About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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April 9, 2014

The State of Alzheimer's Research, 2014

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Posted by Derek

Via Bernard Munos on Twitter, here's a report from the New York Academy of Sciences looking at the current state of Alzheimer's research. Those various tabs are all live; you can get summaries of each one by clicking.

Looking them over breeds a mixture of hope and despair. The whole thing is themed around the 2025 target that many in the Alzheimer's world have been talking about. And while I understand the need for goals, etc., that year seems way too close. If a promising new compound were to be discovered this afternoon, it wouldn't make it. That brings up another point - many of the speakers at this meeting were talking about moving away from a "compound-centric" point of view. I can see (some of) the point, because there may well be other things to do for Alzheimer's patients. But it's also worth remembering that the reason people are talking like this is that no compounds have worked. This outlook is a second choice driven by necessity, not by some sort of obvious first principle.

And I think that, in the end, Alzheimer's will be arrested by compounds - more than one, most likely, and some of them are quite possibly going to be biomolecules, but compounds all the same. Reading the recommendations about adaptive clinical trials (good idea), broader cooperation and use of common clinical standards (another good idea), and all the others just make me wonder: clinical trials of what? That's the real stumper in this field; where to go next. How to go there is a topic that it's easier to reach agreement on.

Comments (41) + TrackBacks (0) | Category: Alzheimer's Disease

March 10, 2014

A Blood Test for Alzheimer's?

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Posted by Derek

Update: more doubts on the statistical power behind this, and the coverage it's getting in the press.

There's word of a possible early diagnostic blood test for Alzheimer's. A large team (mostly from Georgetown and Rochester) has published a paper in Nature Medicine on their search for lipid-based markers of incipient disease. They say that they have a ten-lipid panel that has a 90% success rate in predicting cognitive decline within three years.

I can certainly see how this would be possible - lipids could be markers of membrane trouble and myelin trouble, and we already know that the lipoprotein ApoE4 is linked with Alzheimer's. At the same time, I'd like to see how this looks when more data are available. The absolute number of patients showing the effect isn't large. And there's always a danger, on these biomarker fishing expeditions, of finding a spurious correlation. The fact that it takes ten lipids to get the accuracy up could be OK, or it could be a sign of statistical trouble. (It's a bit like seeing a QSAR model that needs ten parameters to be predictive).

But this could indeed be real, and if it is, a larger sample will nail it down. That should also give a much better idea of the false-positive and false-negative rates, which will be very important in a diagnosis like this. It'll also be interesting to see if the time horizon can be improved past three years. The usual worries about an Alzheimer's diagnostic apply - some people will want to know, and others won't, since there's no treatment. If this works out, though, it would also seem to be very useful for future clinical trials, which are (more and more) focusing on people in the earliest stages of the disease.

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease

January 23, 2014

Alzheimer's Therapies: A Reasonably Gloomy Update

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Posted by Derek

The New England Journal of Medicine has publications from Pfizer / J&J and Lilly on their multiple phase III trials of anti-amyloid antibodies (bapineuzumab and solanezumab, respectively). As the world knows, neither of them hit their primary endpoints. How optimistic one can be after that is a matter for fine distinctions.

Medscape has a look-on-the-bright-side article here. There's some evidence that the antibodies were affecting amyloid, which is (presumably) at least a start:

. . .an analysis of apolipoprotein E (APOE) 4 carriers found a decreased rate of accumulation of amyloid in the brain in a subset of patients taking bapineuzumab who had positron emission tomography (PET) imaging using Pittsburgh compound B, although the difference was smaller than that seen in phase 2 studies using a higher dose of the drug. And, among carriers, bapineuzumab was associated with reduced concentrations of cerebrospinal fluid (CSF) phospho-tau, a marker of neurodegeneration.

"We were getting some target engagement and that's encouraging," said Dr. Salloway. "But we were limited in our ability to lower amyloid because of the dose-related side effects."

Those side effects were signs of edema in the brain imaging of the bapineuzumab patients who carried the APOE4 gene. Their dose was lowered to half a milligram per kilo, while the other patients got up to 1 mpk. The Phase II trials had gone up to 2 mpk, but that dose was dropped completely. At any rate, I think that bapineuzumab has also been dropped completely; I'm unaware of any further work with it. That's as opposed to solanezumab, where Lilly is famously pressing on.

It's at least better-tolerated than bapineuzumab, perhaps because it doesn't specifically target amyloid fibrils, but goes more after the soluble forms. And that, conceivably, is connected with the hints of efficacy that were seen in the patients with milder forms of Alzheimer's, and on this outcropping of solid bedrock rests Eli Lilly's Alzheimer's strategy. It's a tough place to be, but Lilly is already in a tough place, so a roll of the dice like this might be their best shot at this point.

There's a quote in the Medscape piece saying that we've "entered the era of prevention studies" in the disease, but that's too sunny even for an optimistic guy like me. We still have no clear idea of that actual early mechanisms that lead to Alzheimer's. The amyloid hypothesis, though it has a fair amount of evidence on its side, remains unproven, and every attempt to target it pharmacologically has either failed or (if you squint hard) just about failed. The only reason we're running prevention trials with the agents we have is that they failed to do anything in treatment trials. We have staggered into an era of prevention trials because we have nothing else to offer.

That doesn't mean I'm hoping for solanezumab or anything else to fail - far from it. A preventative agent for Alzheimer's would be a great advance. It's just that I'm not hopeful that any of the current therapies will work that way. If one does, it'll be a real long shot bet that's come through, and it's going to be five to ten years before we'll even know enough to say that. So I hope that I don't see too many "Alzheimer's Prevention Trials Underway!" headlines in the general press. The occasional mentions of a "cure by 2025" make a person wonder, though.

There's also a lot of talk about combination therapies, a monoclonal antibody, plus a secretase inhibitor, plus something for tau, and so on. That may well be the way to go, eventually. But it's worth remembering that previous cocktail regimens like this, in other disease areas, combined agents that showed much more robust effects than anything has in Alzheimer's so far. They were good enough, usually, to be approved on their own. In Alzheimer's, as it stands now, we'd be looking at combining two or three drugs that have all struck out in the clinic, and maybe one or two that we don't even have yet, and hoping for the best. I don't see that as a realistic strategy until something works a bit better. Or works at all.

Comments (24) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

January 10, 2014

A Reply on Academic Alzheimer's Research

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Posted by Derek

One of the authors of a paper I commented on has shown up in the comments section to that post, and I wanted to highlight his reply out here on the front page of the blog. Here's J. R. Brender, from the Michigan side of the authorship:

Hi. I appreciate the comments the given about the paper. As one of the authors of the paper (with Ramamoorthy on the NMR part), I would like to clear a few things as time permits.

@ Derek An uncharitable view would be that they have also taken aim at the year 1995, which is about when all three of these ideas were also being worked on for AD.

All three are still be working on and are in (mostly mixed or unsuccessful) clinical trials. Vitamin E in particular went through a phase III clinical trial for mild to moderate Alzheimer's with mixed results
To be fair, none of the other hypotheses have much support either.

@19 from Bob "The paper only uses the word drug once, in the context of including "drug-likeness" as a designed property, and therapeutics once in the conclusion."

Correct. I wasn't aware that at any point we claimed that this was a therapeutic or even a lead compound for a therapeutic. The discussion about drug discovery in academia vs. industry, while interesting, is in my opinion somewhat off-topic. A more relevant question is whether it is worth investigating one compound with a detailed approach (which you are going to have do if you want in any kind of mechanism based inhibitor) or try a high-throughput non-mechanistic approach phenotypic screening. I'm agonist on this point and i think both are viable (or a maybe both non-viable options). Large scale phenotypic screening for Alzheimer's is going to exceed the resources of academic lab. Based on the amount of money spent on pharma and the current success rate, I suspect its been tried on some level and failed at relatively early stage.

@21 from JSR "If the end result of months or years of work by 14 authors and almost as many sources of funding...

The non mass spec work (the bulk of the paper) was supported by a single R21 and a private foundation grant of which this paper is a small part.

@21 from JSR "not ready to publish, especially not in the once hallowed pages of JACS."
"MedChem journals likely would have asked that more work be done to answer some of the same questions Derek raised."
@35 "I’d add ‘who partners with someone who knows how to build / run relevant screening assays"

There are no relevant high-throughput screening assays for amyloid inhibition in common use. This point in particular I would like to stress and is the reason (as one of the commenters guessed) we left some of the expected the out of the paper. A very high percentage of the papers in JACS and J. Med. Chem on amyloid inhibitors consist of a set of compounds with only three sets of data. A high-throughput thioflavin T assay to measure amyloid inhibition, a set of EM images to show amyloid disappearing, and an MTT assay. There is very rarely any kind of pharmokinetics often not even to the extant of calculating drug-likedness (if you don't believe me look up amyloid inhibitor on basically any journal including the med chem ones). Though usually not acknowledged, ThT assay has a very high false positive rate since ThT generally binds at the same site as the inhibitor. Although not in the paper, we have shown this is true for the compound in the paper and many others. EM images suffer from multiple issues due to bias in binding to the grid, selection bias in sampling etc. The MTT assay has a sensitivity problem as suggested, and is not ideal for amyloid for a variety of other reasons.
The conformational antibodies sometimes used are also pretty non-specific, although this is only occasionally acknowledged in the literature. The end result is a lot of compounds with apparently quantifiable information that really isn't. There is no information on where the compound binds and what it binds to (amyloid beta is a mixture of many different, rapidly equilibrating species even when it is claimed to be in a single form).

If you have experience in high-throughput screening, I urge you to team up with an amyloid person (there are many amyloid specific factors that need to be considered). The field desperately needs you. Also, if you know of compounds for which reliable PK data has been obtained let me know (jbrender at I am compiling a database of amyloid inhibitors and an discouraged at what I am finding.

Our goal in the Ramamoorthy NMR lab in particular was to take a single compound and analyze its binding on low MW and fibrillar Abeta , using a labor intensive approach with the aim of developing a future high throughput fluorescence based approach to isolate specific interactions with different Abeta species (some unpublished progress has been made on the fluorescence work).
The study is only one of handful that have identified specific interactions in terms of a structure of Abeta (the new structure we have is the only high-resolution structure not in detergents in organic solvents). ML binds at a specific site on the structure, and looking back at the literature, you can see a similar binding site for many of the compounds in the literature. That to me at least is interesting.

In conclusion, it is not a complete story by any means, just a progress report. But a complete story with Abeta and Alzheimer's is going to take a very long time.

Note: I'm turning off comments here, so they can continue to thread in the previous post. I may have some more to say on this myself, but I'll leave that to another entry.

Comments (0) + TrackBacks (0) | Category: Academia (vs. Industry) | Alzheimer's Disease

January 9, 2014

An All-In-One Alzheimer's Paper

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Posted by Derek

A reader sent along this paper that's come out recently in JACS, from a Michigan/South Korea/UCSB team of researchers. It's directed towards a possible therapeutic agent for Alzheimer's disease. They're attempting to build a molecule that binds beta-amyloid, coordinates metals, and has antioxidant properties all at the same time.

An uncharitable view would be that they have also taken aim at the year 1995, which is about when all three of these ideas were also being worked on for AD. But it's not like the field has cleared up too many of these questions since then, so perhaps that gets a pass, although it should be noted (but isn't in the paper) that no one has ever been able to find any significant effect on Alzheimer's from treatment with either antioxidants or metal chelators. The debate on whether anyone has been able to see anything significant with agents targeting amyloid is still going on (and how).

I bring that up partly for mechanistic plausibility, and partly because of the all-in-one aspect of the molecule that the paper is studying. Any such drug candidate has to justify its existence versus a mixture of therapies given simultaneously, especially since the odds are that it will not be as efficacious against all (or even any) of its subtargets compared to a cocktail of more specific agents. With Alzheimer's, it's tempting to say that well, we're hitting all three of these mechanisms at once, so that has to be a good thing. But are all three of them equally important? The fraction of your compound that's binding amyloid is presumably not available to serve as an antioxidant. The ones that have chelated metals are not available to bind amyloid, and so on.

Most of the paper details experiments to show that the ligand does indeed bind amyloid, both in the soluble form and as fibrils. But there's room to argue there, too. Some in the field think that altering the distribution between those populations could be important (I'm agnostic on this point, as I am about amyloid in general). If you're binding to all of them, though, what happens? There's information on the compound's effect on amyloid oligomerization, but the connection between that and Alzheimer's pathology is also up for argument. These questions, already complicated, are made harder to think about by the absence of any quantitative binding data in the paper - at least, if it's there, I'm not seeing it yet. There are mass spec, LC, and NMR experiments, but no binding constants.

There's also little or no SAR. You'd almost get the impression that this was the first and only compound made and tested, because there's nothing in the main body of the paper about any analogs, other than a comparison to a single quinolinemethanol. Even without binding data, some qualitative comparisons might have been made to see how the amyloid binding responded to changes in the structure, as well as how it balanced with the metal-binding and antioxidant properties.

There's some cell-assay data, viability in the presence of amyloid (with and without metals), and it looks like under A-beta-42 conditions the cells are about 70% viable without the compound, and around 90% with it. (It also looks like the cell viability is only in the lower 80% range just when the compound alone is added; I don't know what the background viability numbers are, because that control doesn't seem to be in there). They also tried the same neuroblastoma line with the Swedish-mutation APP in it (a huge risk factor for an early-onset form of human Alzheimer's), but I can't see much difference in the compound's effects.

But as with any CNS proposal, the big question is "Does the compound get into the brain?" The authors, to their credit, do have some data here, but it's puzzlingly incomplete. They show plasma and brain levels after oral gavage (10 mpk) in CD1 mice, but only at one time point, five minutes. That seems mighty early for an oral dose, at least to me, and you really, really want to see a curve here rather than one early time point. For what it's worth, plasma levels were around 6 ng/g and brain levels were around 14 ng/g at that point, but since this was just done by brain homogenate, it's unclear if the compound really gets in or not. No other tissues were examined.

