New Approaches Yield Promise for Future of Alzheimer’s Disease Drug Trials

Guest: Sanjay Asthana, MD, associate dean of gerontology, University of Wisconsin School of Medicine and Public Health, and director and founder, Wisconsin Alzheimer's Disease Research Center
 
For decades, researchers from around the world have been working to find a cure for Alzheimer’s disease. Dr. Sanjay Asthana explains the challenges Alzheimer’s disease drug trials have faced and introduces us to new, promising approaches to stopping or delaying the disease. 9/11/2018
 

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Sanjay Asthana head shot
Dr Sanjay Asthana

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Show Notes

Dr. Sanjay Asthana is director of the Wisconsin Alzheimer's Disease Research Center. You can listen to him on episode 3 of Dementia Matters, Gender Differences in Alzheimer's Disease.

Transcript

Intro: Welcome to Dementia Matters, a podcast presented by the Wisconsin Alzheimer's Disease Research Center. Our podcast is here to educate you on the latest research, caregiver strategies, and available resources for fighting back against this disease. I'm your host, Nathaniel Chin. Thanks for joining us.

Dr. Nathaniel Chin: Our guest today is Dr Sanjay Asthana, Dean of Gerontology at the University of Wisconsin School of Medicine and Public Health, and the director of the Wisconsin Alzheimer's Disease Research Center. Dr Asthana is a world renowned Alzheimer's disease researcher who has led dozens of Alzheimer's disease clinical trials here in Wisconsin. Dr Asthana also sees patients with memory disorders at the UW Health Memory Clinic. Dr. Asthana, welcome back to Dementia Matters.

Dr. Sanjay Asthana: Absolutely. Thank you. Glad to be here.

Chin: I'm going to start with a definition for our audience, because we're going to talk about clinical trials. So a clinical trial is any research study that involves human beings and looks at how one or more health-related interventions influence health outcomes over a period of time. Does that seem like a fair definition?

Asthana: Yes, that's exactly what it is.

Chin: So then knowing that, why have clinical trials with Alzheimer's disease failed thus far?

Asthana: Yes, you know, as you know, a number of clinical trials have been conducted over years involving patients with Alzheimer's disease. And unfortunately most of those trials have failed, and we think that they might be a number of reasons why majority of these trials have failed. But among the most common reasons why these medications and trials didn't work, it is we don't quite understand all the mechanisms through which Alzheimer's disease is caused. Unless we can understand different ways through which the disease develops in the brain, we won't have treatments for all those mechanisms. Currently, we know that there are two abnormal proteins that get deposited in the brain, one is an amyloid protein, the other one is tau protein. Thus far, the majority of clinical trials have focused on clearing the brain from amyloid protein. So, unfortunately, because we don't quite understand the disease, we don't have the best medications to treat the disease, so that's number one reason why many of the trials have failed. The other reason is that the diagnosis of Alzheimer's disease also can be tricky in some patients. So, it's possible that some of the trials, the investigator thought they had patients with Alzheimer's disease, perhaps they had other forms of dementia, and they may not have had the disease, so the medication didn't work in those patients. And the third major reason is that the medications were probably given at a more advanced stage of the disease, when the disease is severe enough that nothing can change it. So these are some of the common reasons we think that the trials have failed.

Chin: And it's not for a lack of trying because we've had over 400 trials to date and we've spent billions of dollars on it.

Asthana: Absolutely.

Chin: Now you mentioned not knowing all of the targets and that this is a very complicated disease. So what targets have trials looked at and what mechanisms have we investigated?

Asthana: Majority of these trials have tried to clear the brain from the amyloid protein, which gets deposited in Alzheimer's disease. Fewer trials, that also unfortunately did not work, focused on the other abnormal protein called tau protein. And these two proteins are the major targets for treatment so far. But we know that there are many other changes that take place in the brain apart from these proteins, namely either a lot of swelling or inflammation in the brain. There's also quite a bit of damage to what we call synapsis in the brain. That's where information is transferred from one part of the brain to the other. And there's also quite a bit of so called oxidative damage. So, those mechanisms really have not been investigated intensively, although some trials have used anti-inflammatory drugs and those trials have also failed. So, other mechanisms have been looked at, but basically the major mechanisms are the two abnormal proteins named the amyloid and tau protein.

Chin: Well what have we learned though from these trials? Even though they haven't been successful, I'm sure we've gained valuable information from them.

Asthana: Yes, we have. So one of the important messages from these trials is that we need to try medication treatment at a much earlier stage of the disease. Perhaps even when people have no symptoms, but we know from special brain scans and from analysis of the cerebral spinal fluid that they may have the disease pathology going on, but they have no symptoms, so maybe that's the best stage to try the trials and none of the trials have done that yet. Also, I think, we need to really diagnose the disease better so that the right medication can be given to the right patients. And finally I think there's increasing feeling that a single medication may not work for Alzheimer's disease, and we may need a combination of medications. So combination treatments have not yet been tried at a larger level. I think that's another message that we are getting from these trials.

