May 01, 2009
Interview With Alzheimer's Expert (Cont'd from posting)
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Andrew Mickey: Can you give us some examples of other well known and proven biomarkers?
Dr. William Thies: A biomarker is something that allows you to identify the disease and track it. They also allow you to track the effectiveness of your therapy.
Well-known biomarkers from other diseases would include things like serum lipid concentration, glucose concentrations, blood pressure is a biomarker - that should give you an idea for what a biomarker really is.
And finally, the last kind of biomarker that people are looking for in Alzheimer’s does include genetic biomarkers which would allow you to ascertain risk of developing the disease in the population.
So as we develop some of these newer therapies, we would only treat the people who are at high risk of developing the disease – and we could identify these people by using biomarkers. This way people who have very limited risk aren’t exposed to the risk of the medication.
Andrew Mickey: So if you can identify those people at high risk are there preventive treatments available?
Dr. William Thies: Preventive treatments for Alzheimer’s are in the works. We can anticipate that as those treatments come online, there will be a tremendous drive to use those treatments earlier and earlier on in the course of the disease. That’s got to come from two major sources – patients and physicians.
Patients will demand it because nobody wants even the mildest symptoms of Alzheimer’s. If they have it in their family or are identified as high risk, they are going to demand to use some of these medications.
Physicians want to because it is a sort of definitive intervention. Physicians are perfectly happy measuring blood pressure and treating that blood pressure because they know in the long run that prevents heart attacks and strokes. If they had the same type of treatment for Alzheimer’s, they’d use it too.
I think that kind of model is something that we really have to anticipate happening for Alzheimer’s. If you play this out, given some of the numbers that we have, we could end up with about half of the population over 55 on some sort of medication to prevent Alzheimer’s. That gives you an immense market and is the main reason for companies wanting to invest in them and the market.
Andrew Mickey: That is a very big prize for a successful treatment. From the investment side of things, that gets me extremely interested.
Dr. William Thies: I think that’s why the companies are investing as much money as they are. They recognize Alzheimer’s as one of the great opportunities. In the current setting, with many of their traditional big sellers going off patent in the next four or five years, they need to replace that income with other big successes. Many of them like Alzheimer’s as part of the replacement.
Andrew Mickey: So there are some Alzheimer’s treatments that are going off patent?
Dr. William Thies: Well it’s not so much that Alzheimer’s treatments are going to go off patent, although they are going to do that in the next couple of years. It’s the things like Lipitor – the big blood pressure reducing medication – and other top selling drugs that are very widely prescribed which will create a big need for other big sellers.
Andrew Mickey: We’ve covered that quite a bit. They need the big blockbusters and it looks like Alzheimer’s offers the opportunity for a true blockbuster.
Dr. William Thies: Exactly, and when the things we just talked about go off patent they will leave a giant hole in the portfolio. There is an estimate that floats around that over the next five years more than $50 billion in income will go away from the loss of the big blockbuster drugs.
Andrew Mickey: I don’t want to get off subject, but I have been discussing this idea with a number of people, and that is maybe genomics may take a more dominant role in prevention and treatment, and that the era of blockbusters might be coming to an end?
Dr. William Thies: Well, I think if you limit the discussion to personalized medicine, certainly I think that has some potential. And I think it will happen. What we don’t know is how quickly that will happen, and at least at this point, we are still in the era of population based medicine.
As we remain with that model it will have big selling drugs. It will be a while before we get to the point where there are 50 differential diagnoses within Alzheimer’s which represent different populations.
I think that’s possible. We certainly could end up with a complicated regimen for Alzheimer’s like we have for blood pressure where lots of the population is controlled on a fairly simple intervention. And then we have to add more and more sophisticated drugs as people get more and more complicated in the etiology of the hypertension.
Andrew Mickey: I agree with you there. But if we jump back to Alzheimer’s, taking a look at the Alzheimer’s drug market, what’s coming down the line? What’s generating the most excitement? Where is the greatest potential? And who has it?
Dr. William Thies: The most mature theory of Alzheimer’s is the so-called amyloid hypothesis. And we should emphasize that this still is a hypothesis. Until we can show that if we change the amyloid concentration in the brain and it changes the course of the disease, it’s still a hypothesis. We see more drugs in phase III testing for limiting amyloid accumulation.
There are two big efforts, one is from Elan which is in a complicated business arrangement with Wyeth. Also, Wyeth is being acquired by Pfizer maybe. So that suggests that when I say Elan, it’s an intertwined pathway there.
Elan is working on it. They were the guys that brought us the so-called Alzheimer’s vaccine from a few years ago. They identified that you might be able to use elements of the immune system in order to improve people with Alzheimer’s, or to at least slow the rate of progression of the disease. They would do that through increasing the clearance of amyloid from the brain.
They are now back with the second version. They have moved from an active vaccine, which is something that actually stimulates the existing immune system, to something called a passive vaccine, which actually sort of mimics parts of the immune system. And that is in phase III trials and will tell us a lot about the amyloid hypothesis.
Andrew Mickey: Is the amyloid similar to the plaques you mentioned before?