There also don't seem to be any data on what else this compound might do. If you're seriously proposing it as a possible therapy for Alzheimer's, or as a starting point for one, it would be worthwhile to collect some numbers in selectivity screens. Alternatively, if you're not proposing this as a starting point for Alzheimer's therapy, then why do all this work in the first place (and why write it up for JACS)? This is another one of those cases where I'm honestly baffled by what I'm reading. My industrial perspective sees a single compound given a very labor-intensive in vitro workup on a hazy therapeutic rationale, with no analogs, no selectivity data, and no PK other than one time point, and I just shrug my shoulders with a puzzled look on my face. Why do it?

Well, universities aren't drug companies. And the groups involved are, presumably, not focused on making the next big Alzheimer's breakthrough. But what are they focused on? Training students? That's a really worthwhile goal, but I have to wonder if some way could have been found to train them that would have been a bit more congruent with the real world. Picking three rationales, thinking up a single compound to try to combine them, and then spending all your effort on it as if it's a real lead isn't (to my mind) a good fit. I realize that resources are limited, and that this same level of effort just couldn't have been applied to a whole series of compounds the way it would in an industrial setting (not that we'd have done it). But if you're going to do this stuff, a less-intense look at the amyloid-aggregating and cellular effects of a wider series of compounds could have been more valuable than a lot of information about just one.

I feel bad every time I write like this about academic drug-discovery papers, but I can't help it. From my perspective, there's a lot of confusion out there about what drug discovery really entails, and about the relative value of doing a little of it, or doing it in an odd way.

Comments (55) + TrackBacks (0) | Category: Academia (vs. Industry) | Alzheimer's Disease

December 11, 2013

David Cameron, The Press, Alzheimer's, and Hope

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Posted by Derek

One should be cheering the news that Great Britain will double funding for Alzheimer's and dementia research. But there's something odd about the way it's being presented, at least to my eyes. Here's a story from the Guardian that might illustrate what I mean:

The health secretary, Jeremy Hunt, said he hoped the dementia summit would have the same effect as the G8 summit in Gleneagles on HIV/Aids in 2005.

"Today should be an optimistic day," he told BBC Breakfast. "Tony Blair had the G8 summit in Gleneagles in 2005 on HIV/Aids and actually that did turn out in retrospect to be a turning point in the battle against Aids.

"I think if you bring the world's leaders together, health ministers from across the world, and we are all resolved that we really are going to do something about this as we face up to an ageing society."

If 2005 was some sort of widely-recognized turning point in HIV control, I must have missed it. I'll be glad to be corrected, but the last sentence in that quote makes me wonder, because it isn't a sentence. Try it out: the first part isn't connected with the second. He thinks that if you bring the world's leaders together, then. . .what will happen? "If" implies some sort of resolution in a sentence, and there isn't any. How about the second part? They're all resolved that they're really going to do something - fine, but isn't that the easiest part? The simplest part? I mean, coming out and saying that you'd like to "do something" about a problem that everyone would like to see solved is not that big a step, is it?

Well, doubling research funding is certainly doing something, there's no taking away from that. Much is made in the various press articles about Lilly's Alzheimer's scan, which Britain's National Heath Service is going to make available to some patients. Now, Lilly has been talking bravely about Alzheimer's for some time now, and to be fair to them, they've been spending pretty bravely, too. No doubt their hope has been that their imaging agent would match up with some successful therapy they'd develop, but the "successful therapy" part has been the hard one.

But British Prime Minister David Cameron has also been talking about finding a cure by 2025. I hope we do - I may need it by then - but it's going to take a generous slug of luck for that to happen. I don't hold out much hope for anything currently in development as a cure, although I'd like to be wrong about that. And something that's not in development would barely make it through, on an optimistic timetable, by 2025. We certainly don't know enough about Alzheimer's to say that we're on track, so someone will have to get lucky. You wouldn't know that from the British newspapers, though. They've also been excited about the potential of Eli Lilly's solanezumab, which must make the UK the only area outside of Indianapolis where that state of mind obtains.

That's the part that worries me about the public statements in this area. Politicians (and CEOs) are prone to ringing declarations that make it sound as if all that's really needed is gumption and willpower - good faith will carry the day. But that just isn't true in research. It really isn't. Nerve and perseverance are necessary, and how, but they're nowhere near sufficient. To pretend otherwise is to engage in magical thinking, and the history of Big Proclamations in the biomedical field should be enough to prove that to anyone.

Back in 2003, we were supposedly going to eliminate death and suffering from cancer by 2015 (and Senator Arlen Spector asked if maybe we couldn't move the timetable up to 2010). On a lesser level, back in 2009, there were statements that a cure for the common cold was at hand. Sorry about that. The British press has a particular weakness for proclaimed Alzheimer's cures, not that the US press doesn't go for them, too.

No, saying it will not make it so. I don't know how to make it so, other than by spending a lot of money and a lot of time, and working really hard, and hoping for the best. But that's not the stuff of headlines.

Comments (60) + TrackBacks (0) | Category: Alzheimer's Disease | Cancer

July 12, 2013

Lilly Goes All In on Solanezumab

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Posted by Derek

So Eli Lilly is going to double down on solanezumab, their antibody treatment for Alzheimer's that did not show impressive results in earlier trials. The company is going into an even bigger Phase III, with a more carefully selected patient population, in hopes of showing a benefit.

Yikes. On one level, I sort of admire this - it's a decision that takes a lot of nerve to make, will cost a huge amount of money, and is attacking one of the most intractable clinical problems we have. But on that ever-present other hand, what are the odds? If I'm an investor in Lilly stock, am I happy about this move, or not? The only thing I can see to calm the nerves this time, if there's such a thing in an Alzheimer's clinical trial, is better diagnostic criteria from the start:

Eric Siemers, senior medical director of Lilly's Alzheimer's program, said an estimated 25 percent of patients in the two earlier Expedition trials might not actually have had beta-amyloid deposits or Alzheimer's disease, so solanezumab could not have helped them.

He said many patients were enrolled in those trials on the basis of symptoms, without undergoing sophisticated diagnostic procedures now available to confirm the presence of beta-amyloid deposits.

In the new study, Lilly's recently approved radioactive imaging agent, called Amyvid, will be used to screen patients, Siemers said. Biochemical measures in the spinal fluid can also help assess whether patients have Alzheimer's, he said.

I'll say this for them: this trial, you'd think, is going to be the answer. It's going to cost hundreds of millions by the time it's all over, but by gosh, Lilly (and the rest of us) should know if solanezumab is of any use in Alzheimer's. Unless, of course, another bath of equivocal coulda-maybe-worked numbers come out of this one, too. But that's also an answer. Under these conditions, "sort of worked" is going to mean "did not work". I don't see what else is left.

And given Lilly's patent positions and sales forecasts, it looks like they are, to a significant extent, betting the company on this. Drama, this industry could do with less drama. But we seem to be stuck with it.

Comments (31) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

June 14, 2013

A Beta-Secretase Inhibitor Hits the Skids in Alzheimer's

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Posted by Derek

The brutal drumbeat of Alzheimer's clinical failure continues at Eli Lilly. After the Phase III failure of their gamma-secretase inhibitor semagacestat, and a delusional attempt to pretend that the anti-amyloid antibody solanezumab succeeded, now comes word that the company has halted studies of a beta-secretase inhibitor.

This one wasn't for efficacy, but for tox. The company says that LY2886721 led to abnormalities in liver function, which is the sort of thing that can happen to anyone in Phase II. There is that thioamidine thing in it, but overall, it's not a bad-looking compound, particularly by the standards of beta-secretase inhibitors. But what does that avail one? We'll never find out what this one would have done in a real Phase III trial, although (unfortunately) I know how I'd lay the odds, considering what we know about Alzheimer's drug in the clinic. Beta-secretase inhibitors are an even higher-stakes bet than usual in this field, because mechanistically they have pretty strong support when it comes to inhibiting the buildup of amyloid protein, but they also have clear mechanistic liabilities: the enzyme seems to be important in the formation of myelin sheaths, which is not the sort of thing you'd want to touch in a patient population that's already neurologically impaired. Which effect wins out in humans? Does a BACE inhibitor really lower amyloid in the clinic? And does lowering amyloid in this way really affect the progression of Alzheimer's disease? Extremely good questions, all of those, and the only way to answer them is to round up a plausible drug candidate (not so easy for this target), half a billion dollars (for starters) and try it out.

This failure makes Lilly perhaps the first company to achieve a dread milestone, the Amyloid Trifecta. They have now wiped out on beta-secretase, on gamma-secretase, and on antibody therapy. And you know, I have to salute them for it. They've been making a determined effort against a terrible disease, trying all the most well-founded means of attack, and they're getting hammered into the ground like a tent peg for it. Alzheimer's. At the rate things are going, Lilly is going to end up in a terrible position, and a lot of it has to do with battering themselves against Alzheimer's. Remember this next time someone tells you about how drug companies are just interested in ripping off each other's baldness cures or something.

Comments (29) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

May 30, 2013

Update on Bexarotene for Alzheimer's

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Posted by Derek

Here's a follow-up on the news that bexarotene might be useful for Alzheimer's. Unfortunately, what seems to be happening is what happens almost every time that the word "Alzheimer's" is mentioned along with a small molecule. As Nature reports here, further studies are delivering puzzling results.

The original work, from the Landreth lab at Case Western, reported lower concentrations of soluble amyloid, memory improvements in impaired rodents, and (quite strikingly), clearance of large amounts of existing amyloid plaque in their brain tissue. Now four separate studies (1, 2, 3, 4) are out in the May 24th issue of Science, and the waters are well muddied. No one has seen the plaque clearance, for one thing. Two groups have noted a lowering of soluble amyloid, though, and one study does report some effects on memory in a mouse model.

So where are we? Here's Landreth himself on the results:

It was our expectation other people would be able to repeat this,” says Landreth about the results of the studies. “Turns out that wasn’t the case, and we fundamentally don’t understand that.” He suggests that the other groups might have used different drug preparations that altered the concentration of bexarotene in the brain or even changed its biological activity.

In a response published alongside the comment articles, Landreth emphasizes that some of the studies affirm two key conclusions of the original paper: the lowering of soluble β-amyloid levels and the reversal of cognitive deficits. He says that the interest in plaques may even be irrelevant to Alzheimer’s disease.

That last line of thought is a bit dangerous. It was, after all, the plaque clearance that got this work all the attention in the first place, so to claim that it might not be that big a deal once it failed to repeat looks like an exercise in goalpost-shifting. There might be something here, don't get me wrong. But chasing it down is going to be a long-term effort. It helps, of course, that bexarotene has already been out in clinical practice for a good while, so we already know a lot about it (and the barriers to its use are lower). But there's no guarantee that it's the optimum compound for whatever this effect is. We're in for a long haul. With Alzheimer's, we're always in for a long haul, it seems. I wish it weren't so.

Comments (13) + TrackBacks (0) | Category: Alzheimer's Disease

March 25, 2013

The FDA's New Alzheimer's Guidance: Wonder or Blunder?

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Posted by Derek

You can get either answer, depending on whom you ask. Last month, the agency unveiled new guidelines for developing Alzheimer's therapies. They're trying to deal with the difficulty of showing actual cognitive improvement in more advanced patients, while at the same time figuring out how to evaluate therapies in early-stage patients who really aren't cognitively impaired yet. It's a worthy problem, for sure, and a good thing to be thinking about. Two of the agency's scientists laid out the thinking in a NEJM editorial:

The current landscape of research and drug development in Alzheimer's disease offers a study in contrasts. On the positive side, numerous discoveries over the past decade have begun to unmask complex pathophysiological processes that underlie disease progression. Such advances have, in part, resulted from large, well-organized observational studies, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), that have elucidated various disease biomarkers that reflect, or even predict, the progression of disease. On the negative side, drug discovery has been disappointing. Despite all best efforts to translate mechanistic insights concerning Alzheimer's disease into new drug products, several candidate agents have failed to demonstrate efficacy in large, well-designed, phase 3 clinical trials of late-stage disease.

That they have, and how. Avoiding these, or at least finding out ways to fail more cheaply, is very much on the minds of everyone working in the field. The New York Times, though, had a rather unexpected fit about the whole idea, culminating in this editorial:

. . .The goal is commendable — to find ways to prevent or slow the progression of this terrible disease before it can rob people of their mental capacities. But the proposal raises troubling questions as to whether the agency would end up approving drugs that provide little or no clinical benefit yet cause harmful side effects in people who take the medications for extended periods. . .

. . .F.D.A. officials say they would never approve drugs based on cognitive effects alone unless absolutely convinced that patients with very early-stage Alzheimer’s that is likely to progress to full-blown dementia could be reliably identified. It will be up to the drug companies or other sponsors of clinical trials to do the convincing.

The F.D.A.’s proposal is open for comment for 60 days. Independent analysts need to look hard at whether the F.D.A. should lower the bar for these drugs — or should demand a very high level of proof of safety and effectiveness before exposing still-healthy people to possible harm. Even if drugs are eventually approved under this new approach, it will be imperative to force manufacturers to conduct follow-up studies, as required by law, to see if patients benefit in the long run. . .

That's not a crazy point of view at all, though - I've worried about something similar myself. But I think that the Times is a bit too worked up over the current FDA guidance. On the other hand, as BioCentury has it in their latest issue (March 25), there are people in the biotech industry who have been talking up the new guidelines as some sort of regulatory breakthrough. "Not So Fast", is the response:

. . .The only reasonable conclusion to be drawn from a careful reading of both the guidance and the commentary is that while FDA would be willing to accelerate approval of AD drugs, the science isn’t there to allow it to do so. . .

The guidance states FDA would grant accelerated approval to a treatment for AD “based on the use of a biomarker as a single primary surrogate efficacy measure” — if a biomarker that reliably predicted clinical benefit existed.

As the guidance notes — and as anyone who follows the field knows — “no reliable evidence exists at the present time that any observed treatment effect on such a measure is reasonably likely to predict ultimate clinical benefit (the standard for accelerated approval), despite a great deal of research interest in understanding the role of biomarkers in AD.”

