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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: derekb.lowe@gmail.com Twitter: Dereklowe

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July 17, 2014

TDP-43 and Alzheimer's

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Posted by Derek

There are quite a few headlines today about a link between Alzheimer's and a protein called TDP-43. This is interesting stuff, but like everything else in the neurodegeneration field, it's going to be tough to unravel what's going on. This latest work, just presented at a conference in Copenhagen, found (in a large post mortem brain study of people with diagnosed Alzheimer's pathology) that aberrant forms of the protein seem to be strongly correlated with shrinkage of the hippocampus and accompanying memory loss.

80% of the cohort with normal TDP-43 (but still showing Alzheimer's histology) had cognitive impairment at death, but 98% of the ones with TDP-43 mutations had such signs. That says several things: (A) it's possible to have classic Alzheimer's without mutated TDP-43, (B) it's possible to have classic Alzheimer's tissue pathology (up to a point, no doubt) without apparent cognitive impairment, and (C) it's apparently possible (although very unlikely) to have mutated TDP-43, show Alzheimer's pathology as well, and still not be diagnosed as cognitively impaired. Welcome to neurodegeneration. Correlations and trends are mostly what you get in that field, and you have to make of them what you can.

TDP-43, though, has already been implicated, for some years now, in ALS and several other syndromes, so it really does make sense that it would be involved. It may be that it's disproportionately a feature of more severe Alzheimer's cases, piling on to some other pathology. Its mechanism of action is not clear yet - as mentioned, it's a transcription factor, so it could be involved in stuff from anywhere and everywhere. It does show aggregation in the disease state, but that Cell paper linked to above makes the case that it's not the aggregates per se that are the problem, but the loss of function behind them (for example, there are increased amounts of the mutant protein out in the cytoplasm, rather than in the nucleus). What those lost functions are, though, remains to be discovered.

Comments (2) + TrackBacks (0) | Category: Alzheimer's Disease | Biological News

July 14, 2014

Targacept Fumbles the Bad News on Alzheimer's

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Posted by Derek

Targacept has been working on some very hard therapeutic areas over the years, and coming up dry - dramatically so. They may have just done it again.

They've been testing TC-1734 in Alzheimer's over the last year or so, a partial agonist at nicotinergic receptors. That was a long-shot mechanism to start with, although to be sure, every Alzheimer's drug is a long-shot mechanism. This would be a stopgap compound even if it worked, like the existing acetylcholinesterase compound Donepezil.

And the company has apparently released the results of the clinical trial on its web site, inadvertently, you'd have to assume. The news first came out from BioRunUp on Twitter, and the text of the announcement was the the compound had failed to show superiority to Donepezil. The company has made no official announcement (as I write, anyway), and the press release itself appears to have been taken down a little while ago. But here's a screen shot, if you're interested. The stock (TRGT) has already reacted to the news, as you'd imagine it would, suddenly dropping like a brick starting at just before 2:30 PM EST. Not a good way to get the news out, that's for sure. . .

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

July 8, 2014

An Alzheimer's Blood Test? Not So Fast.

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Posted by Derek

There all all sorts of headlines today about how there's going to be a simple blood test for Alzheimer's soon. Don't believe them.

This all comes from a recent publication in the journal Alzheimer's and Dementia, from a team at King's College (London) and the company Proteome Sciences. It's a perfectly good paper, and it does what you'd think: they quantified a set of proteins in a cohort of potential Alzheimer's patients and checked to see if any of them were associated with progression of the disease. From 26 initial protein candidates (all of them previously implicated in Alzheimer's), they found that a panel of ten seemed to give a prediction that was about 87% accurate.

That figure was enough for a lot of major news outlets, who have run with headlines like "Blood test breakthrough" and "Blood test can predict Alzheimer's". Better ones said something more like "Closer to blood test" or "Progress towards blood test", but that's not so exciting and clickable, is it? This paper may well represent progress towards a blood test, but as its own authors, to their credit, are at pains to say, a lot more work needs to be done. 87%, for starters, is interesting, but not as good as it needs to be - that's still a lot of false negatives, and who knows how many false positives.

That all depends on what the rate of Alzheimer's is in the population you're screening. As Andy Extance pointed out on Twitter, these sorts of calculations are misunderstood by almost everyone, even by people who should know better. A 90 per cent accurate test on a general population whose Alzheimer's incidence rate is 1% would, in fact, be wrong 92% of the time. Here's a more detailed writeup I did in 2007, spurred by reports of a similar Alzheimer's diagnostic back then. And if you have a vague feeling that you heard about all these issue (and another blood test) just a few months ago, you're right.

