board. Admittedly, this idea can work for other neurotransmitters (dopamine in Parkinson's disease, or serotonin in depression.) But (just as in the Parkinson's case) it doesn't address the underlying disease; it just tries to ameliorate the symptoms while things get inexorably worse.
But what about people who don't have Alzheimer's? As mentioned above, I can tell you that that question has crossed the mind of everyone working in the memory-enhancement field. What if your drug makes diseased brains more normal, and normal brains. . .better than that? The FDA hasn't dealt much with such issues, understandably, and I can't think of a company that's had the nerve to ask them. But while the market for an effective Alzheimer's drug would be large, the market for a safe memory drug for the general population could be gigantic. The benefits could be similarly huge.
The closest analogy I can think of is the obesity market. Right now, there's no good drug therapy for obesity, period, although people spend billions of dollars trying to say otherwise. Most people's idea of a good obesity drug would be the Magic Pizza Pill - you know, the one you take, and then you can eat all the pizza you want. Don't hold your breath for it; I don't think it's possible. But even a reasonably effective obesity drug would be a huge seller.
And the unspoken assumption about any such drug is that a significant number of the people taking it would not necessarily be all that obese. There are certainly enough obese people to make for a successful drug, and more coming all the time, but there are plenty of folks who would just want to look a little better. Nothing wrong with that, since even modest weight loss is very likely a good thing. But the regulatory assumption is that weight-loss drugs would go primarily to the morbidly obese, whose lives are in more immediate danger. That's not nearly as large a potential market (although at the rate we're going, it could end up being one.)
Companies working on memory-enhancing drugs have had the same thoughts, and done the same math. That said, many of the current therapies being tried for Alzheimer's aren't in this category, since they're more specifically aimed at what seem to be the disease processes. Even among those groups working on memory in general, the odds of dramatically improving function are low. You'd figure that the system is fairly well optimized by now. But what if you did find one? How many people would line up for it? It would be an off-label indication with a vengeance.
I doubt if I would take it myself, not until plenty of others had done so for at least a few years. I'm very nervous and twitchy about CNS medications in general (probably from having worked in the field, as I mentioned!) I have no desire to mess with my brain chemistry unless absolutely necessary.
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February 27, 2002
Posted by Derek
I'd like to take the time to sympathize with Elan Pharmaceuticals over what's happened to their Alzheimer's trial. They had the initiative (and the nerve) to pick up and run with an unusual discovery: that a protein that precipitates in the brains of Alzheimer's patients, beta-amyloid, can be attacked by an immune response.
I'm not going to take sides in the "does amyloid cause Alzheimer's, or does Alzheimer's give you amyloid" controversy. Most money is on the first choice, but there's a vocal minority for the second that makes some good points. At any rate, the idea of going after amyloid deposits by raising antibodies to them was pretty gutsy.
In general, you want to think twice about raising an immune response to one of your own proteins. It's like the old rule of black magic - don't call up anything that you don't know how to send back down. It seems, though, that amyloid, weird and insoluble stuff that it is, looks useless and foreign enough that it can be treated as an invader.
The brain is also considered an immune-privileged organ. You wouldn't have high hopes for a vaccine approach to work there. But they actually cleared amyloid deposits from the brains of rodents (in a special strain bred to have amyloid problems.)
Elan took this into human trials as fast as they could. Unfortunately, they've run into what some feared might be the downfall of the whole approach. Several patients are showing signs of central nervous system inflammation. The immune response appears to have gotten out of hand.
There may be a way to fix this, but it'll be a while before anyone is able to try this approach again. A lot of ground work will have to be done first. It's a pity, because this had the potential to be a home run against a disease that's consumed minds, lives, and a vast amount of research time, money, and talent.
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February 14, 2002
Posted by Derek
That neuroscience business came up, I guess, because I have a minor background in it. I broke into the drug business doing work on schizophrenia, and followed that with several years on Alzheimer's.
If some of the people in the field read this - well, don't take it the wrong way - but I'd almost as soon have a job breaking concrete with my nose. The central nervous system is a very, very hard area to work in. That's partly because brain function is hideously complex: it's an interesting question whether a human brain even has enough ability to comprehend its own workings. But it's partly because a key part of the drug-testing cascade is often missing.
That's animal testing. (And it really is a key part - eventually I'll get into it with the anti-in vivopeople, and I'll argue that position as long as it takes.) The problem with many central nervous system targets is that the animal models either don't exist, or (even worse) exist but are untrustworthy. That last situation is a killer: the models persist because there is a constituency that believe in their relevance. You'll be running into those folks over and over if you try to do without, and they're going to refuse to believe in your drug candidate unless it's been through the wildebeest swim maze, the platypus tail flick assay, whatever.
The models are so hard because you're often trying to affect behavior that is unique to humans - like remembering phone numbers. Whether a rat can remember not to run into the electrified part of the cage is of doubtful relevance. I think that there are many kinds of memory storage, and I don't believe that rats partake of the kinds that we're most worried about. It's true that there must be common molecular mechanisms for all types of memory (at some level) but messing with those processes indiscriminately (the only way we know how, in many cases) is a recipe for trouble. Let's not even get started on the topic of animal models for schizophrenia.
There's been a lot of progress in Alzheimer's the last two or three years. I enjoy reading about it, and I wish everyone working there all the luck in the world. I may need your compounds some day, guys, so keep banging away. But I'm glad that I'm not having to bang away with you.
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