. . .The process of reaching scientific consensus on an appropriate assessment tool will take years. And no one knows how much longer it will take for regulators to generate sufficient confidence in the tool to use it as the sole basis for approving an AD drug.

I think that's the key part of all this. It's fine that the FDA is open to the idea of biomarkers for Alzheimer's; we're probably going to have to do it that way. But no one knows how to do that yet, and it's not like the agency is just going to pick one of the current measures and tell everyone that that's fine. What I would expect this latest initiative to do, actually, is to end up pushing more money into the hunt for such biomarkers, with perhaps less going to direct shots-on-goal. That's disappointing, from one perspective, but the shots on goal will bankrupt us all at the current rate.

Comments (8) + TrackBacks (0) | Category: Alzheimer's Disease | Regulatory Affairs

March 5, 2013

TauRx's Funding Is Odd

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Posted by Derek

I still get inquiries about TauRx and their work on Alzheimer's. There's an awful lot of pent-up demand in that field, and it's getting worse every year. The latest is that the company has ten million more dollars in a follow-on investment option from the Dundee Corporation of Toronto.

Who they? That's what I wondered, too, and the press release occasions more questions than it answers:

Dundee Corporation is a Canadian independent publicly traded asset management company listed on the Toronto Stock Exchange (“TSX”) under the symbol “DC.A”. Asset management activities are focused in the areas of the corporation’s core competencies and include resources, real estate and infrastructure, and more recently, the agriculture sector.

What, then, are they doing investing in biopharma? You can lose your shirt over here, guys, and you can most especially lose it in Alzheimer's. TauRx also has major funding from the Genting Burhad group. And you may well ask "Who they?", too, because they're a large Malaysian company whose core business is casinos and resorts. Now, they're also into cruise ships, and oil and gas, and power generation and (perforce) real estate, but biotech would seem to be rather far down the list.

This is a. . .unique funding setup for a biopharma company. I have to think that there's a reason for it, but I'm not quite sure what the reason is. Speculation, anyone? Thanks to John Carroll of FierceBiotech on Twitter, who doesn't understand what's going on, either.

Comments (16) + TrackBacks (0) | Category: Alzheimer's Disease | Business and Markets

January 25, 2013

CETP, Alzheimer's, Monty Hall, and Roulette. And Goats.

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Posted by Derek

CETP, now there's a drug target that has incinerated a lot of money over the years. Here's a roundup of compounds I posted on back last summer, with links to their brutal development histories. I wondered here about what's going to happen with this class of compounds: will one ever make it as a drug? If it does, will it just end up telling us that there are yet more complications in human lipid handling that we didn't anticipate?

Well, Merck and Lilly are continuing their hugely expensive, long-running atempts to answer these questions. Here's an interview with Merck's Ken Frazier in which he sounds realistic - that is, nervous:

Merck CEO Ken Frazier, speaking in Davos on the sidelines of the World Economic Forum, said the U.S. drugmaker would continue to press ahead with clinical research on HDL raising, even though the scientific case so far remained inconclusive.

"The Tredaptive failure is another piece of evidence on the side of the scale that says HDL raising hasn't yet been proven," he said.

"I don't think by any means, though, that the question of HDL raising as a positive factor in cardiovascular health has been settled."

Tredaptive, of course, hit the skids just last month. And while its mechanism is not directly relevant to CETP inhibition (I think), it does illustrate how little we know about this area. Merck's anacetrapib is one of the ugliest-looking drug candidates I've ever seen (ten fluorines, three aryl rings, no hydrogen bond donors in sight), and Lilly's compound is only slightly more appealing.

But Merck finds itself having to bet a large part of the company's future in this area. Lilly, for its part, is betting similarly, and most of the rest of their future is being plunked down on Alzheimer's. And these two therapeutic areas have a lot in common: they're both huge markets that require huge clinical trials and rest on tricky fundamental biology. The huge market part makes sense; that's the only way that you could justify the amount of development needed to get a compound through. But the rest of the setup is worth some thought.

Is this what Big Pharma has come to, then? Placing larger and larger bets in hopes of a payoff that will make it all work out? If this were roulette, I'd have no trouble diagnosing someone who was using a Martingale betting system. There are a few differences, although I'm not sure how (or if) they cancel out For one thing, the Martingale gambler is putting down larger and larger amounts of money in an attempt to win the same small payout (the sum of the initial bet!) Pharma is at least chasing a larger jackpot. But the second difference is that the house advantage at roulette is a fixed 5.26% (at least in the US), which is ruinous, but is at least a known quantity.

But mentioning "known quantities" brings up a third difference. The rules of casino games don't change (unless an Ed Thorp shows up, which was a one-time situation). The odds of drug discovery are subject to continuous change as we acquire more knowledge; it's more like the Monty Hall Paradox. The question is, have the odds changed enough in CETP (or HDL-raising therapies in general) or Alzheimer's to make this a reasonable wager?

For the former, well, maybe. There are theories about what went wrong with torcetrapib (a slight raising of blood pressure being foremost, last I heard), and Merck's compound seems to be dodging those. Roche's failure with dacetrapib is worrisome, though, since the official reason there was sheer lack of efficacy in the clinic. And it's clear that there's a lot about HDL and LDL that we don't understand, both their underlying biology and their effects on human health when they're altered. So (to put things in terms of the Monty Hall problem), a tiny door has been opened a crack, and we may have caught a glimpse of some goat hair. But it could have been a throw rug, or a gorilla; it's hard to say.

What about Alzheimer's? I'm not even sure if we're learned as much as we have with CETP. The immunological therapies have been hard to draw conclusions from, because hey, it's the immune system. Every antibody is different, and can do different things. But the mechanistic implications of what we've seen so far are not that encouraging, unless, of course, you're giving interviews as an executive of Eli Lilly. The small-molecule side of the business is a bit easier to interpret; it's an unrelieved string of failures, one crater after another. We've learned a lot about Alzheimer's therapies, but what we've mostly learned is that nothing we've tried has worked much. In Monty Hall terms, the door has stayed shut (or perhaps has opened every so often to provide a terrifying view of the Void). At any rate, the flow of actionable goat-delivered information has been sparse.

Overall, then, I wonder if we really are at the go-for-the-biggest-markets-and-hope-for-the-best stage of research. The big companies are the ones with enough resources to tackle the big diseases; that's one reason we see them there. But the other reason is that the big diseases are the only things that the big companies think can rescue them.

Comments (4) + TrackBacks (0) | Category: Alzheimer's Disease | Cardiovascular Disease | Clinical Trials | Drug Development | Drug Industry History

December 12, 2012

Eli Lilly's Brave Alzheimer's Talk

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Posted by Derek

I'm a bit baffled by Eli Lilly's strategy on Alzheimer's. Not the scientific side of it - they're going strongly after the amyloid hypothesis, with secretase inhibitors and antibody therapies, and if I were committed to the amyloid hypothesis, that's probably what I'd be doing, too. It is, after all, the strongest idea out there for the underlying mechanism of the disease. (But is it strong enough? Whether or not amyloid is the way to go is the multibillion dollar question that can really only be answered by spending the big money in Phase III trials against it, unfortunately).

No, what puzzles me is the company's publicity effort. As detailed here and here, the company recently made too much (it seemed to me and many others) of the results for solanezumab, their leading antibody therapy. Less hopeful eyes could look at the numbers and conclude that it did not work, but Lilly kept on insisting otherwise.

And now we have things like this:

"We are on the cusp here of writing medical history again as a company, this time in Alzheimer's disease," Jan Lundberg, Lilly's research chief, said in an interview.

Just as the Indianapolis-based company made history in the 1920s by producing the first insulin when type 1 diabetes was a virtual death sentence, Lundberg said he is optimistic that the drugs Lilly is currently testing could significantly slow the ultimately fatal memory-robbing disease.

"It is no longer a question of 'if' we will get a successful medicine for this devastating disease on the market, but when," said Lundberg, 59.

Ohhh-kay. The problems here are numerous. For one thing, as Lundberg (an intelligent man) well knows, insulin-for-diabetes is a much straighter shot than anything we know of for Alzheimer's. It was clear, when Lilly got their insulin business underway, that the most devastating symptoms of type I diabetes were caused by lack of insulin production in the body, and that providing that insulin was the obvious remedy. Even if it did nothing for the underlying cause of the disease (and it doesn't), it was a huge step forward. As for Alzheimer's, I understand that what Lundberg and Lilly are trying to get across here is the idea of a "successful medicine", rather than a "cure". Something that just slows Alzheimer's down noticeably would indeed be a successful medicine.

But "when, not if"? With what Lilly has in the clinic? After raising hopes by insisting that the Phase III results for solanezumab were positive, the company now says that. . .well, no, it's not going to the FDA for approval. It will, instead, conduct a third Phase III trial. This decision came after consulting with regulators in the the US and Europe, who no doubt told them to stop living in a fantasy world. So, sometime next year, Lilly will start enrolling for another multiyear shot at achieving some reproducible hint of efficacy. Given the way solanezumab has performed so far, that's about the best that could be hoped for, that it works a bit in some people, sometimes, for a while, as far as can be told in a large statistical sample. Which sets up this situation, I fear.

And this is "on the cusp. . .of writing medical history"? Look, I would very much like for Lilly, for anyone, to write some medical history against Alzheimer's. But saying it will not make it so.

Comments (19) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

December 4, 2012

Merck Presses Ahead on Alzheimer's:

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Posted by Derek

One Alzheimer's compound recently died off in the clinic - Bristol-Myers Squibb's avagacestat, a gamma-secretase inhibitor, has been pulled from trials. The compound "did not establish a profile that supported advancement" to Phase III, says the company. Gamma-secretase has been a troubled area for some time, highlighted by the complete failure of Lilly's semagacestat. I wondered, when that one cratered, what they were thinking at BMS, and now we know.

But Merck is getting all the attention in Alzheimer's today. They've announced that their beta-secretase inhibitor, MK-8931, is moving into Phase III, and the headlines are. . .well, they're mostly just not realistic. "Hope for Alzheimer's", "Merck Becomes Bigger Alzheimer's Player", and so on. My two (least) favorites are "Merck Races to Beat Lilly Debut" and "Effective Alzheimer's Drug May Be Just Three Years Away." Let me throw the bucket of cold water here: that first headline is extremely unlikely, and the second one is insane.

As I've said here several times, I don't think that there's going to be any big Lilly debut into Alzheimer's therapy with their lead antibody candidate, solanezumab. (And if there is, we might regret it). The company does have a beta-secretase (BACE) inhibitor, but that's not what these folks are talking about. And looking at Merck's compound, you really have to wonder if there's ever going to be one there, either. I like Fierce Biotech's headline a lot better: "Merck Ignores Red Flags and Throws Dice on PhII/III Alzheimer's Gamble". That, unfortunately, is a more realistic appraisal.

It's interesting, though, that Merck is testing this approach in a patient population that includes patients with moderate cases. After solanezumab and bapineuzumab appears to have hit that target without any clear signal that they had improved symptoms for patients with more fully developed cases, there has been a growing move to shift R&D into earlier-stage patients, whose brains have not already been seriously damaged by the disease. Merck is likely to face growing skepticism that it can succeed with the amyloid hypothesis when tackling the same population that hasn't delivered positive data.

And BACE has been a rough place to work in over the years. The literature is littered with oddities, since finding a potent compound that will also be selective and get into the brain has been extremely difficult. I actually applaud Merck for having the nerve to try this, but it really is a big roll of the dice, and there's no use pretending otherwise. I wish that the headlines would get that across, as part of a campaign for a more realistic idea of what drug discovery is actually like.

Comments (17) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

November 21, 2012

TauRx Goes Into Phase III For Alzheimer's

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Posted by Derek

I can't even count the number of e-mails I've gotten over the last few years asking about TauRx and their Alzheimer's program, which made a big splash back in 2008. Finally, there's some news to report. The company is starting Phase III clinical trials, and has announced new financing to see these through. The company is based in Singapore, and they're getting money from a large multinational company in the region.

Good for them. The tau-based therapy they're working on is a very interesting idea, and (of course) extremely significant if it actually works. I'm happy to see that it's going to get a real chance to prove itself, and I look forward to seeing the results. Their earlier compound ("Rember") was reformulated methylene blue, but they now seem to have an improved version to go ahead with (and not just in Alzheimer's, apparently).

I know I'll get more mail about this, but let me save time by telling those interested to go here, to a site run by TauRx about their clinical trials. It seems that they have started enrolling patients in North America.

Comments (20) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

November 20, 2012

And Since We're Talking About Insider Trading

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Posted by Derek

Here's something from just this morning, a whopping large case on illegal trading in Wyeth and Elan stock. This one involves a hedge fund manager, Mathew Martoma, and (quite disturbingly), Dr. Sidney Gilman of the University of Michigan, who was the lead investigator on a very large bapineuzumab trial for Alzheimer's. His conduct appears, from the text of the complaint, to be completely inexcusable, just a total, raw tipoff of confidential information.

I blogged at the time about the trial results, not knowing, of course, that someone had been pre-warned and was trading 20 per cent of Elan's stock volume on the news (and at least ten per cent of Wyeth's). So I take back anything I said about insider trading cases becoming more small-time over the years; this case has jerked the average right back up.

Update: Adam Feuerstein on Twitter: "Gilman's presentation of bapi data at 2008 ICAD meeting was so poorly done. It was shockingly bad. Now we know why."

Comments (18) + TrackBacks (0) | Category: Alzheimer's Disease | Business and Markets | Clinical Trials | The Dark Side

November 9, 2012

JNK3 - Something New for Alzheimer's?

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Posted by Derek

There's been an interesting recent development in the biology of Alzheimer's disease. c-Jun N-terminal kinase 3 (JNK3, known to those in the field, semi-affectionately, as "Junk-Three") is expressed mostly in the CNS, and has been implicated as a player in Parkinson's and neurodegeneration in general. There's been evidence of its relevance to Alzheimer's (for example, here's a connection to tau protein), but it's hard to say what's actually going on.

