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Scientific American interview with Dr. Fillit

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marty
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Scientific American interview with Dr. Fillit

Postby marty » Wed Jan 11, 2017 1:38 pm

https://blogs.scientificamerican.com/ta ... 91a4e304fb



The last six months have witnessed the failure of two drugs in late-stage clinical trials for which the research community had high hopes. In truth, these new reports should not have come as too much of a surprise. Drug after drug continues to show little or no effect in helping the more than 5 million patients in the U.S. diagnosed with Alzheimer’s.

Scientists who study neurodegenerative diseases have started to call for new approaches that go beyond targeting the amyloid in plaques and the tau in tangles, proteins that have been thought to be culprits in killing brain cells. One organization—The Alzheimer’s Drug Discovery Foundation (ADDF)—has for years provided funding to move untried ideas into clinical trials. Howard Fillit, the organization’s executive director, recently gave Scientific American his surprisingly optimistic view of where research and drug development for Alzheimer’s is headed.

[An edited transcript of the conversation follows.]

There have been recent failures of late-stage clinical trials and a figure often cited is that more than 99 percent of Alzheimer's drugs fail. Given all that, what level of confidence do you have for the field moving forward?
There's a lot of reason for hope. There are over 130 different clinical trials going on now. I remember the days when there were none. We have had many failures. But I think one of the big advances that is creating hope is that we know how to do clinical trials better now. In a study that is being conducted by Biogen, everyone who was recruited into that study actually had Alzheimer's disease, for the first time.

That was the first study in which you had to have a positive amyloid scan, which was a scan ADDF helped to develop, and so we've learned a great deal about how to do clinical trials. Clinical trials that were done five, 10 years ago might have had 30 or 40 percent of people in the trial that didn't even have Alzheimer's.

Do you think any of these drug failures have called into question the idea that amyloid may be culpable as a disease-causing agent?
In the 1980s we started research primarily with the pathology of plaques and tangles, and in 1984, it was discovered that this molecule beta-amyloid was a primary component of the senile plaques in Alzheimer's—and tau was recognized later as a molecule that was a major component of the tangles.

So in early days of drug discovery and development, we really focused on the pathology and that's why beta-amyloid seemed to be a very good target for development of new drugs. We've learned a great deal about the biology of beta-amyloid, although we still don't know exactly what it does. But we know a lot about how it's processed in the brain, and that's led to drugs that tried to inhibit an enzyme (gamma secretase) that helps produce beta-amyloid. Side effects basically killed that approach.

Then the idea was discovered that maybe in humans we don't overproduce beta-amyloid—but we fail to clear it—and all these misfolded proteins are contributing to the buildup of plaques. Now monoclonal antibodies, “vaccines” so to speak, are being tested that are intended to bind the plaques so that they can then be cleared by immune cells to help protect brain cells from dying.

Ultimately science is a process of research, and drug research is going to fail most of the time. A good experiment is one that raises more questions than it answers. Amyloid was an obvious candidate from looking at the pathology. A lot of science has been done, and we're finally in phase III human clinical trial experiments.

It’s not that surprising that we’re seeing failures in the clinical trials, even though we’ve made tremendous advances in basic research and we’ve cured mice with Alzheimer’s pathology over 500 times in the scientific literature. Mouse models are notoriously poor predictors of drug success in humans for most diseases—and especially for Alzheimer’s disease, a uniquely human disease of the mind.

Consider this perspective. Cholesterol was discovered as a biomarker, a risk factor, for heart disease in the 1950s. But it took 25 years before we had the first drug for heart disease that targeted cholesterol. If you look at the literature, there's a lag time of about 20 to 30 years between discovery of a risk factor like cholesterol or amyloid, and development of an effective therapeutic.

Isn’t there a growing perception that there’s a need for targets beyond just amyloid?
Our approach at ADDF is very simple. We see aging as the leading risk factor for Alzheimer's, and I think the basic strategy that is taking hold across the field is that aging is the most powerful risk factor by far—and that we need to learn from the biology of aging to develop drugs for the disease.

For example, inflammation is a hallmark of aging, and we know there's both inflammation in the central nervous system and throughout the body as a whole that contributes to Alzheimer's disease. So our foundation is funding a number of studies, the-second largest part of our portfolio, to address both kinds of inflammation.

What about other strategies?
Neuroprotection is the largest part of our portfolio. We're very excited about this. Again, in the biology of aging your brain is getting hit by multiple factors: oxidation, inflammation, toxic misfolded proteins (amyloid, tau and many others), vascular hypoxia (diseased blood vessels that reduce delivery of oxygen) to name a few. What we need is an approach, regardless of the form of injury involved, that activates the brain’s innate neuroprotective mechanisms for any of these insults.