Dr. William Thies: Amyloid is in the plaques, and tau is in the tangles. You have probably heard both of those words. There is some really good evidence that the amyloid hypothesis is right. There are certainly centers who think it isn’t.
One other thing we do know is that there are three genes that are deterministic for Alzheimer’s. If you had the wrong form of the gene, you will get the disease. Fortunately, those are very narrowly distributed to about 200 families across the globe. But from a research standpoint they have been important. The common characteristic of all those genes is they result in an over accumulation of amyloid and this has driven a great deal of the enthusiasm for the amyloid hypothesis.
In addition to the Elan effort, there is also a large Eli Lilly effort which is working on, again, an amyloid aggregation inhibitor. This segregates one of the enzymes which make amyloid.
So when we look back at what we’ve learned in the last 25 or 30 years, understanding the basic chemistry of amyloid has been a fundamental need. As we have learned about some of the enzymes that are involved in the formation of amyloid, we now have the potential to have a very drug like intervention where we go on and inhibit that enzyme and try to generate beneficial effects.
A secretase inhibitor looks much more like a normal drug. It’s a small molecule and can be manufactured in a chemistry lab. It is different than the Elan drug in that it is a so called biological preparation. It is an antibody that would make a direct impact on amyloid.
There are also other compounds being studied that are outsiders to
the amyloid hypothesis. One is derived from an antihistamine. These have been known
about for some time as an existing medication, but they haven’t been very
successful as an antihistamine.
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Andrew Mickey: That brings me to one question about the regulatory environment. For example, with the obesity drugs you can measure weight loss directly. How do they track, or how would you prove to the FDA, how effective a particular Alzheimer’s drug is? Also, prior to approval, do you need to prove that you know how it works, too?
Dr. William Thies: The way that they measure the impact of Alzheimer’s drugs is on cognitive measures. There are multiple scales for measuring the course of the disease. We can measure people’s memory, we can measure other kinds of functional abilities (e.g. can they balance or can they find their way around the neighborhood and get back home again, can they dress themselves, feed themselves) to test effectiveness of a therapy.
The current drugs have been approved on the basis of something called the ADAS-Cog, which is a broad cognitive examination of a person’s memory, some executive functions such as planning and abstract thinking, and other kinds of cognitive abilities. This will probably be the case for the next few drugs as well.
Another is called the Clinical Global Impressions Scale. This measures whether the physician thinks that the individual is getting better. So with those two, the current drugs have been able to show some benefit.
Now, a question that I think still remains is how meaningful is that benefit?
Obviously, as we observe that someone is talking, we can see an improvement in cognitive function, so there’s a benefit. But what is really at stake here is whether the drugs will give people practical benefits like extending their quality of life and delaying the need of certain types of care such as nursing homes.
This is still an open debate. The fact is that the current medications are relatively modest in their effectiveness and they effect different people differently. Some people have a robust effect, and for some people the effect is minimal.
The new drugs will almost certainly be evaluated on the same or similar scales. But if you look at the disease modifying medications and prevention strategies, they in fact may not make people “better.” They may just keep well people well, or they may keep people at the same level that they are at when they start taking the drug. I mean, that’s been one of the keys to the identification of the current medication is they do make people better for a short period of time. The separation between the treated and untreated group becomes obvious very rapidly. And with the disease modifying drugs, if they don’t make people better, what you are going to see is a slower rate of progression. The challenge is that you’ve got a relatively slow rate of decline early on in the disease, slow rate of loss of function, and now you try to slow that even further. To get those two lines to separate is going to be hard. That is part of why Alzheimer’s clinical trials are now 18 or 24 months long – so that the untreated group has enough time to show a decline and the treatment can demonstrate that it is effective.
Those lines are inherently fuzzy because of the difference between individuals in doing these kinds of examinations. Even for healthy people, we have a lot of variation in our cognitive focus.
Here’s an example – I come to the office some days, and I get to the end of the day and I’m wondering why I came here. Other days, everything works in good order and I’m really focused throughout the entire day.
That same thing happens with Alzheimer’s – even in a controlled trial setting. You get a person on a bad day for their first examination and on a good day for the six month examination -- they may actually look better on the test when there is no real effect from the treatment. That’s one of the reasons that clinical trials have to involve a lot of participants – to balance that out.
So it takes a lot to separate those kind of differences. The current trials will run for nearly two years. These trials now become fabulously expensive. They not only have to recruit a big bunch of people (the Elan and Lilly efforts are going to be in the thousands of people by the time they are done), they may have to keep them under observation for a couple of years. Keeping a population of people under observation who are inherently older because of the nature of the disease, gets harder and harder. This may tend to increase dropouts and that sort of thing.
All of that suggests that doing these trials is not going to be an easy task. It’s one of the reasons why people are so excited about a potential biomarker for the disease. If you knew and could track the biomarker, you could shorten the trial. You’d get statistically significant differences fairly soon.
You would also trigger the debate of whether affecting the
biomarker was a worthwhile achievement.
Andrew Mickey: Do you see stem cells as playing a potentially dominant role in Alzheimer’s treatment in the near term or the future?