A group at Ohio State has cranked up the interest level. They found that deleting JNK3 in a mouse model of amyloid deposition showed some rather dramatic effects, knocking the amyloid levels down by 90% and improving the cognitive function of the mice relative to controls. The hypothesis is that some unknown factor in Alzheimer's pathology leads to increased JNK3 activity, which sets off downstream effects in the mTOR and AMPK systems. (Given how central those proteins are, I can believe almost anything if you tell me that they're involved). These effects (on protein production and other systems) increase JNK3 activity even more, and a vicious cycle could be well underway.

Now, inhibitors of these enzymes have been the subject of research for quite a while now. Here's the most recent paper on such compounds, but there are quite a few others scattered through the literature - here's a 2010 review of them. Selectivity has been a problem, as has cell penetration - and if you're targeting the CNS, which you'd surely have to do for this approach to Alzheimer's, you have the blood-brain barrier to think about, too. (That link goes to a new paper that's worth a post of its own next week).

So no, there aren't any obvious JNK3 inhibitors ready to go into human Alzheimer's trials. On the other hand, a lot of companies have chemical matter in this area, and this new result makes it worthwhile to go back and see what there might be in the files. AD is one of the biggest "unmet medical need" areas out there, and plausible targets for it are always going to attract attention. Watch this area to see who goes for this one.

Comments (10) + TrackBacks (0) | Category: Alzheimer's Disease

October 31, 2012

The Coming Battle Over Alzheimer's Disease

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Posted by Derek

Solanezumab is a story that won't go away. Eli Lilly's antibody therapy for Alzheimer's is the subject of a lot of arguing among investors: some people (and I'm one of them) think that there is no strong evidence for its efficacy, not yet, and that the amount of time and effort devoted to finding that out means that there likely isn't any meaningful efficacy to be found. Others are more optimistic, which is why Lilly's stock has risen in recent months.

The latest point of contention is an independent analysis of biomarker data which came out this week at a conference in Monaco. This suggests that there was a meaningful change in the amount of circulating beta-amyloid after treatment, which could mean that the antibody was working as planned to increase clearance of soluble amyloid, thus altering the amyloid balance in the CNS. It should be noted that this line of attack depends on several factors - first among them, that amyloid is a causative factor in Alzheimer's, and secondly, that clearing it from the periphery can affect its concentration and distribution inside the brain. There's evidence for both of these, and there's evidence against both of them. Such questions can only be answered in the clinic, and I'm glad that Lilly, Roche/Genentech, and others are trying to answer them.

What I want to focus on today, though, is an issue that comes up in passing in the Fierce Biotech link above:

Biomarkers and pooled data may help support further studies of the drug, as well as other programs that rest on the beta amyloid hypothesis, but they don't prove that solanezumab works as hoped. Nevertheless, the first sign of success in this field has fueled tremendous enthusiasm that something in the pipeline could eventually work--perhaps even pushing regulators to approve new therapies with something less than clear efficacy data. And any newly approved drug would find a massive market of millions of desperate patients.

That's a big "perhaps", one that's worth tens of billions of dollars. What I worry about is pressure building for the FDA to approve an Alzheimer's therapy (solanezumab or something else) based on these hints of mechanistic efficacy. The problem is, solanezumab hasn't shown much promise of improving the lives of actual Alzheimer's patients. Lilly's own trials showed a possible improvement in a measure of cognitive decline, but this did not show up again in a second patient group, even when they specifically modified the endpoints of the trial to look for it. And neither group showed any functional effects at all, which I think are what most Alzheimer's patients (and their family members) would really want to see.

But there really is such a huge demand for something, anything, with any hint of hope. People would line up to buy anything that got FDA approval, no matter how tenuous the evidence was. And that puts the agency in a very tough position, similar to the one it was in with the Avastin breast cancer issue. Update: there was, to be sure, more of a safety question with Avastin at the same time. You can argue that one of the main purposes of the agency is to make sure that medicines that people can be prescribed in this country will actually do some good, rather than raise hopes for nothing. You could also argue that responsible adults - and their physicians, and their insurance companies - should be able to make such choices for themselves, and should be able to spend their time and money in the ways that they best see fit. You could argue that companies with marginally effective (or ineffective) therapies face a huge moral hazard, in that their incentives are to get such treatments onto the market whether they do anyone else any good or not. None of these are foolish positions, but they are also, in places, mutually incompatible. Alzheimer's disease might well turn into the next place in which we thrash them out.

Comments (17) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Prices | Regulatory Affairs

October 12, 2012

Another Prospective Alzheimer's Trial

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Posted by Derek

I wrote here about a prospective Alzheimer's trial that's starting soon among a population in Colombia, and now comes word of another large effort along the same lines. DIAN, the Dominantly Inherited Alzheimer's Network, will test several current Alzheimer's candidates in groups of people around the world with genetic mutations that make them susceptible to the disease. The hope is that these different mutations will provide a fast-forward-button look at the progress of Alzheimer's in the general population, and help to settle the question of which mechanisms (if any) are appropriate to fight it. They'll go two years of clinical observation (memory tests and brain imaging), and then the plan is to switch everyone to the most efficacious therapy and continue monitoring for real-world benefits.

Currently, it looks like there will be three candidates, with two from Eli Lilly: their beta-secretase inhibitor LY2886721, and their circulating-amyloid antibody Solanezumab, currently the subject of controversy about its efficacy or lack of same. The Roche antibody gantenerumab, which appears to bind more to amyloid that's already precipitated, completes the trio.

This is an excellent idea, and I'm very glad to see so much work being done on prospective trials like these. There's always the danger that working in genetic-mutation populations will give you an answer that's not generally applicable, but I think that we know enough about the specific mutations to make a call on that, should anything stand out. The worry, naturally, is that nothing will stand out. The DIAN trial and the Roche crenezumab trial in Colombia are all aimed at various parts of the amyloid hypothesis, which has been the dominant strain of thought in Alzheimer's etiology for decades. If nothing distinctive comes out of these efforts, that hypothesis will have taken some major hits - but they'll have to be major hits to damage it in the first place.

The best result will be if something looks useful in preventative or early-stage Alzheimer's. Second best would be a painful realization that the amyloid hypothesis is insufficient. And way down at the bottom would be a bunch of "Well, maybe. . ." clinical data showing that some of the agents seemed to help some of the patients, some of the time, to an extent, but maybe not enough to be effective by real-world standards. Anything but that, please.

Comments (10) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

October 9, 2012

Lilly's Solanezumab: Did It Actually Work?

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Posted by Derek

"Hope Rises For Alzheimer's Treatment, Scientists Say". Not this scientist. That's a composite of headlines, but it captures the unfortunate tone.

We're talking about solanezumab, Eli Lilly's antibody therapy. The company presented analysis of their trial data yesterday, and put a very optimistic face on things. But wait, you say, didn't Lilly already report on this? And didn't the drug miss all its endpoints? Yes, indeed it did. But this is a secondary analysis by the Alzheimer's Disease Cooperative Study, a third-party look at the data. It's hard for me to imagine an optimistic take on the numbers that Lilly itself didn't find, to be honest, but here we have it:

But after a secondary analysis of the first study showed that there was a 42% reduction in the rate of cognitive decline among a subpopulation of patients in the solanezumab arm with only a mild form of the disease, investigators decided to hunt for confirmation of that endpoint in a second Phase III. They didn't find it, seeing the numbers fall short of statistical significance after switching from one measure (ADAS- Cog11) to another (ADAS-Cog14). But by "pooling" the data they came up with a 34% reduction in cognitive decline in that particular group. None of the data indicated a significant reduction in the rate of functional decline.

This looks to me like grasping at straws. I understand that people want to see any tiny edge of possible efficacy as an avenue for further research, but I can't help but think that the path to an effective Alzheimer's therapy would announce itself a bit more clearly than this. Anything should. Chasing after these sorts of results looks like the path to another Phase III trial that might just manage to miss its endpoints by an even narrower margin. The best one could hope for would be a therapy that might, possibly, help a few patients in the early stage of the disease a bit, for a while. Maybe.

The problem is that the pent-up need for anything effective in Alzheimer's is so great that vast hordes of people will likely rush to take anything - or put their aging relatives on anything - that might offer any shred of hope. And I know just where those people are coming from, and I sympathize greatly. Eli Lilly, for its part, is strongly motivated to have something in its large and expensive Alzheimer's portfolio actually work - the company is facing a very, very rough time with its patent expirations, and something like this is about the only thing that could pull them back from the cliff. On all sides, this is not a situation that encourages sound decision-making.

Comments (20) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

August 24, 2012

Lilly's Solanezumab: A Miss or a Win?

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Posted by Derek

Lilly has reported results from its anti-amyloid antibody, solanezumab, and. . .well, it's mixed. And it's either quite good news, or quite bad. You make the call.

The therapy missed its endpoints (both "cognitive and functional", according to the company) in two clinical trials, so that's clearly bad news. Progression of Alzheimer's disease was not slowed. But I'll let the company's press release tell the tale from there:

The EXPEDITION1 study did not meet co-primary cognitive and functional endpoints in the overall mild-to-moderate patient population; however, pre-specified secondary subgroup analyses in patients with mild Alzheimer's disease showed a statistically significant reduction in cognitive decline. Based on those results, Lilly modified the statistical analysis plan (SAP) for EXPEDITION2 prior to database lock to specify a single primary endpoint of cognition in the mild patient population. This revised primary endpoint did not achieve statistical significance.

Now, this news - what you've just read above - actually is sending Lilly's stock up as I write this, which tells you how beaten-down Eli Lilly investors are, or how beaten-down investors in Alzheimer's therapies are. Or both. The headlines are all about how the drug missed in these trials, but that the company sees some hope. But man, is it ever a faint one.

What I'm taking away from the company's statement is that they had a cognition endpoint defined at the beginning of the trial (as well they should). We can assume that it was not a wildly optimistic one; no one is wildly optimistic in this field. And solanezumab missed it in the first Phase III data. But the patients with milder Alzheimer's, when they looked more closely, showed a trend towards efficacy, so they modified the endpoints (that is, lowered the bar and narrowed down to a select population) in the data for the second Phase III before it finished up. And even then, the antibody missed. So what we have are trends, possible trends, but nothing that really gets to the level of statistical significance.

But note, they're talking cognitive efficacy, and there's nothing said about those functional endpoints. If I'm interpreting this right, that means that there was a trend towards efficacy in tests like remembering words and lists of numbers, but not a trend when it came to actually performing better in real-life circumstances. Am I seeing this correctly? Lilly will be presenting more data in October, and we'll know more then. But I'm not getting an optimistic feeling from all this.

I assume that the company is now talking about going back and rounding up a population of the mildest Alzheimer's patients it can find and giving solanezumab another shot. Given Lilly's pipeline and situation, I suppose I'd do the same thing, but this is really a back-to-the-wall move. I think that you'd want to see something in a functional endpoint to really make a case for the drug, for one thing, and out in the real world, diagnosing Alzheimer's that early is not so easy, as far as I know. Good luck to them, but they are really going to need it.

Comments (59) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

August 7, 2012

Bapineuzumab Still Does Not Work Against Alzheimer's

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Posted by Derek

As expected (by all but the most relentlessly optimistic observers), the anti-Alzheimers antibody bapineuzumab has now failed in its most likely patient population. Results came out last night about from patients who do not carry the ApoE4 mutation, the only group that seemed to offer hope in earlier clinical trials. The therapy missed its endpoints versus placebo, and according to Pharmalot, subgroup analysis offered no hope that there was some further fraction of patients that might be responding. (You would have had to have been a pretty hardy investor to carry on even if something had shown up).

But apparently Pfizer and J&J are those hardy investors, because (as that link shows), they're apparently going on with an already-in-progress Phase II study of the antibody dosed subcutaneously. That baffles me - I don't know enough about antibody dosing to say if that makes a difference, but it seems odd to think that it would. And clinical work on another active immunization therapy is going on as well (as opposed to dosing a pre-made antibody).

Good luck to them on that - I mean that sincerely, because the Alzheimer's field needs any successes it can find. The immunological approach has been a long and hard one, and hasn't delivered much encouragement so far. But on the other hand, it's immunology, which means that it's still a wild black box in many ways and capable of all kinds of unexpected results. But that said, it's still hard to imagine that Eli Lilly's competing antibody solanezumab has much chance of working, at this point. We'll hear about that one soon, and I very much expect to be using the phrase "missed endpoints" again. I might be using the phrase "subgroup analysis", though, in which case the phrase "more money" will also make an appearance.

Comments (18) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

July 26, 2012

An Alzheimer's Update: Amyloid Lives?

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Posted by Derek

There's a good state-of-the-field post over at Chemiotics on Alzheimer's, in the wake of the bapineuzumab news the other day.

Of particular interest is the recent finding by deCODE and Genentech researchers that there's a mutation in the Alzheimer's precursor protein (APP) that actually seems to be protective against the disease. There are several APP mutations that are known to bring on amyloid-driven Alzheimer's at much earlier ages, but seeing one that goes the other way does lend more support to the idea that amyloid really is a causative agent:

The mutation seems to put a brake on the milder mental deterioration that most elderly people experience. Carriers are about 7.5 times more likely than non-carriers to reach the age of 85 without suffering major cognitive decline, such as memory loss. They also perform better on the cognitive tests that are administered thrice yearly to Icelanders who live in nursing homes.

For Stefánsson, this suggests that Alzheimer’s disease and cognitive decline are two sides of the same coin, with a common cause — the build-up of amyloid-β plaques in the brain, something seen to a lesser degree in elderly people who do not develop full-blown Alzheimer’s. “Pathologists have always suspected that there was a substantial overlap between Alzheimer’s disease and normal age-related changes,” says Stefánsson. A drug that mimics the effects of the mutation, he says, would have the potential both to slow cognitive decline and to prevent Alzheimer’s.

Stefánsson and his team discovered that the mutation introduces a single amino-acid alteration to APP. This amino acid is close to the site where an enzyme called β-secretase 1 (BACE1) ordinarily snips APP into smaller amyloid-β chunks — and the alteration is enough to reduce the enzyme’s efficiency.