Even after that statistical problem, things are not as simple as the headlines would have you believe. This new work is a multivariate model, because a number of factors were found to affect the levels of these proteins. The age and gender of the patient were two real covariants, as you'd expect, but the duration of plasma storage before testing also had an effect, as did, apparently, the center where the collection was done. That does not sound like a test that's ready to be rolled out to every doctor's office (which is again what the authors have been saying themselves). There were also different groups of proteins that could be used for a prediction model using the set of Mild Cognitive Impairment (MCI) patients, versus the ones that already appeared to show real Alzheimer's signs, which also tells you that this is not a simple turn-the-dial-on-the-disease setup. Interestingly, they also looked at whether adding brain imaging data (such as hippocampus volume) helped the prediction model. This, though, either had no real effect on the prediction accuracy, or even reduced it somewhat.

So the thing to do here is to run this on larger patient cohorts to get a more real-world idea of what the false negative and false positive rates are, which is the sort of obvious suggestion that is appearing in about the sixth or seventh paragraph of the popular press writeups. This is just what the authors are planning, naturally - they're not the ones who wrote the newspaper stories, after all. This same collaboration has been working on this problem for years now, I should add, and they've had ample opportunity to see their hopes not quite pan out. Here, for example, is a prediction of an Alzheimer's blood test entering the clinic in "12 to 18 months", from . . .well, 2009.

Update: here's a critique of the statistical approaches used in this paper - are there more problems with it than were first apparent?

Comments (30) + TrackBacks (0) | Category: Alzheimer's Disease | Analytical Chemistry | Biological News

June 26, 2014

Alzheimer's Bonds

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Posted by Derek

I wrote a couple of years ago about Andrew Lo of MIT, and his idea for securitization of drug discovery. For those of you who aren't financial engineers, that means raising funds by issuing securities (bonds and the like), and that's something that (as far as I know) has never been used to fund any specific drug development project.

Now Pharmalot has an update in an interview with Lo (who's recently published a paper on the idea in Science Translational Medicine). In particular, he's talking about issuing "Alzheimer's bonds", to pick a disease with no real therapies, a huge need for something, and gigantic cost barriers to finding something. Lo's concerned that the risks are too high for any one company to take on (and Eli Lilly might agree with him eventually), and wants to have some sort of public/private partnership floating the bonds.

We would create a fund that issues bonds. But if the private sector isn’t incentivized on its own, maybe the public sector can be incentivized to participate along with some members of the private sector. I will explain. But let’s look at the costs for a moment. The direct cost of treating the disease – never mind home care and lost wages – to Medicare and Medicaid for 2014 is estimated at $150 billion. We did a calculation and asked ourselves what kind of rate of return can we expect? We came up with $38.4 billion over 13 years. . .

. . .Originally, I thought it could come from the private sector. We’d create a fund – a mega fund of private investors, such as hedge funds, pension, various institutional investors. The question we asked ourselves is will they get a decent rate of return over a 13-year period? The answer, which is based on a best guess, given the risks of development and 64 projects, and we believed the answer was ‘no.’ It wouldn’t be like cancer or orphan diseases. It’s just not going to work. I come from that world. I talked to funds, philanthropists, medical experts. We did a reality check to see if we were off base. And it sounded like it would be difficult to create a fund to develop real drugs and still give investors a reasonable rate of return – 15% to 20%.

He's now going around to organizations like the Alzheimer's Association to see if there's some interest in giving this a try. I think that it's going to be a hard sell, but I'd actually like to see it happen. The difficulty is that there's no way to do this just a little bit to see if it works: you have to do it on a large scale to have any hope of success at all, and it's a big leap. In fact, the situation reminds one of. . .the situation with any given Alzheimer's drug idea. The clinical course of the disease, as we understand it now, does not give you any options other than a big, long, expensive path through the clinic (which is why it's the perfect example of an area where all the risk is concentrated on the expensive late stages). Lo is in the position of trying to address the go-big-or-go-home problem of Alzheimer's research with a remedy that requires investors to go big or go home.

The hope is that you could learn enough along the way to change the risk equation in media res. There's an old science fiction story by A. E. van Vogt, "Far Centaurus", which featured (among other things - van Vogt stories generally had several kitchen sinks included) a multidecade suspended-animation expedition to Alpha Centauri. The crew arrive there to find the planets already covered with human-populated cities, settled by the faster-than-light spaceships that were invented in the interim. We don't need FTL to fix Alzheimer's (fortunately), but there could be advances that would speed up the later parts of Lo's fund. But will this particular expedition ever launch?

Comments (24) + TrackBacks (0) | Category: Alzheimer's Disease | Business and Markets | Clinical Trials | Drug Development

June 9, 2014

Good News! Our Alzheimer's Drug Didn't Work!

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Posted by Derek

Alzheimer's disease is one of the notorious rocks of drug development. Around it are piles of debris, shipwrecks of clinical research programs large and small. But late last week, as yet another company sailed in close, something new happened.