We’re supporting the development of a drug that binds to a receptor (a docking site) called p75 on the surface of neurons. When the drug binds, it activates cell survival pathways.

Aren’t there still other approaches?
We're also very interested in epigenetics (the cellular machinery that turns genes on or off). Epigenetic processes can be modified by environmental and other kinds of cellular injury. In some ways, epigenetics is the connection between lifestyle and other risk factors and neuronal dysfunction and dementia in aging.

The whole epigenetic field is exploding, especially in cancer, and the whole field of epigenetic drugs is exploding. We're excited about a company in Barcelona that we're funding called Oryzon, which is a leader in developing epigenetic drugs for cancer and Alzheimer’s. We've been supporting their epigenetic drugs for Alzheimer’s, and they're now going into Phase II (midstage) clinical trials.

Another approach is to try to prevent neuronal energy failure. The brain is 2 or 3 percent of body weight, and it uses 25 percent of body's energy supplied by glucose and oxygen. Neurons are highly active cells and have tremendous energy requirements. As a result, if their ability to use energy declines, they're at great risk for dysfunction and death.

If somebody's glucose drops below 60, they immediately go unconscious. If somebody is drowning, they can’t breathe, they immediately go unconscious. That' how sensitive the brain is to acute energy failure.

What is called the “mitochondrial hypothesis” has been around since the 1980s, but it hasn’t received enough support. With aging, we know that mitochondria (cellular energy factories) start to fail. They're a primary source of oxidants that are injurious in the brain and throughout the body. In addition, insulin resistance—a failure of glucose utilization—occurs. So we're repurposing drugs for diabetes for Alzheimer’s. We’re running a clinical trial of Liraglutide for Alzheimer’s at the Imperial College of London.

What is your vision for how Alzheimer’s might be treated in the future, if this multi-faceted approach is implemented?
The disease will be treated just like diabetes, hypertension and cancer are treated. Most diabetics and hypertensives are on two, three, four drugs. By the way, diabetes and cancer and hypertension are also diseases of aging, and we haven't conquered any of them—even though we’ve been doing research on these illnesses for at least 90 years—but we've made inroads on all of them. I expect with Alzheimer's, a patient will be on two, three, four, five drugs targeting different pathways in the brain, and I think that's a goal that's achievable. We'll be able to delay the onset of Alzheimer's by five years so that the average person will die without ever becoming demented.

Do you see that happening within 10 or 20 years?
I think it's going to happen pretty soon. I think in 10 years it's very likely we'll have achieved that goal of having effective therapeutics in multiple categories that will have enough effect on the disease process that we'll be able to delay the disease process beyond the average life expectancy.

circular
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Re: Scientific American interview with Dr. Fillit

Postby circular » Thu Jan 12, 2017 4:04 pm

Thanks marty! Nice to get an overview from ADDF!
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Julie G
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Re: Scientific American interview with Dr. Fillit

Postby Julie G » Mon Jan 16, 2017 10:21 am

The headline for me: Fillit predicts that we’ll have multiple therapeutic options/Pharma that postpones AD beyond the average life expectancy in the next ten years. That's huge.

It's encouraging to see ADDF expanding their focus to include drugs that support epigenetics, address inflammation and neural energy failure- while still working on the abeta angle. I personally find it very hopeful to see Pharma finally targeting the same pathways we’re addressing through diet/lifestyle/supplements.

circular
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Re: Scientific American interview with Dr. Fillit

Postby circular » Mon Jan 16, 2017 11:20 am

I was particularly struck by this:
It’s not that surprising that we’re seeing failures in the clinical trials, even though we’ve made tremendous advances in basic research and we’ve cured mice with Alzheimer’s pathology over 500 times in the scientific literature. Mouse models are notoriously poor predictors of drug success in humans for most diseases—and especially for Alzheimer’s disease, a uniquely human disease of the mind. [Emphasis added]

This should serve as a major red flag. Evidence-based medicine is good to always remind us that mouse studies are just that; yet it seems to me that I see over and over in the alternative/integrative arenas, and in my own thinking, that as long as the direction of the research suggests a trend that the intervention is helpful, even if that research is just mouse studies, then have at it. My feeling has been that if I'm comfortable there are no clues suggesting a downside when the intervention is applied conservatively (eg dose) something is safe to try based on positive mouse studies. But I hadn't realized just how irrelevant the mouse studies, absent subsequent evidence-based confirmation, appear to be for us. Is 'irrelevant' a fair characterization given the numbers quoted?
ApoE 3/4 > Thanks in advance for any responses made to my posts.


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