The flip side of this news is that targeting beta-secretase has already been the subject of a huge amount of work in the drug industry. That's good, in that we're not exactly starting from scratch, but that's bad, since the lack of success so far shows you that it's not exactly an easy thing to do. But there are still plenty of people taking cracks at it - CoMentis and Astellas have a compound in development, as do Merck, Lilly, Takeda, and others. Here's hoping that something from this class finally works out, and that this latest result isn't a red herring from a small mutation population.

Comments (9) + TrackBacks (0) | Category: Alzheimer's Disease

July 24, 2012

Bapineuzumab Does Not Work Against Alzheimer's

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Posted by Derek

This long, long story may finally be coming to an end. Immune-based therapies against beta-amyloid (and the associated amyloid plaques) have been in development for many years now (an excellent review here), and Elan has been in the thick of it for most of that time. Phase II results for this antibody came out in 2008 (here's the publication), and since then, everyone's been waiting to see if anything good would come of the phase III trials.

But not with a lot of hope. That's because the Phase II data weren't too encouraging, press releases aside. The subset of patients with without the ApoE4 mutation showed what appeared to be some slowing in their rate of deterioration; the patients with have that mutation showed basically no beneficial effects at all (edited, got this reversed at first - DBL). There was a bit of biomarker data released earlier this year, which didn't convince people much one way or another. And now we have the numbers for the first of four Phase III trials.

Endpoints were not met - bapineuzumab seems to have definitely failed to help the patients in this study. Note that these were mild-to-moderate Alzheimer's patients who carry the ApoE4 mutation. There's another study going on with non-carriers, and two similar studies to these going on outside the US, but after this miss, what are the chances that they'll report anything beneficial? No, if we were going to see something, you'd think that we'd have seen it here. Edit: not necessarily so, because the only hints of efficacy in Phase II were in ApoE4 noncarriers. But that wasn't all that convincing, and my own advice is still not to get any hopes up for the results of the next study).

There's another odd feature to this news: Elan was working with Wyeth, who were acquired by Pfizer. They then signed another development deal with J&J (Janssen) to spread the risk around. The trial results that came out yesterday were from the Janssen end of things (Pfizer's paying for the outside-the-US trials). But the press release was from Pfizer - as far as I can see, J&J has not sent out anything yet. And as for Elan, their press release is titled: "Elan Announces Pfizer’s Release of A Top-Line Result In First Of Four Bapineuzumab Phase 3 Trials". It says nothing about what that result might be - just that Pfizer released it, and it reminds people that more results are coming. Hmm. Was it agreed on that Pfizer would be the people to release these results? Or is that the sound of gritted teeth in the distance?

One other question: will this result finally shake the faith of the people who've been buying Elan stock all these years? Or was the failure of patients to respond the fault of hedge funds and short sellers instead? You know, the usual suspects. . .

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

June 13, 2012

Live By The Bricks, Die By The Bricks

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Posted by Derek

I wanted to highlight a couple of recent examples from the literature to show what happens (all too often) when you start to optimize med-chem compounds. The earlier phases of a project tend to drive on potency and selectivity, and the usual way to get these things is to add more stuff to your structures. Then as you start to produce compounds that make it past those important cutoffs, your focus turns more to pharmacokinetics and metabolism, and sometimes you find you've made your life rather difficult. It's an old trap, and a well-known one, but that doesn't stop people from sticking a leg into it.

Take a look at these two structures from ACS Chemical Biology. The starting structure is a pretty generic-looking kinase inhibitor, and as the graphic to its left shows, it does indeed hit a whole slew of kinases. These authors extended the structure out to another loop of the their desired target, c-Src, and as you can see, they now have a much more selective compound.
But at such a price! Four more aromatic rings, including the dread biphenyl, and only one sp3 carbon in the lot. The compound now tips the scales at MW 555, and looks about as soluble as the Chrysler building. To be fair, this is an academic group, which mean that they're presumably after a tool compound. That's a phrase that's used to excuse a lot of sins, but in this case they do have cellular assay data, which means that despite this compound's properties, it's managing to do something. Update: see this comment from the author on this very point. Be warned, though, if you're in drug discovery and you follow this strategy. Adding four flat rings and running up the molecular weight might work for you, but most of the time it will only lead to trouble - pharmacokinetics, metabolic clearance, toxicity, formulation.

My second example is from a drug discovery group (Janssen). They report work on a series of gamma-secretase modulators (GSMs) for Alzheimer's. You can tell from the paper that they had quite a wild ride with these things - for one, the activity in their mouse model didn't seem to correlate at all with the concentration of the compounds in the brain. Looking at those structures, though, you have to think that trouble is lurking, and so it is.

"In all chemical classes, the high potency was accompanied by high lipophilicity (in general, cLogP >5) and a TPSA [topological polar surface area] below 75 Å, explaining the good brain penetration. However, the majority of compounds also suffered from hERG binding with IC50s below 1 μM, CyP inhibition and low solubility, particularly at pH = 7.4 (data not shown). These unfavorable ADME properties can likely be attributed to the combination of high lipophilicity and low TPSA.

That they can. By the time they got to that compound 44, some of these problems had been solved (hERG, CyP). But it's still a very hard-to-dose compound (they seem to have gone with a pretty aggressive suspension formulation) and it's still a greasy brick, despite its impressive in vivo activity. And that's my point. Working this way exposes you to one thing after another. Making greasy bricks often leads to potent in vitro assay numbers, but they're harder to get going in vivo. And if you get them to work in the animals, you often face PK and metabolic problems. And if you manage to work your way around those, you run a much higher risk of nonspecific toxicity. So guess what happened here? You have to go to the very end of the paper to find out:

As many of the GSMs described to date, the series detailed in this paper, including 44a, is suffering from suboptimal physicochemical properties: low solubility, high lipophilicity, and high aromaticity. For 44a, this has translated into signs of liver toxicity after dosing in dog at 20 mg/kg. Further optimization of the drug-like properties of this series is ongoing.

Back to the drawing board, in other words. I wish them luck, but I wonder how much of this structure is going to have to be ripped up and redone in order to get something cleaner?

Comments (39) + TrackBacks (0) | Category: Alzheimer's Disease | Cancer | Drug Development | Pharmacokinetics | Toxicology

May 18, 2012

Strangely Good Results in Diabetes and Cardiovascular Disease

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Posted by Derek

I've read a couple of medical papers recently that show how tricky it is to draw conclusions on what patients would be best helped by a specific therapy. Many of you will have seen the paper in The Lancet on the use of statins in low-risk patients. This isn't something you'd necessarily think would do much good - it all depends on what the benefits are, at the margin, of lowering LDL. But the results appear surprisingly strong:

In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered.

A note to the conspiratorially minded, should any such come across this: it's worth noticing that this "maybe everyone should take statins" result comes after the major ones have gone off patent. Pfizer, Merck et al. would have greatly enjoyed this recommendation had it occurred ten years ago, but it didn't (and probably couldn't have, since we didn't have as much data as we do now).

Now to another (often related) disease, type II diabetes. It's been found that bariatric surgery improves glycemic control in the very obese patients who are candidates for the procedure. And that makes sense - obesity is absolutely a risk factor for type II in the first place. But as more and more of these surgeries are being done, something odd is becoming apparent:

Clinicians note that bariatric operations can dramatically resolve type 2 diabetes, often before and out of proportion to postoperative weight loss. Now two randomized controlled trials formally show superior results from surgical compared with medical diabetes care, including among only mildly obese patients. The concept of 'metabolic surgery' to treat diabetes has taken a big step forward.

Why this happens is a very good question indeed. Patients seem to benefit greatly within the first two weeks after gastric bypass surgery, well before any significant weight loss has occurred. My first guess is that it's something to do with secretion of hormones from the gut itself, and you'd also have to think that nutrient sensing gets profoundly altered. It's not going to be easy to turn this into an approved therapy, though. Running randomized clinical trials for dramatic surgical procedures (versus noninvasive care) is difficult, as you'd imagine:

Despite these compelling clinical observations, RCTs of surgery versus nonsurgery are sorely needed. Ample precedents exist wherein RCTs reversed longstanding paradigms derived from nonrandomized clinical trials. Some of the best evidence in bariatric surgery, from the Swedish Obese Subjects study (a long-term observation of various operations versus conventional care), is prone to allocation bias because participants were not randomized. Subjects who actively chose surgery may be more motivated overall and generally take better care of themselves. The NIH is unlikely to reconsider its guidelines without pertinent RCTs, and insurance companies are unlikely to pay for operations that are not NIH-sanctioned.

Both of these results point out the completely nonlinear nature of living systems. It can work for good, as in these cases, or for bad. Alzheimer's, the subject of yesterday's post, is a perfect example of the latter: one protein, out of perhaps a few million, has one of its hundreds of amino acids changed in one small way on its side chain. And it's a death sentence. Good to know that things can work in the other way once in a while.

Comments (14) + TrackBacks (0) | Category: Alzheimer's Disease | Cardiovascular Disease | Diabetes and Obesity

May 17, 2012

A Preventative Trial for Alzheimer's: The Right Experiment

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Posted by Derek

Alzheimer's disease is in the news, as the first major preventative drug trial gets underway. I salute the people who have made this happen, because we're bound to learn a lot from the attempt, even while I fear the chances for success are not that good.

A preventative trial for Alzheimer's would, under normal circumstances, be a nightmarish undertaking. The disease is quite variable and comes on slowly, and it's proven very difficult to predict who might start to show symptoms as they age. You'd be looking at dosing a very large number of people (thousands, even tens of thousands?) for a very long time (years, maybe a decade or two?) in order to have a chance at statistical significance. And you would, in the course of things, be giving a lot of drug to a lot of people who (in the end) would have turned out not to need it. No, it's no surprise that no one's gone that route.

But there's a way out of that impasse: find a population with some sort of amyloid-pathway mutation. Now you know exactly who will come down with symptoms, and (unfortunately) you also know that they're going to come down with them earlier and more quickly as well. There are several of these around the world; the "Swedish" and "Dutch" mutations are probably the most famous. There's a Colombian mutation too, with a well-defined patient population that's been studied for years, and that's where this new study will take place.

About 300 people will be given an experimental antibody therapy to amyloid protein, crenezumab. This was developed by AC Immune in Switzerland and licensed to Genentech, and is one of many amyloid-targeted antibodies that have come along over the years. (The best-known is bapineuzumab, currently in Phase III). Genentech (Roche) will be putting up the majority of the money for the trial ($65 million, with $16 million from the NIH and $15 million in private foundation money). Just in passing, weren't some people trying to convince everyone a year ago that it only costs $43 million total to develop a new drug? Har, har.

100 people with the mutation will get the antibody every two weeks, and 100 more will get placebo. There are also 100 non-carriers mixed in, who will all get placebo, because some carriers have indicated that they don't want to know their status. Everyone will go through a continuing battery of cognitive and psychological tests, as well as brain imaging and a great deal of blood work, which (if we're lucky) could furnish tips towards clinical biomarkers for future trials.

So overall, I think that this trial is an excellent idea, and I very much hope that a lot of useful information comes out of it. But I've no firm hopes that it will pan out therapeutically. This will be a direct test of the amyloid hypothesis for Alzheimer's, and although there's a tremendous amount of evidence for that line of thought, there's a lot against it as well. Anyone who really thinks they know what will happen in this situation hasn't thought hard enough about it. But that's the best kind of experiment, isn't it?

Comments (18) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Development

April 3, 2012

Bapineuzumab: An Alzheimer's Update

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Posted by Derek

The bapineuzumab saga has been going on for years now. (Every Alzheimer's therapy attempt either has gone on or will go on for years; it's such a slow-moving and heterogeneous disease that the clinical trials are some of the worst in the business). The results so far have not been all that encouraging, but they haven't been discouraging enough (given the state of the field) to give up on, either. Now there's another bit of data, and it's of a piece with the rest.

This Archives of Neurology paper has some results from two small 12-month patient cohorts looking at the antibody's effect on markers for Alzheimer's in the cerebrospinal fluid (CSF). (These were patients from two larger studies who agreed to be sampled for this part). And it's. . .well, you'd hope for better. Two types of tau protein (total and phosphorylated) were monitored, and while they did show an effect compared to the beginning of the study, only the phosphorylated tau was significant versus the placebo group. And what about soluble beta-amyloid? No change at all, looking over several forms (N-terminal modified, etc.)

The paper tries (in my opinion) to put a good face on these numbers, saying that the CSF phosphorylated tau levels have correlated with brain pathology in other studies, and that the amyloid levels may well reflect other clearance pathways or binding to bapineuzumab itself, and should thus be interpreted with caution. (If there had been any trend in the numbers, though, we probably wouldn't be acting so cautiously). But as the paper says, "An important question remains whether such changes in CSF biomarkers correlate with clinical benefit". That it does, and we're going to have to wait for the phase III results in order to say anything. That has been one long-running and expensive trial, for sure, and I hope that there's something worthwhile waiting at the end of it. Alzheimer's patients (and their families) really need something to give them some hope. Maybe the ApoE4 connection will help; I understand that the Phase III trials are focusing on that. But in any case, I'm hoping for a surprise, to be honest, because my expectations aren't high.

Comments (9) + TrackBacks (0) | Category: Alzheimer's Disease

February 13, 2012

Bexarotene for Alzheimer's

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Posted by Derek

Here's another intriguing Alzheimer's result, in a field that could certainly use some. A group at Case Western (no, not the gyre guy) has reported on the effects of the RXR ligand Bexarotene (brand name Targretin) in several different mouse models of the disease. Dosing with the compound seems to quickly lower the levels of the soluble forms of beta-amyloid in the rodents' brains, most likely by increasing the expression of the lipoprotein ApoE. (That one's long been associated with Alzheimer's).

Update: a reader notes that Merck seems to have some interest in a related mechanism, using LXR to upregulate ApoE in Alzheimer's. And this upcoming Keystone Conference is sure to feature a lot of interesting discussion on the topic as well.

Follow-up showed that more than the soluble forms had been cleared, though. A significant amount of the insoluble amyloid plaques had been removed at long time points (several days), and the hypothesis there is some sort of immune reponse (an approach that's been tried for years now through vaccines, with very mixed success). Having a single drug (which has already been approved for some oncology indications) that appears to work rapidly on both the soluble and insoluble forms of amyloid is both dramatic and unexpected.