Chin: So why is it so important that we get earlier and earlier? In particular, right now we're recruiting a lot from mild cognitive impairment.

Asthana: Right. Yeah. You know, I think the population, once again that we have been targeting so far, have too much damage to their brain. There are not many functional brain cells left so that we could get some improvement in symptoms. At early stages of the disease, majority of the brain cells and neurons are still working, there are fewer that have died, and at that stage, if we can have treatments that can prevent further death of brain cells or even could help in the generation of new brain cells or perhaps prolong the lifespan, then I think they at the stage where we'll see the most, the most benefit.

Chin: So we want to get to them before there's a tipping point where we can't return.

Asthana: Exactly.

Chin: Well, so then knowing this, knowing how important it is to get to people who don't have symptoms, what role do biomarkers play in identifying the right population?

Asthana: Yeah, so as you know, Dr. Chin, that biomarkers are perhaps the most important area of research in Alzheimer's disease. So by biomarker we mean we may have certain proteins that we can measure either in the blood or in the cerebral spinal fluid. Or we can do special brain scans which can pick up the abnormal amyloid and tau proteins. So there's really substantial evidence to suggest that at least 15 to 20 years before someone develops the disease, there are changes in these biomarkers. So these biomarker changes appear years, if not decades before the symptoms develop.

Chin: So do you see biomarkers being one of the pivotal filtering tools that researchers have to get people in the right studies for clinical trials?

Asthana: Yes, we do. Yes, in fact, the newer clinical trials, we're trying to take only those people in the trials who have biomarker evidence of the disease. And also these biomarkers can serve as a measure of response to treatment. So let's say that at the start of the trial, someone has abnormal biomarker levels and as they participate in the trial and the treatment is given over months or years, but these biomarkers may show improvement which suggests that the brain cells are improving and there's fewer deaths. So biomarkers are not only evidence of disease but also a response to treatment.

Chin: So a recent study was mentioned at a big conference this summer, involving a compound called BAN2401, and I suspect that's because it's in such early stages, they don't have a name for it yet. This compound was looking to remove amyloid from the brain and it created a lot of excitement when they discussed it at the conference. Can you explain the compound and the clinical study?

Asthana: Yes, so this is one of the compounds which as you know at a recent international meeting, they presented some preliminary results of the trial and this compound, as you mentioned, it really works through the amyloid protein. It tries to clear the brain from this amyloid protein. The results that they shared were at a very early stage of the trial. There were only 300 people who were given this medication and they showed that the brain was clear of this protein and also there were some indications that their memory test might've improved a little bit. These results are very early and preliminary and they are conducting much larger trials. So hopefully in the larger trial the results will be positive and this may be very encouraging for everyone. But still we have to wait to get more results and it may take a few years before those results will be available.

Chin: Does this study, or studies like it, will they start looking at disease modifying treatment in addition to cure? So even if the study doesn't cure Alzheimer's disease, if people are responding clinically, that's a meaningful outcome.

Asthana: Very much so, yes. So of course the ultimate aim is to cure the disease, um until we have treatments which can do that, we're hoping that medications like what you mentioned early on, can slow the disease progression so that people may stay free of symptoms much longer and even if they have the disease, the progression is much slower. These disease modifying treatments are the key advancement in the field.

Chin: Are there any other promising studies or even general approaches that you see on the horizon?

Asthana: Yes, very much so. So as you know, there are many other non-pharmacological interventions that we think might be promising in either delaying the disease or perhaps even stopping its progression. And among those include exercise, which of course is a increasingly being shown to be very effective in terms of reducing risk for Alzheimer's disease and also slowing its progression. Healthy lifestyles, especially people who have diseases like heart disease, high blood pressure, diabetes, high cholesterol, if you manage those diseases effectively, we know that it reduces the risk for Alzheimer's disease progression. And also dietary changes. They are certain diets, although at large studies have to confirm the efficacy, but diet, healthy lifestyle and add exercise are also being tried in clinical trials to see if they can be effective.

Chin: And some of those are being conducted here.

Asthana: Absolutely they are. And we are quite well known in those years of research and plan to expand those studies as well.

Chin: Well, with that, I'd like to thank you again for being on Dementia Matters and I'm sure we're going to have you back in the future.

Asthana: Thank you. It's a pleasure to be with you.

Outro: Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center. The Wisconsin Alzheimer's Disease Research Center combines academic, clinical, and research expertise from the University of Wisconsin School of Medicine and Public Health, and the Geriatric, Research, Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. It receives funding from private, university, state, and national sources including an NIH/NIA grant for Alzheimer's Disease Centers. This episode was produced by Rebecca Wasieleski and edited by Alex Wehrli. Our music is "Cases to Rest" by Blue Dot Sessions. If you're interested in learning more about the Wisconsin ADRC, check out our website at adrc.wisc.edu. If you have any questions or comments, don't hesitate to let us know. Thanks for listening.