Unfortunately, that may not mean "new" an in "good". A small company called AFFiRiS (that's really how they spell it) was testing a vaccine against beta-amyloid (an idea that has been tried numerous times before, although with the immune system you never know what'll happen next). Here's what happened next:

On June 4, AFFiRiS AG offered a smattering of results from its Phase 2 clinical trial of AD02, an active vaccine for Alzheimer’s disease derived from the company’s proprietary method of making synthetic antigens based on the Aβ peptide. At a press conference in Vienna, company scientists reported that among older people with early Alzheimer’s, a placebo group fared better than any other. Patients in this group reportedly had less cognitive decline over the course of 18 months, correlating with less hippocampal shrinkage. This group had been injected not with any Aβ-based antigen, but only with what the company calls an immunomodulator that was part of the AD02 formulation. Company scientists then named this placebo formulation AD04, and said they planned to explore options for clinical development.

Now, not every story about this actually picks up on this switcheroo. Try this one: you'd think that the company marched into the clinic with several vaccine ideas and got one of them to work. But that's not what happened.

I'm having a lot of trouble with this idea. Serendipitous discoveries there are, and this may be one of them. But I very much doubt it. The company provided no real data in their announcement - no error bars, no actual numbers. The "immunomodulator" was present in the actual vaccine formulation, but those patients (apparently) showed no effect. That Alzforum story linked above also notes that the company took two clinical rating scales, usually used separately and combined them into their own composite score. It is generally a safe bet that no one does that unless that was the only way that their results look promising.

So no, I have to disagree with the company that these results represent some sort of breakthrough. Breakthroughs in the clinic have clearly stated sample sizes, and error bars, and don't require any mixing and stirring of the numbers. Odds are excellent that this is noise. AFFiRiS (can't say I enjoy typing that) can move ahead with its mysterious immunomodulator if they like, and for the sake of Alzheimer's patients everywhere we can hope that it does something. But when a small company tries to say "Oh look, turns out our control group is actually a new Alzheimer's therapy! Isn't that great!", well, I think some skepticism is appropriate.

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

May 15, 2014

Citalopram for Alzheimer's?

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Posted by Derek

Here's a surprise - the well-known antidepressant citalopram appears to decrease formation of beta-amyloid (press release here). There have been some connections reported between serotonin signaling and amyloid production, but this makes it rather explicit. The paper not only reports rodent data, but shows human levels of beta-amyloid were decreased by nearly 40% in the CSF relative to controls.

This would make a person think that a preventative/early patient trial of the drug to see if it slows the progression of Alzheimer's has to be coming up very shortly. As an approved medication, the barriers are low, and the rewards are high. It could end up being one of the better whacks at the amyloid hypothesis in general. We need all the reads on that one that we can get, so these results good news from a scientific standpoint, no matter what the medical effects.

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

May 8, 2014

Alzheimer's Antibodies: Can the Current Ones Even Work?

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Posted by Derek

As everyone in the field knows, there's a lot of work that has been poured into anti-beta-amyloid antibodies as a potential therapy for Alzheimer's. There are plenty of questions, starting with the amyloid hypothesis itself, but even if you stipulate that, the question that this paper asks is key: do these antibodies engage their target?

And the answer, according to this large team from Melbourne, is, well. . .

. . .All of the antibodies were able to bind Aβ in mouse tissue. How- ever, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins.

Now that's interesting, isn't it? The paper uses SPR as one analytical technique, which showed that bapineuzumab and crenezumab bound to synthetic chip-immobilized Aβ at nanomolar levels, while solanezumab was probably picomolar. And mass spec showed that the antibodies recogized Aβ from transgenic mouse tissue. But human tissue, that was something else altogether. Bapineuzumab was able to pull out amyloid proteins in some experiments, but the other two were nearly inactive.

It appears that solanezumab and crenezumab are actually quite similar, and are both ineffective. The transgenic mouse studies may, according to this paper, have been a tremendous red herring:

Based on mouse studies, it has been suggested that solanezumab does not work directly on brain Aβ, but instead works as a peripheral sink targeting peripheral Aβ which in turn lowers CNS Aβ by mass action. Indeed when we examined plasma from tg2576 mice, solanezumab was able to detect Aβ1–40 in plasma. However, none of the therapeutic antibodies were able to detect Aβ in either the plasma or the cellular fraction from human AD subjects. . .

The authors suggest that the fact that these antibodies do recognize pure Aβ but still perform so poorly in vivo might be due to cross-reactivity. This is the sort of thing that would surely have been checked by the companies involved, but this paper does report substantial cross-reactivity in human plasma and against some other proteins. One in particular might be worth noting:

One of the proteins pulled down by both solanezumab and crenezumab was the Il12 receptor; this is interesting as a recent publication showed that modulation of the Il12 signaling pathway resulted in cognitive improvements in a transgenic mouse model of AD. It should be noted that a driving force for the selection of solanezumab as a drug candidate for the preventative trials was the post hoc analysis that showed a small, but significant improvement in cognition in the mild AD subjects in Phase 3 trials. . .

So has all this been a waste of time? And is Lilly's continued work on solanezumab, and Genentech's on crenezumab, likely doomed? Thoughts welcomed in the comments. What I'd like to know, even before we get to those big questions, is what these sorts of experiments showed internally, and why these (rather alarming) results haven't been seen by others so far. Or have they?

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

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 (42) + 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 t