The Case Western group saw improvement on behavior and memory in the mice as well, as you might well hope. Since this drug has already been through the FDA, you'd hope that the way is clear to trying this same idea out in human patients. That, of course, is where many bright ideas in Alzheimer's have come to grief. If the drug doesn't affect ApoE expression in quite the same way, or if the lipoprotein doesn't act similarly in humans, or if that plaque-clearing mechanism, whatever it is, doesn't kick in or goes awry, then these results could end up just being another wonderful rodent study that didn't translate. But it's absolutely worth finding out, and I hope that we do in short order.

Update: this study is already triggering more interest in the Alzheimer's community than can be contained, which has been the story every time something promising shows up. . .

Comments (36) + TrackBacks (0) | Category: Alzheimer's Disease

February 7, 2012

Tau Spreads On Its Own?

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Posted by Derek

I've been meaning to mention the very interesting work that's shown up on tau protein in Alzheimer's. That's generally taken a back seat to amyloid in the protein-pathologies-of-Alzheimer's derby, but no one has been able to rule it out as a causative event, either. And the progress of tau pathology through the brain is quite suggestive - it tends to start in one region (the entorhinal cortex) and spread from there. The question is, what's driving that process? Is it tau itself spreading, or perhaps something inside the cell that causes tau problems is spreading, or is it some set of external conditions (that lead to tau pathologies) which is spreading?

This latest work goes a good way towards settling that question. (Here's one group's paper in PLoS One; the other paper in Neuron doesn't seem to be up yet, which has caused some controversy). The researchers in question engineered mice that express human tau protein localized to the entorhinal cortex (EC). They then sat back and watched what happened, taking sample along the way.

And what happened was a spectacular result. They found human tau in the EC initially, as expected. But over time, it began to show up in brain regions that are synaptically connected to the EC, and then it spread to the regions that are connected to those. This is human tau protein, remember - the only cells in the brains of these mice that should be able to make it are in the EC. In other words, the protein itself appears to be spreading from neuron to neuron, apparently through the synaptic junctions:

In general, our NT mouse model replicates the spatial and temporal aspects of the earliest stages (I–III) of Braak staging of tauopathy in Alzheimer's disease. We have demonstrated that tau pathology initiating in the EC can spread to other synaptically connected brain areas as the mice age, supporting the idea that AD progresses via an anatomical cascade as opposed to individual events occurring in differentially vulnerable regions.

They also now have a very interesting (and potentially very useful) mouse model of Alzheimer's pathology. There are still a huge number of open questions about Alzheimer's, don't get me wrong. But this is a real advance, in a field that doesn't see as many of those as everyone would like. Now to figure out how that protein is spreading (How's it excreted from the cell? How's it taken up by the next ones in line?) and why.

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease

August 5, 2011

Bernard Munos Rides Again

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Posted by Derek

I've been meaning to link to Matthew Herper's piece on Bernard Munos and his ideas on what's wrong with the drug business. Readers will recall several long discussions here about Munos and his published thoughts (Parts one, two, three and four). A take-home message:

So how can companies avoid tossing away billions on medicines that won’t work? By picking better targets. Munos says the companies that have done best made very big bets in untrammeled areas of pharmacology. . .Munos also showed that mergers—endemic in the industry—don’t fix productivity and may actually hurt it. . . What correlated most with the number of new drugs approved was the total number of companies in the industry. More companies, more successful drugs.

I should note that the last time I saw Munos, he was emphasizing that these big bets need to be in areas where you can get a solid answer in the clinic in the shortest amount of time possible - otherwise, you're really setting yourself up with too much risk. Alzheimer's, for example, is a disease that he was advising that drug developers basically stay away from: tricky unanswered medical questions, tough drug development problems, followed up by big huge long expensive clinical trials. If you're going to jump into a wild, untamed medical area (as he says you should), then pick one where you don't have to spend years in the clinic. (And yes, this would seem to mean a focus on an awful lot of orphan diseases, the way I look at it).

But, as the article goes on to say, the next thought after all this is: why do your researchers need to be in the same building? Or the same site? Or in the same company? Why not spin out the various areas and programs as much as possible, so that as many new ideas get tried out as can be tried? One way to interpret that is "Outsource everything!" which is where a lot of people jump off the bus. But he's not thinking in terms of "Keep lots of central control and make other people do all your grunt work". His take is more radical:

(Munos) points to the Pentagon’s Defense Advanced Research Projects Agency, the innovation engine of the military, which developed GPS, night vision and biosensors with a staff of only 140 people—and vast imagination. What if drug companies acted that way? What areas of medicine might be revolutionized?

DARPA is a very interesting case, which a lot of people have sought to emulate. From what I know of them, their success has indeed been through funding - lightly funding - an awful lot of ideas, and basically giving them just enough money to try to prove their worth before doling out any more. They have not been afraid of going after a lot of things that might be considered "out there", which is to their credit. But neither have they been charged with making money, much less reporting earnings quarterly. I don't really know what the intersection of DARPA and a publicly traded company might look like (the old Bell Labs?), or if that's possible today. If it isn't, so much the worse for us, most likely.

Comments (114) + TrackBacks (0) | Category: Alzheimer's Disease | Business and Markets | Clinical Trials | Drug Development | Drug Industry History | Who Discovers and Why

July 26, 2011

Alzheimer's: The News Is Not Getting Better

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Posted by Derek

Is there something going on with patients in Alzheimer's trials that we didn't expect? There have been reports of an unexpected side effect (vasogenic edema) in several trials, for drugs that work through completely different mechanisms.

It makes some sense in the case of antibody-based therapies like bapineuzumab (where this problem first got attention) and solanezumab. After all, the immune system is pretty powerful stuff, and you could certainly imagine these sorts of side effects (either directly or from some effect of clearing out amyloid debris). As those reports indicate, the problem may lessen with time, and may be more severe in patients with the APOE4 allele, a known (but not understood) risk factor for Alzheimer's.

But this latest report is for the Bristol-Myers Squibb gamma-secretase inhibitor avagacestat (BMS-708163). That shouldn't be involved with any inflammatory/immune mechanisms, nor, really, with amyloid clearance. A secretase inhibitor should just keep new amyloid from being formed and deposited, which should be beneficial if the beta-amyloid theory of Alzheimer's is correct, which is what we're all still in the middle of deciding these days. Expensively and excruciatingly deciding.

Meanwhile, the most recent big clinical failure in this area continues to reverberate. Lilly's gamma-secretase inhibitor semagacestat, the first that went deep into the clinic, imploded when the company found that patients in the treatment group were deteriorating faster than those in the control group. Seven months on, they're still worse. What does this mean for the BMS compound targeting the same mechanism? That is the big, important, unanswerable question - well, unanswerable except by taking the thing deep into big clinical trials, which is what BMS is still committed to doing.

For more on Alzheimer's drug development - and it hasn't been pretty - scroll back in this category.

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease | Toxicology

August 24, 2010

Alzheimer's: Down With Amyloid?

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Posted by Derek

Here's a fascinating short interview with Mark Smith of Case Western, a leading anti-amyloid-hypothesis guy in the Alzheimer's field. As you'd imagine, he's taking the recent failure of Lilly's gamma-secretase inhibitor in stride.

As you might imagine, he's not shy:

"Everything comes down to how one interprets data. There is a lot of scientific noise out there and most people like to play “follow the leader”. The structure of granting agencies actually discourages anything else. I sense the tide turning but think that the dead horse will be likely flogged for a while yet. For example, the Alzheimer’s field is already moving toward earlier and earlier “diagnosis”. Until these people are subjected to anti-amyloid approaches the field will continue [to support the amyloid theory].

I have received a lot of stick for my scientific talks where for over a decade I have challenged the amyloid hypothesis. I typically tell the audience that my views are controversial and that I would really appreciate someone pointing out a flaw in my logic or presenting evidence that shows that I am wrong. Neither has ever happened."

Comments (6) + TrackBacks (0) | Category: Alzheimer's Disease

August 18, 2010

Lilly's Gamma Secretase Inhibitor for Alzheimer's: Worse Than Nothing

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Posted by Derek

Well, well, well. We finally have solid clinical data from a large trial of a gamma-secretase inhibitor for Alzheimer's disease. And it doesn't work.

Background, for those outside the field: a hallmark of Alzheimer's is the appearance of plaques in the brain. These are insoluble clumps of a protein called amyloid-beta, surrounded by dead and dying neurons. This amyloid is split off (for some reason) from the middle of a larger precursor protein (APP), and there are two enzymes that make the cuts to release it: gamma-secretase and beta-secretase. Shutting down one or both of those has long been seen as the most direct route to keeping amyloid from accumulating, and compounds that do this have been sought for at least twenty years now.

Now this is interesting. The road to secretase inhibition data in the clinic has been a long one, to say the very least - I worked in this field myself in the early 1990s, when we were still guessing at the enzymes involved. I would not like to even guess about the man-hours that have been spent along the way. Gamma-secretase has been a beast of a target. One nasty surprise along the way was the discovery that it also processes Notch, which is a developmental signaling pathway that you'd really rather avoid, but people have persevered, and pushed compounds into the clinic.

(As an aside, I'd have to say that beta-secretase has been even harder. There are an awful lot of structures out there billed as beta-secretase (BACE) inhibitors - and so they are, in your choice of labware. Despite huge efforts, it's been extremely hard to make an inhibitor with a reasonable chance of getting into the brain and being a drug. The only one I know of is CTS21166, from CoMentis, about which news has been rather scarce recently).

Myriad had taken a sort-of kind-of gamma-secretase inhibitor (Flurizan) into the clinic, and failed dismally. But Eli Lilly's semagacestat (LY450139) has long been the most advanced pure gamma-secretase inhibitor. It inhibits the enzyme directly, and had shown dose-dependent lowering of amyloid formation in humans, which is all you can ask. There were side effects noted from Notch, mostly in the GI tract, but the profile was still good enough to go on into Phase III two years ago. And now we have the results.

Nothing. Worse than nothing - they saw real declines in cognitive function compared to the placebo group. It's not getting as much play in the news this morning, but it also appears - insult to injury - that the drug was associated with a greater risk of skin cancer. Update: a commenter points out that this risk was known). Lilly has halted any development, and told all the study centers to stop dosing immediately. All the patients who received it will be monitored to see how they do over the next few months.

This is about as bad a result as could possibly be obtained, and I think it really has to torpedo the idea of gamma secretase as a drug target. Unless someone comes up with a very compelling and intricate argument to explain these results, I don't see how anyone can risk going down this particular road again. What must they be thinking today over at Bristol-Myers Squibb, where they've been developing a direct competitor, BMS708163? And how about the other drug candidates behind them?

And what does this say about the amyloid hypothesis itself? Nothing good. This is the crucial period for the whole idea, with several different approaches finally yielding late-stage clinical data. And it's starting to look as if the whole idea may have been just a terrible diversion.

Comments (39) + TrackBacks (0) | Category: Alzheimer's Disease

August 13, 2010

Alzheimer's Markers and Collaboration

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Posted by Derek

I'm of two minds on this New York Times article on Alzheimer's research. It details some recent progress on biomarkers for the disease, and that work does look to be useful. A lot of people have proposed diagnostics and markers for Alzheimer's and its progression over the years, but none of them have really panned out. If these do, that's something we haven't had before.

But my first problem is something we were talking about here the other day. Biomarkers are not necessarily going to help you in drug development, not unless they're very well validated indeed. We really do need them in Alzheimer's research, because the disease progression is so slow. And this effort is really the only way to find such things - a good-sized patient sample, followed over many years. But unfortunately, 800 people (divided out into different patient populations) may or may not be enough, statistically. We're now going to have to take the potential assays and markers that this work has brought up and see how well they work on larger populations - that's the only way that they'll be solid enough to commit a clinical trial to them. Both the companies developing drugs and the regulatory agencies will have to see convincing numbers.

That general biomarker problem is something we really can't do anything about; the only cures are time, effort, money, and statistical power. So it's not a problem peculiar to Alzheimer's (although that's a tough proving ground), or to this collaborative effort. But now we come to the collaborative effort part. . .overall, I think that these sorts of things are good. (This gets back to the discussions about open-source drug discovery we've been having here). Bigger problems need sheer manpower, and smaller ones can always benefit from other sets of eyes on them.

The way that this Alzheimer's work puts all the data out into the open actually helps with that latter effect. All sorts of people can dig through the data set, try out their hypotheses, and see what they get. But I think it's important to realize that this is where the benefit comes from. What I don't want is for people to come away thinking that the answer is that we need One Big Centralized Effort to solve these things.

My problem with the OBCE model, if I can give it an acronym, is that it tends to cut back on the number of ideas and hypotheses advanced. Big teams under one management structure don't tend to work out well when they're split up all over the place. There's managerial (and psychological) pressure, from all directions, to get everyone on the same idea, to really get in and push that one forward with all the resources. This is why I worry about all the consolidation in the drug industry: fewer different approaches get an airing when it's all under the roof of one big company.

So this Alzheimer's work is just the sort of collaboration I can admire: working on a big problem, sharing the data, and leaving things open so that everyone with an idea can have a crack at it. I just hope that people don't get the wrong idea.

Comments (3) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Press Coverage | Who Discovers and Why

July 27, 2010

Alzheimer's and Amyloid, Again

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Posted by Derek

I wanted to mention this good article in the New York Times on the amyloid hypothesis and Alzheimer's. That's a topic I've covered often here, but this is a good overview of the field. And it's a good overview of the field's big questions, too: is amyloid really the cause of Alzheimer's? Do we have any therapies that can slow amyloid deposition, or not? If so, do any of them actually show any real-world benefit to patients?

This gets into the broader question of biomarkers as well. The FDA is insisting, as they should, that any potential Alzheimer's therapy should show improvements in memory or cognition, not just improvements in number of plaques or the like. Getting that sort of data is very difficult, but it's really the only way to avoid yet another "You'd Have Thought That. . ." moment. We've been having too many of those over the last few years. As the FDA's director of neurology puts it:

“You only care if down the road the patient gets better,” Dr. Katz said. “What we are concerned about is approving a drug based on a lab test and being wrong about what happens to the patient clinically.”

