An Important Test for the Amyloid Hypothesis

8:55 minutes

What causes the memory loss and cognitive decline associated with Alzheimer’s disease? For decades researchers have known that the peptide beta amyloid starts to build up in the brains of Alzheimer’s patients and clump together. These amyloid “plaques,” along with too much tau protein, are the hallmarks of Alzheimer’s disease. But it’s not clear which is responsible for the cognitive effects associated with the disease. The theory that beta amyloid is the true culprit is known as the “amyloid hypothesis.”

There are a number of drugs currently in development that in some way target beta amyloid, either by removing it from the brain or stopping it from forming in the first place. In a new study out this week in Science Translational Medicine, researchers for the drug maker Merck described how its experimental drug verubecestat successfully curbed beta amyloid formation in monkeys and mice. The drug acts as an inhibitor to beta-secretase 1, or BACE1 protein, which is essential for the formation of beta amyloid. If the drug is successful in improving cognitive function in a Phase III clinical trial that wraps up next year, it would put an end to the mystery of beta amyloid’s role in Alzheimer’s disease.

Merck’s Director of Neuroscience Matthew Kennedy shares why these early results have him feeling hopeful. He is joined by Alison Goate, the director of the Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai.

Segment Guests

Alison Goate

Alison Goate is the director of the Ronald M. Loeb Center for Alzheimer’s Disease at the Icahn School of Medicine at Mount Sinai in New York, New York.

Matthew Kennedy

Matthew Kennedy is Director of Neuroscience at Merck Research Laboratories in Boston, Massachusetts.

Segment Transcript

IRA FLATOW: This is Science Friday. I’m Ira Flatow. The amyloid hypothesis– sounds like the title of a great mystery novel, doesn’t it? Well, it’s not a book– yet. But it does have something to do with a mystery– the mystery of what causes Alzheimer’s disease.

Scientists know that a substance called beta amyloid and the protein tau both build up in the brains of people with Alzheimer’s. But they don’t really know which one is responsible for the cognitive decline and the memory loss that comes with the disease. The theory that beta amyloid is the true culprit is what’s known as the amyloid hypothesis. But now a new drug being developed by Merck is getting ready to test this theory. It’s already been shown to limit the formation of beta amyloid in mice and monkeys, and if it proves effective on people in a big phase 3 trial next year, it could help clear up this mystery.

With us to discuss this are my guests Matthew Kennedy, Director of Neuroscience at Merck, and Alison Goate, Director of the Loeb’s Center for Alzheimer’s Disease at Mount Sinai. She joins us by Skype. Both of you, welcome to Science Friday.

ALISON GOATE: Thank you, Ira.

IRA FLATOW: Nice to have you both. Matthew, so this drug has been shown to limit the formation of beta amyloid in mice and monkeys. What, tell me again, is the point of doing that?

MATTHEW KENNEDY: Yes, so this data in our new paper reflects an investment of almost 16 years’ worth of work to discover this drug Verubecestat. Really, it’s a comprehensive summary of the preclinical and the early clinical phase one safety and activity data that we used to make the decision to progress Verubecestat into two late stage pivotal phase three trials.

And those trials will actually be running in two different types of Alzheimer’s disease patients– in mild to moderate patients, these are patients with frank symptoms, and also in a type of Alzheimer’s that’s now called prodromal Alzheimer’s disease– these are people at very early stages of the disease. And our first trial in mild to moderate patients is actually planning to be read out in 2017.

IRA FLATOW: Mm-hmm. Alison, how will this, if it pans out to be true, how will this narrow down what causes Alzheimer’s?

ALISON GOATE: I think that this will provide evidence that the amyloid hypothesis is correct and that drugs that are targeted to prevent the build up of this beta amyloid peptide could be successful in treating disease. And as Matthew just pointed out, it’s going to be important to look– both in the early stage of the disease and in later stages of disease. Because earlier studies have demonstrated that these amyloid peptide accumulates in the brain over probably a 15 year period, and this is a period before we see any clinical symptoms. So it might be important to use these kinds of drugs in people even before they show symptoms if we can identify that they have that amyloid accumulation. So this is going to be very important to look at these two separate patient populations.

IRA FLATOW: Will you actually able to tell, be able to tell that there is no amyloid in the patients, if the drug work works out, Matthew?