Dr. William Thies: Stem cell work may be important in the very long term. It’s hard to say. In the short term, though, the likelihood that the stem cells are going to revolutionize Alzheimer’s treatment in the next three to five years is almost zero.
Andrew Mickey: Is there anything that you would like to mention with regards to current treatments?
Dr. William Thies: It is about a $1 billion market. Five drugs have been approved by the FDA for Alzheimer’s; four are used with some regularity. Three of them use the same mechanism of action. One is different. There’s a lot more room for development.
Andrew Mickey: What do you think about as far as a time frame in terms of the next generation of Alzheimer’s treatment?
Dr. William Thies: That’s always a tough question.
Some of the drugs we talked about could potentially be here relatively soon. There’s a real possibility they’ll be here in a three to five year time frame.
But one of the basic rules for drug development – one that we should never forget – is that you are not done until you are done. When you start into a phase III clinical trial, the only way to do that ethically is if you don’t know the answer that’s going to come out of that trial.
If you know the drug is going to be effective, it’s unethical if you withhold it. If you know the drug is going to be ineffective, it’s unethical to give it to anybody.
One other thing which is not well understood, is the sense that when drugs get into final stages of testing, we cannot know how it’s going to come out. The answer is we really don’t and so when you ask me how much time, I can project a time if everything works the way you wanted it to, but in fact there is no guarantee that will happen.
Andrew Mickey: That’s a very good point. It’s tough to project technological development and especially given the time frame involved…
Dr. William Thies: It certainly is. I think in terms of your audience, if you are looking at this from an investment perspective, I think the major question for people who invest is, what is the timeline that I can expect a specific return on investment.
I mean, I have no doubt that if you invest in Alzheimer’s disease probably in the next 15 years you are going to have a very positive return. But the fact is, most people are not looking at that kind of timeline.
Andrew Mickey: I agree. The timeline is just one of the first parts of our investment equation. We consider a lot of other factors like size of opportunity, risk, opportunity cost – which is closely related to time – and many others.
From my perspective, given the numbers you talked about earlier, there is an opportunity here. And we’ll continue to keep an eye on everything, but there are always so many factors we focus on, but I agree with you completely there.
On a different note, can you tell me a little bit about the role of the Alzheimer’s Association?
Dr. William Thies: The Alzheimer’s Association is only 25 years old. That’s a proper timeframe for modern Alzheimer’s research. We have been involved since the very beginning advocating for investment in research when there was virtually none. Also, growing along with the growing field and from the research that we ourselves fund.
We are the biggest organization of this type and we are one of the few organizations in the non-profit space that really does embrace a dual mission, that is, we are dedicated to both research and care. I think we are one of the few that have been able to effectively balance that to a great extent, and still we are the number one non-profit funder for Alzheimer’s research.
We also advocate for more federal funding for research. Because, while I hate to admit that the federal government actually does have more money than I do, they, if fact, do. And between them, us, and the private sector, we mostly try to support the basic science of Alzheimer’s disease. That includes identifying potential targets that drug companies can then move into a drug development scheme in order to develop new therapies.
We also interact with agencies like the FDA to try to bring appropriate groups of experts to the researchers, as they are looking at these problems. The guys who worked at the FDA and with Alzheimer’s disease are terrific, but they are in need of outside advice for much of what they do. That’s not just for Alzheimer’s disease, but for everything else too. That’s the model that they used.
I help them bring together the right group of people by identifying experts, identifying view points, making sure that those are correct and certainly important to us. We invest in those kinds of things that have been long term resources for the community - the Alzheimer’s communities.
Finally, there is something going on right now called the Alzheimer’s Disease Neuroimaging Initiative. This is a very large, multicenter study, led by the NIA, that is funded both by public and private dollars in order to look at imaging biomarkers and chemical biomarkers for Alzheimer’s disease. The Association is heavily involved in being the advocate for the origination, continuation and organization to the extent that there has been a good methodology for the rest of the world. The Association has really been the home for promoting in other parts of the world.
One more thing, we run the biggest scientific conference on Alzheimer’s disease in the world called the International Conference on Alzheimer’s Disease. (http://www.alz.org/icad/)
Andrew Mickey: Held in July 2009 in Vienna?
Dr. William Thies: Yes. If you are interested in tracking Alzheimer’s research news, the conference is always a great resource.
We interact with companies at something called the Research Roundtable. It is membership organization for companies, where they come together to talk about things that affect all of them. They can’t really call themselves together on their own because of anti-trust rules against it. But we can call them all together and do it under an umbrella that is positive.
In addition to that, we are the major supplier of support services for people with Alzheimer’s disease. So right now you are talking to me out of the national office in Chicago, but we have 77 local chapters and over 300 points of service where we support, assist and inform people with the disease and their families. We do this by giving them information, access to services in the community and try to help them understand that this is the disease process which ends up being very important with the ability of families to deal with the consequences.
Andrew Mickey: Well, I would like to thank for your time. It’s a good bit and I think you did help me understand quite a bit more I can tell you that and I think a lot of people will get a lot of value from this.
Dr. William Thies: Great to speak with you.
Alzheimer’s Association - www.alz.org - 800-272-3900
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