With Alzheimer’s, Dr. Katz said, “the great fear is that maybe amyloid has nothing to do with the disease.” If that were the case, and the agency approved a drug that blocked amyloid formation, millions of healthy people could end up taking something useless or even dangerous. And because it takes so long for Alzheimer’s to develop, it could be decades, if ever, before anyone knew the drug did not work.

“It is a conundrum,” Dr. Katz said. “We all hope to get to the point in our understanding of the disease process where everyone in the field says: ‘Look. We know it now. Amyloid causes Alzheimer’s, and we have drugs that decrease amyloid.’ But we are not there yet.”

Biomarkers, ideally, are supposed to speed up drug development. But validating a good one might just as slow a process as if you didn't have a biomarker at all. What I worry about is a situation where the first people to discover these things end up with no chance to benefit from their work, but actually end up helping out other groups much more. And while there's a place for altruism in medical research, I doubt if making it the driving force will lead to success. . .

Comments (17) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

June 11, 2010

Alzheimer's: Extracting Data From Failed Trials

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Posted by Derek

It's no secret that Alzheimer's disease has been a disastrous area in which to do drug discovery. Every large drug company has had failures in the area, and many smaller ones have gone out of business trying their hands. (I had several years in the field myself earlier in my career, trying three different approaches, none of which panned out in the end).

Now the Coalition Against Major Diseases has announced an open-access database of clinical trial results from failed drug candidates in the area. J&J, GlaxoSmithKline, Abbott, SanofiAventis, and AstraZeneca have contributed data from 11 failed drug candidates, and more look to be on the way from other companies. I hope that Eli Lilly, Merck (their own compounds and those from Schering-Plough), and Pfizer all join in on this - right off the top of my head, I can think of failed drugs from all of them, and I know that there are plenty more out there. (Pfizer seems to have dodged a question about whether or not they're participating, to judge from that Wall Street Journal article linked to above).

It'll be difficult to comb through all this to extract something useful, of course. But without sharing the data on these compounds, it would be utterly impossible for anything to come out of their failures. I think this is an excellent idea, and well worth extended to other therapeutic areas.

Comments (12) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Industry History

May 17, 2010

The Memory Goes Because. . .the Acetyl Groups Go?

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Posted by Derek

I've been meaning to write about this paper from a recent issue of Science. They've been studying the differences between young (3-month) mice and old (16-month) mice - their ability to learn, and to remember. Markers of neuronal plasticity and the like are pretty similar between the groups, although the older mice definitely show some impairments in spatial learning and recall. Looking down at the genetic level, for effects on chromatin handling, didn't seem to show much, either - the young and old mice have similar levels of histone deacetylase and histone acyltransferase enzymes.

But a look at the real levels of acetylated histones showed something different: the older mice seemed to be deficient in one particular type of acetylation, H4K12. That particular lysine residue was acetylated much more readily in the younger animals in response to a fearful event, but the older animals didn't upregulate the process. A broad-based search using microarrays showed that a wide range of genes were regulated by the young mice when learning to avoid a fear stimulus, but were not altered to nearly the same degree in the older ones. And as it turns out, the H4K12 acetylation looks to be one of the common factors in the regulation of these genes.

The authors went so far as to use Vorinostat (SAHA), a marketed histone deacetylase inhibitor, to test this hypothesis. Administering that to the older mice (directly into the brain; it doesn't really cross on its own) led to both H4K12 effects and to beneficial effects on learning.

This is a long way from being a therapy, but it's a very interesting lead towards one. The effects of messing around with histone acylation states could be profound (both in the sense of "profoundly good" as well as "profoundly bad"), so it's going to be quite a while before the dust settles enough for us to know what to do. But I'm encouraged to see things like this coming up. Given that I'm 48, we're going to have to keep moving right along in order to have something ready by the time I'm going to need it!

Comments (14) + TrackBacks (0) | Category: Aging and Lifespan | Alzheimer's Disease | The Central Nervous System

April 6, 2010

A Brief and Not At All Intemperate Evaluation of the Current Literature

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Posted by Derek

In keeping with my Modest Literature Proposal from earlier this year, I would like to briefly point out a Journal of Medicinal Chemistry paper on potential Alzheimer's therapies. Whose lead compound has a nine-carbon alkyl chain in the middle of it. And weighs 491. And has two quaternary nitrogens. Which structural features will, in all likelihood, lead to said compound demonstrating roughly this amount of blood-brain barrier penetration, assuming it reaches sufficient blood levels to get that far. That is all.

Comments (22) + TrackBacks (0) | Category: Alzheimer's Disease | Pharmacokinetics | The Scientific Literature

April 5, 2010

Rapamycin for Alzheimer's?

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Posted by Derek

Last summer a paper was published (PDF) showing rapamycin dosing appeared to lengthen lifespan in mice. (In that second link, I went more into the background of rapamycin and TOR signaling, for those who are interested). Now comes word that it also seems to prevent cognitive deficits in a mouse model of Alzheimer's.

The PDAPP mice have a mutation in their amyloid precursor protein associated with early-onset familiar Alzheimer's in humans, and it's a model that's been used for some years now in the field. It's not perfect, but it's not something you can ignore, either, and the effects of rapamycin treatment do seem to be significant. (The paper uses the same dose that was found to extend lifespan). The hypothesis is that rapamycin allowed increase autophagy (protein digestion) to take place in the brain, helping to clear out amyloid plaques.

What I also found interesting, though, was the rapamycin-fed non-transgenic control animals. In each case, they seem to show a trend for increased performance in the various memory tests, although they don't quite reach significance. This makes me wonder what the effects in humans might be, Alzheimer's or not. After that lifespan report last year, it wouldn't surprise me to find out that some people are taking the stuff anyway, but it's not going to be anywhere near enough of a controlled setting for us to learn anything.

This report is definitely going to start a lot of people thinking about experimenting with rapamycin for Alzheimer's - there are a lot of desperate patients and relatives out there. But together with that lifespan paper, it might also start some people thinking about it whether they're worried about Alzheimer's or not.

Comments (16) + TrackBacks (0) | Category: Aging and Lifespan | Alzheimer's Disease | Biological News

March 16, 2010

Beta-Amyloid: An Antibiotic?

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Posted by Derek

Now here's something that I don't think anyone expected. A recent paper in PLoS One makes the case that beta-amyloid, the protein that has been fingered for decades as a major player in Alzheimer's disease, is actually part of the body's antimicrobial defenses.

Well, it's good to hear that it's doing something. Many people had hypothesized that it was a useless (indeed, harmful) byproduct, a waste stream from aberrant processing of the amyloid precursor protein (APP). Still, there have been reports over the years that beta-amyloid was substrate for active transport pumps, might be a ligand for various receptors, etc., but not everyone was willing to take these results seriously.

But it turns out that some of A-beta's properties are similar to those of innate host defense peptides. When this latest team checked the amyloid protein's activity, it turns out to be pretty active. The prototype peptide in this area, LL-37, appears to have a broader spectrum of activity, but A-beta beats it against several organisms, most notably the yeast C. albicans. And as it turns out, brain homogenates from Alzheimer's patients are much more active against yeast in vitro than samples from age-matched controls without the disease. But that only holds true for parts of the brain (like the temporal lobe) that are known to be high in amyloid. Samples from the cerebellum (which doesn't usually show Alzheimer's pathology) had no activity. (One has to wonder if this is the first time - or at least the first time in a very long while - that anyone's evaluated human brain homogenates for their microbicidal activity).

This could lead to a complete rethink of Alzheimer's pathology. It's been known for a long time that there's a big inflammation component to the disease - perhaps the problem (or at least the trigger) is an underlying infection that sets off the innate immune system in the brain. Larger than normal amounts of beta-amyloid are produced in response, but it starts to precipitate out.

The more familiar adaptive immune system has limited access to the CNS, although that's not stopping people from trying to use it. But that approach (and many others) presume that beta-amyloid is a cause of the disease. Perhaps it isn't. Maybe it's the body's attempt at a solution - and if that's true, we need to look elsewhere for the cause, and soon. This is one of the most thought-provoking looks at Alzheimer's that I've seen in a long time. Here's hoping it leads to something new.

Update: here are some more comments on this paper, and here are some speculations about amyloid as a protective agent.

Comments (25) + TrackBacks (0) | Category: Alzheimer's Disease

March 4, 2010

Dimebon, Grasping at Straws

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Posted by Derek

Robert Langreth, an editor at Forbes, points to a possible way that Dimebon could get approval for Alzheimer's: for its behavioral effects, not anything to do with amyloid or memory.

I'm not buying it, I have to say. Even Langreth's source admits that behavioral numbers didn't reach statistical significance. I don't see how this will be enough to rescue this one, even if one of the ongoing trials does use a behavioral score as an endpoint.

Update: Langreth has an earlier piece on how Dimebon appears to have been overhyped from the beginning, a viewpoint I concur with. The same thing happens with any drug for Alzheimer's, and is a constant problem in cancer and obesity, too.

Comments (16) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | The Central Nervous System

March 3, 2010

Dimebon Comes Crashing to Earth

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Posted by Derek

Earlier this month I wrote about Medivation and their Russian-derived clinical candidate for Alzheimer's disease, Dimebon (latrepirdine). At the time, I wrote that "A lot of eye-catching numbers from small Phase II trials tend to flatten out in the wider world of Phase III, and if forced, that's the way I'd bet here."

Unfortunately, that's just what appears to have happened. The results are out today, and Dimebon has not showed any efficacy at all versus placebo. From the data given in the press release, the comparison is just absolutely flat; you could have been giving the study patients breath mints and seen the same numbers. Since the design of this trial was similar to the smaller Phase II trials that showed such interesting results, there's clearly something going on that we don't understand. But that's the motto for all central nervous system research, isn't it?

I'm really not sure if there's a way forward for this drug. When you go to a larger, more well-controlled trial and revert back to baseline, it's hard to make a case for continued development. Pfizer (Medivation's partner here) still has a lot of money and a lot of desire to find a good Alzheimer's drug. But I don't think they'll be in the mood to spend much more of it here.

Comments (30) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

February 3, 2010

A Modest Literature Proposal

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Posted by Derek

Looking through the latest papers to show up in the Journal of Medicinal Chemistry, this one on BACE-1 inhibitor compounds caught my eye. Perhaps I'm about to be unfair to it. At any rate, I'm going to ask of it something it doesn't provide: data in something that's alive. Doesn't have to be a person, a dog, or even a rat. A cell would do: something with a membrane to cross, with metabolic processes, and with the ability to accept or reject someone's new compound. Enzymes just have to sit there and take whatever you throw at them; living systems fight back.

I sometimes think that we'd be better served if each of the medicinal chemistry journals were split. In J. Med. Chem.'s case, we would then have the Journal of In Vitro Medicinal Chemistry and the Journal of In Vivo Medicinal Chemistry. The criteria for publishing in the two journals would be exactly the same, except to get into the latter one, you would have at least had to have tried your compounds out on something besides an in vitro assay. Doesn't mean that they have to have worked - you just have to have looked.

Although the case of compounds with molecular weights of 900 that have four amides and a sulfonamide in them, and are directed against a target in the central nervous system, might still be a bit of a stretch. I supposed what irritates me about this paper is that it starts off talking about Alzheimer's disease. And that's natural enough in a study dedicated to finding inhibitors of BACE-1, but the problem is, Alzheimer's disease occurs in human beings. And these compounds do not look to have much chance of doing anything inside any human's body. The best I can say for them is that they might give someone else an insight into something that they might be able to do to make something that might have a better chance of working.

Cranky folks like me would probably refer to the latter of my two new journals as just "J. Med. Chem.", and would refer to the former one by a variety of other easy-to-remember names. I offer this suggestion for free to the scientific publishing community, who will, I'm sure, reciprocate with things of equal value.

Comments (26) + TrackBacks (0) | Category: Alzheimer's Disease | The Central Nervous System | The Scientific Literature

Dimebon for Alzheimer's: A Black Box Indeed

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Posted by Derek

Dimebon (dimebolin) is a perfect example of the black-box nature of drug research for the central nervous system. Any medicinal chemist who looks at its structure would immediately say "CNS", but shrug when asked what specific receptors it might hit. I'd have guessed histamine (correctly), since loratidine used to pay my salary, and I also would have guessed a clutch of 5-HT stuff as well. But it also has activity at AMPA and NMDA glutamate receptors, L-type calcium channels, and more. If you can tell me what it's really doing up there, you shouldn't bother: hang up on me and start calling people with money, because you're ready to take over the CNS therapeutic area for sure.

This blunderbuss is getting a lot of attention these days, since the data for a Phase III trial against Alzheimer's should be available sometime in the spring. The road to that was a strange one. Dimebolin was used for years as an antihistamine in Russia, although I'm not aware if it had any particular reputation for cognitive enhancement in its time as a Soviet allergy pill. It was picked up in screening done during the 1990s at a research institute in the (once secret) military/industrial research city of Chemogolovka Chernogolovka, about two hours from Moscow. It showed effects on learning in rodent models, and gradually advanced to human trials for Alzheimer's. Impressive data came out in 2008, and Medivation, who own the rights to it here, partnered with Pfizer for development.

Update: the city mentioned above is surely Chernogolovka, but it's interesting that it's appeared many times as Chemogolovka in the English press and literature. I chalk that up to the "rn" looking very much like an "m", and to the mistaken name being semi-plausible in a Stalinist-industrial way, as witness Magnitogorsk. Chernogolovka's much older, though.)

That Bloomberg report I linked to above has a lot of people excited, since there hasn't been a new therapy for Alzheimer's in quite a while (or, arguably, a decent one ever). I don't know what to think, myself. It's absolutely possible that the drug could turn out to have beneficial effects, but it's just as possible that it could miss meeting the high expectations that many investors seem to have for it. (Medivation's stock is up 80% over the last year, for example). A lot of eye-catching numbers from small Phase II trials tend to flatten out in the wider world of Phase III, and if forced, that's the way I'd bet here. (I am most definitely not giving investment advice, though - Alzheimer's drug development is a total crap shoot, and should only be approached with money you can afford to see incinerated).