MATTHEW KENNEDY: Yeah, we do actually have very good tests that allow us now to be able to see the amyloid in the brains of living patients. And these tests are called amyloid PET tracer tests. And these use an actual small molecule that’s radiolabeled that can be given to patients in very small quantities. And it enters into the brain and binds to the amyloid plaques. So we can actually measure how much is there in that way. And we can look at that over time. We’re actually using that tracer in our trials. In fact, our second trial that’s in the very early stages of Alzheimer’s disease, prodromal AD patients, that’s actually a criteria to get into the trial. These are individuals that if you knew them well, you actually wouldn’t be able to tell that they had a memory problem. But they do score very slightly with some cognitive impairment on very sensitive tests. But they also are scanned for the presence of amyloid in the brain. And so all of the patients that are being treated with Verubecestat in that trial do, in fact, have amyloid plaque deposition in their brain.

IRA FLATOW: Dr. Goate, what does beta amyloid do in the brains of normal people, in normal patients? So this is an important question, Ira, that we really don’t know the answer to, people have been studying. So this beta amyloid peptide is produced from a precursor that was identified now some 30 years ago. But we really don’t know either the normal function of the precursor protein or whether beta amyloid itself has any specific function. And this is being difficult to find out because there are a couple of other very similar proteins that are called APP-like proteins that have some functional overlap probably with APP. And so as a result, we don’t know for sure whether there is any function for that beta amyloid fragment that’s being produced.

IRA FLATOW: I find it interesting that we hear so much talk about the causes of Alzheimer’s, but the more I talk to researchers like Dr. Kennedy and, Dr. Cooke, to both of you, it seems like you really don’t know a whole lot about what’s going on in the brain. Would that be overstating something?

ALISON GOATE: Yeah, I think so. I mean I think we could say that we’ve actually learned a huge amount in the last 30 years since we found– discovered APP and mutations in APP that cause Alzheimer’s disease. But it’s certainly true that we still have a lot to learn. But I think that this study and others are really getting as closer towards testing this hypothesis and seeing whether these base inhibitors might actually be useful therapies.

IRA FLATOW: Dr. Kennedy, what are the questions that still remain for this drug that you’re testing?

MATTHEW KENNEDY: The major question that we’re asking right now is– will Verubecestat at the doses that we’re using that create very large reductions in the synthesis of this abeta peptide that should impair the ability of the plaques to continue to grow and be formed. Will this level of inhibition of abeta synthesis actually bring cognitive benefit to patients? And that’s the big question.

And our project actually really focused as hard as it could really to efficiently bring this molecule forward to patients. So it’s a bit unusual for us to move directly from our Phase 1 study into this large Phase 3 study. But actually as a drug discoverer, Verubecestat represents really the best kind of molecule you’d want to be able to bring forward. It has an unambiguous effect on the activity of this key enzyme. So it’s going to allow us to ask a very clear question in patients.

And independent of what the outcome is next summer of this first trial, whether it be positive or not, we’re going to be able to use that data. The whole field will use that data, I think, to be able to redirect the clinical space and focus either on much earlier stage patients– as we’re doing in our second trial, which we find out about the next year– and also begin to think about how we can bring more treatments that we’re currently working on in the labs against say, for instance, the tau protein that you mentioned. Because it is a very complex disease.

IRA FLATOW: Dr. Goate, so in your mind, if this drug does work, does it prove the amyloid hypothesis is correct?

ALISON GOATE: Yeah, I think it would. I think that it would be demonstrating directly that if you lower the beta amyloid levels that you can prevent the onset of Alzheimer’s disease. And that is one of the predictions of the amyloid hypothesis. It doesn’t mean that other things might not also be important. But it certainly demonstrates the importance of that amyloid peptide.

IRA FLATOW: Mm-hmm. And Dr. Kennedy when will we expect to see whether it’s working or not?

MATTHEW KENNEDY: Well, there have been well over 1,000 individuals that have actually been dosed with Verubecestat up to this point, for up to a year. And next summer will be the point where we’ll learn in July the outcome of the first trial in mild to moderate patients. Then about a year or so later, we’ll determine the outcome of the trial for prodromal patients. So we’re very excited to learn those results next year.

IRA FLATOW: Well, we’ll be watching along with you. I want to thank you both for taking time to be with us today. Matthew Kennedy, Director of Neuroscience at Merck. And Alison Goate, Director of the Loeb’s Center for Alzheimer’s Disease at Mount Sinai here in New York. Thanks again for taking time to be with us.

ALISON GOATE: Thank you very much, Ira.


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