I hope that Dimebon actually works, though - the world could use something that does. Just don't let anyone convince you that they know how it works, if it makes it through. Unraveling that will take quite a while. . .

Comments (10) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | The Central Nervous System

January 13, 2010

Two Doses of Crazy

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Posted by Derek

I'd like to take the time this morning to deal with two conspiracy theorists, and I'll take them in order of increasing foil-hat thickness. First up is Joe Collier, an emeritus professor who writes a blog for the British Medical Journal. He notes the recent study that suggested that cell phone emissions could have a beneficial effect in rodent models of Alzheimer's. I didn't give that any play on this blog - too many other things going on, and I don't find any rodent models of Alzheimer's particularly trustworthy to start with. But the study also showed (apparently beneficial) effects on normal rodents, and is certainly worth following up on.

But Collier takes this result and runs with it:

So what happens next? Faced with the prospect, albeit remote, of losing a lucrative market, I predict that the industry will want to quash the electromagnetic treatment theory as soon as possible. To this end, I would expect that the industry propaganda machine will go into overdrive in an attempt to undermine the credibility and findings of Arendash, and to overwhelm the decision makers (ultimately the funders) so that the use of drugs is maintained. The power of industry as an information generator and distributor is unmatched, and industry will use all its persuasive skills. . .

And so on, and so on. The problem (well, one problem) with this line of reasoning is that it could also be extended to other new drugs for Alzheimer's. If the industry wanted to keep selling the existing Alzheimer's drugs at all cost, why would we go to the trouble of trying to develop better ones? We are, you know - I have no idea how much money has vanished down that particular pipe, but it sure has been a lot, and I've helped flush some of it through myself. But we're not the monolithic "drug industry" over here. We're a bunch of companies climbing all over each other trying to make money, take each others' market share, and get to the clinic faster than the other guys down the road. That's what keeps things moving - everyone who's done industrial drug discovery has read a new press release or seen a new patent filing and heard the footsteps coming up from behind.

So I have a counterprediction for Collier. The South Florida study will, in fact, be followed up on. It's interesting enough. And if there's something to it, someone will find a way to optimize the effect and make money off it. And the drug industry will not mobilize to squash it, either - honestly, we have enough to do trying to get our own stuff to work. I haven't seen a single statement from a drug company about this study so far myself, and if Joe Collier has, I'd invite him to produce it.

Next! OK, now we move on to something that seems to be getting some more headlines in the past week or two, and that people have been e-mailing me about. One Wolfgang Wodarg, a German doctor and SPD politician, has been telling everyone that the handling of the H1N1 flu epidemic should be investigated because, he says, it's all a "fake pandemic" whipped up by the drug companies. (You can get all the Wodarg you need, and more, at his web site). Stories in the more excitable press make him sound like the head of all the health agencies of Europe, but people are confusing the Council of Europe (where Wodarg heads a subcommittee) with the EU, among other things they're mixing up.

The World Health Organization is now fielding questions about whether they oversold the epidemic, but it's a sure bet that (if it taken off more drastically) they'd be fielding even more about why they weren't prepared for it. At any rate, if you think that the Monolithic Drug Industry can simultaneously push around the WHO, the CDC, and the public health agencies of every other country in the world, I invite you to think again. If we could do all that, we'd at least be in good enough financial shape that we wouldn't be laying thousands of people off and doing ridiculous mergers out of desperation.

Wodarg, for his part, seems to have been sounding all kinds of alarms for a long time now. Back in the fall, he was telling everyone that the vaccine was going to give them cancer, for example. In case anyone's wondering, I treat his suggestions with the contempt that they appear to richly deserve.

Comments (34) + TrackBacks (0) | Category: Alzheimer's Disease | Infectious Diseases | Snake Oil | Why Everyone Loves Us

December 23, 2009

An Alzheimer's Compound Runs Into Big Trouble

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Posted by Derek

Another interesting approach to Alzheimer's therapy has just taken a severe jolt in the clinic. Elan and Transition Therapeutics were investigating ELEND005, also known as AZD-103, which was targeted at breaking down amyloid fibrils and allowing the protein to be cleared from the brain.

Unfortunately, the two highest-dose patient groups experienced a much greater number of severe events - including nine deaths, which is about as severe as things get - and those doses have been dropped from the study. I'm actually rather surprised that the trial is going on at all, but the safety data for the lowest dose (250mg twice daily) appear to justify continuing. The higher doses were 1g and 2g b.i.d., and the fact that they were going up that high makes me think that the chances of success at the lowest dose may not be very good.

So what is this drug? Oddly enough, it's one of the inositols, the scyllo isomer. Several animal studies had shown improvements with this compound, and there were promising results for Parkinson's as well. At the same time, scyllo-inositol has been implicated as a marker of CNS pathology when it's found naturally, so it's clearly hard to say just what's going on. As it always is with the brain. . .

Comments (18) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | The Central Nervous System | Toxicology

October 19, 2009

Short Topics From All Over

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Posted by Derek

(1) Bnet Pharma on "How Not to Write a Pharma Press Release". Privately held Epeius is sending out bulletins loaded with phrases like "more stunning results" and "Epeius Biotechnologies draws the sword of targeted gene delivery from the stone of chemistry and physics". If they were publicly traded, this would be fun to watch. . .

(2) The rise of Micropharma? We'll come back to this subject:

The drug discovery pipelines of the major pharmaceutical companies have become shockingly depleted, foreshadowing a potential crisis in the ability of Big Pharma to meet the pharmaceutical demands created by the ever-changing spectrum of human disease. However, from this major crisis is emerging a major opportunity, namely micropharma – academia-originated biotech start-up companies that are efficient, innovative, product-focused, and small. In this Feature, we discuss a “new ecosystem” for drug development, with high-risk innovation in micropharma leading to Big Pharma clinical trials. . .

(3) Cleaving amyloid precursor protein into beta-amyloid has long been thought (by many) to be the key pathological event in Alzheimer's. But what about the piece of APP that's left inside the cell?

(4) A favorite post around here for some time has been "Sand Won't Save You This Time", about the wonderfulness of chlorine trifluoride. Well, here's a method to produce very interesting-looking compounds that uses. . .bromine trifluoride. How much do you want these products, that's what you have to ask yourself. To be sure, the authors do mention that "Although commercial, bromine trifluoride is not a common reagent in every organic laboratory, and many chemists do not feel at ease with it because of its high reactivity. . .". You have to go to the Supporting Information file before you start hearing about freshly preparing the stuff from elemental fluorine.

Comments (35) + TrackBacks (0) | Category: Academia (vs. Industry) | Alzheimer's Disease | Business and Markets

July 20, 2009

Amyloid in Trouble

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Posted by Derek

Here's an interesting look at the current state of the Alzheimer's field from Bloomberg. The current big hope is Wyeth (and Elan)'s bapineuzumab, which I last wrote about here. That was after the companies reported what had to be considered less-than-hoped-for efficacy in the clinic. The current trial is the one sorted out by APOE4 status of the patients. After the earlier trial data, it seems unlikely that there's going to be a robust effect across the board - the people with the APOE4 mutation are probably the best hope for seeing real efficacy.

And if bapineuzumab doesn't turn out to work even for them? Well:

“Everyone is waiting with bated breath on bapineuzumab,” said Michael Gold, London-based Glaxo’s vice president of neurosciences, in an interview. “If that one fails, then everyone will say we have to rethink the amyloid hypothesis.”

Now that will be a painful process, but it's one that may well already have begun. beta-Amyloid has been the front-runner for. . .well, for decades now, to be honest. And it's been a target for drug companies since around the late 1980s/early 1990s, as it became clear that it was produced by proteolytic cleavage from a larger precursor protein. A vast amount of time, effort, and money have gone into trying to find something that will interrupt that process, and it's going to be rather hard to take if we find out that we've been chasing a symptom of Alzheimer's rather than a cause.

But there's really no other way to find such things out. Human beings are the only animals that really seem to get Alzheimer's, and that's made it a ferocious therapeutic area to work in. The amyloid hypothesis will die hard if die it does.

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Industry History | The Central Nervous System

February 26, 2009

Does Glucophage Make Alzheimer's Worse?

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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 (23) + TrackBacks (0) | Category: Alzheimer's Disease | Diabetes and Obesity | Drug Industry History | Toxicology

January 8, 2009

Short Items: India, Sanjay Gupta, Satori Pharmaceuticals

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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

Where Are the Drugs?

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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

Rember for Alzheimer's: Methylene Blue's Comeback

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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 (115) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Patents and IP | Regulatory Affairs

July 30, 2008

Bapineuzumab: Good For Anything or Not?

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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 (3) + TrackBacks (0) | Category: Alzheimer's Disease

July 23, 2008

Patents Stopping an Alzheimer's Wonder Drug?

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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

Another Alzheimer's Compound Goes Down

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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

Protecting Amyloid's Parent?

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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

Elan Tries Again

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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

In Which I Hate A Wonder Drug

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Posted by Derek

Schering-Plough has had its share of troubles over the years, but the company has also seen itself saved by some pretty unlikely compounds. Vytorin (ezetimibe) is the example I’ve spoken about here, and if the drug doesn’t seem like a savior at the moment, well, you have to keep in mind that it was the biggest thing for them since Claritin went off-patent ten years ago.

Now there’s another one potentially coming up. Expectations are building for a thrombin receptor antagonist compound, SCH 530348. And I have a history with this one, too: while the labs down one hallway from me were discovering ezetimibe, down the other hallway they were laying the foundation for this one. There’s a big difference, though, in the way I saw the two.

This thrombin antagonist is an unlikely drug for several reasons. For one thing, its structure is not the sort of thing most medicinal chemists would go out of their way to make. But there’s a good reason for that: to a first approximation, it wasn’t made with medicinal chemistry in mind. 530348 is based on a natural product called himbacine, whose fame, such as it is, rests on its properties as a semi-selective muscarinic antagonist. And that’s how Schering-Plough got interested in this class of compounds; thrombin had nothing to do with it.

At the time (early to mid 1990s) the company had a team working on Alzheimer’s disease, and I’ll go ahead and mention again that I was one of the people involved. (Five minutes on SciFinder would tell you that, anyway). We were quite interested in selective muscarinic antagonists, particularly for the m2 subtype, and himbacine was at the time one of the more selective compounds with that profile. So one of the group leaders at the company, Sam Chackalamannil, decided to synthesize it and do some SAR around the structure.

That was no small undertaking. Himbacine’s not one of the most complex natural products by any means, but it’s no stroll to the beach, either, especially when compared to the usual sorts of drug structures. It took a lot of time, a lot of ingenuity, and (most importantly) a lot of effort to do it. And I. . .well, I thought this was a terrible idea.

I really did. By the time himbacine itself got made, the project team had muscarinic compounds that were more selective and more potent (and a lot easier to make, to boot). I would listen to Chackalamannil’s people presenting their long, difficult routes during meetings, and I’d sit there imagining the company going slowly bankrupt if everyone adopted this approach, the revenue slowly sinking as the number of JACS communications rose. I couldn’t see the point, and although I don’t think I ever quite had the nerve to say so to Chackalamannil himself (hi, Sam!), I said it to plenty of other people.

So, is it time for me to eat crow? Well, one plateful, at least. Some of the himbacine analogs hit in the high-throughput screen for thrombin activity, to everyone’s surprise, and some further compounds (now shed of their muscarinic activity) were even better. The drug discovery effort culminated in 530548, which now might be about to benefit a huge number of people and make the company a ton of money, if everything goes well.

Of course, if these things hadn’t hit in the thrombin assay, I could have remained secure in my opinion. After all, they were never worth very much as muscarinics, as far as I know. (Of course, our muscarinic compounds, in the end, never were worth very much as Alzheimer’s drugs, which is something to keep in mind). So that’s the question: how likely is it for molecules like this to work? It’s very hard to answer that, but given this data point, I guess the answer is “at least a little more likely than I thought”. The very fact that they didn’t look like most other things in the screening deck was probably in their favor. I still think that these compounds were a long shot, but this is a business that lives on long shots. This one came through, and congratulations to everyone involved.

Comments (8) + TrackBacks (0) | Category: Alzheimer's Disease | Cardiovascular Disease | Drug Development

May 6, 2008

Alzheimer's: A Report From the Front

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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. . .

Comments (13) + TrackBacks (0) | Category: Alzheimer's Disease

February 28, 2008

ApoE4: Test or Not?

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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.

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease

February 11, 2008

Fast Plaques in a Slow Disease

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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. . .

Comments (6) + TrackBacks (0) | Category: Alzheimer's Disease | The Central Nervous System

October 15, 2007

Checking The Numbers on the Alzheimer's Test

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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. . .)

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease | Biological News

May 17, 2007

Beta-Secretase: Not So Fast?

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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. . .

Comments (7) + TrackBacks (0) | Category: Alzheimer's Disease

April 2, 2007

Failure: Not Your Friend, But Definitely Your Companion

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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?

Comments (15) + TrackBacks (0) | Category: Alzheimer's Disease | Cancer | Drug Development | The Central Nervous System | Who Discovers and Why

April 14, 2005

How Good Is Aricept, Anyway?

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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. . .

Comments (8) + TrackBacks (0) | Category: Alzheimer's Disease

January 23, 2005

A Trial Too Far

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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!

Comments (7) + TrackBacks (0) | Category: Alzheimer's Disease | Toxicology

November 9, 2004

Gumming Up the Amyloid Works

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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.

Comments (3) + TrackBacks (0) | Category: Academia (vs. Industry) | Alzheimer's Disease

August 3, 2004

Silent Mutations and Noisy Ones

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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

Back on the Air

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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

Alzheimer's Vaccine Refuses to Die

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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

Sleeping Dragons

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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="">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

Maybe They Can Formulate It in Madelaines

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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

Who Dares, Wins?

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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

Modeling the Brain?

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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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