The Alzheimer’s Vaccine Interview: From Concept to Clinical Trial
By,  Paul D. Costa

PDC:   Dale, what lead you to Alzheimer’s Research and in particular the concept of an inoculation that would treat patients with Alzheimer’s disease?

DS: In 1987, I was a young scientist and there was a new little start-up biotech company called Athena Neurosciences. The interesting goal of that company was to study the causes of Alzheimer’s disease. And at that time there was strikingly little known about the Alzheimer’s disease process.

Back in 1987 strikingly little was known about Alzheimer’s disease. In fact all that was known about it was appreciated that it affected many many people. It was the most common reason for elderly people to become demented. But no one knew quite why – no one knew why it was occurring. One of the folks I spoke with named Dennis Selco, out at Harvard, and he had become very interested with something that we now call beta amyloid.

What is beta amyloid? It is the building block of plaque lesions in Alzheimer’s disease. Let me tell you about these. One thing that is quite clear in the Alzheimer’s disease process is that after the victims die if you look at the brain tissues you see the amyloid plaques marking the brain like bruises, and in fact, they are brain tissue debris. That was the one solid piece of evidence we were looking at in 1987 – the beta amyloid was the building block, but we really had a long way to go to understand how the disease process really worked.

Even at that there were inconsistencies. We did not know where it came from, how it got there, why it was produced, or why some individuals had a lot of it and others had not so much. That’s where we started.

Over the past fifteen years, this beta amyloid has become the villain of this disease we are trying to conquer and get rid of. It is very akin to cholesterol in heart disease. The hypothesis has been that if we get rid of the plaques, these patients will be better for that. Then the hope of all hope is that the patients can think better again and do normal functions again. If we get rid of the plaques the patients could go back to living a normal life. That’s where we started. 

PDC: It doesn’t seem like the disease was well understood by the general medical research or physician levels. What were the significant milestones, in your opinion, that helped progress?

DS: Over the years we made steps and passed milestones along the why. First we understood how the peptide is made in biochemical terms. And of great significance was the developing of a mouse model of the disease process. What that is specifically is a mouse – the PDAPP mouse that has defective human gene 4 – and as a result of having this extra gene, as the mouse ages, they get the very same plaque lesions as humans Alzheimer’s patients.
            This was in the 1990’s and it was a key component in research. It allowed us to speculate and test premises then to a degree that before would have been impossible. We could then ask if simple treatments like Aspirin or Ibuprofen would be beneficial. We could give the mice these compounds and in a little while, after we had treated them for a while – see if we had done them any good.  In this case that would mean we could see if we had reduced the pathology of these plaque lesions.

PDC: So the mouse model allowed you a sort of non-human clinical trial basis?

DS: In the confines of our laboratory, yes. But, it was in these mid-90’s experiences when we were brainstorming about various things we might now be able to try, I had an extremely simple idea.  

My idea was to vaccinate, actually immunize the mice with the very problem – the amyloid peptide itself. The idea was that if these mice mounted an immune response against the amyloid peptide – it might actually help them out – it might actually reduce the plaque lesions, plaque counts and the numbers and that sort of thing.

You might say, “That was a really simple idea so you must have jumped on it right away”. No, and the reason was that curiously enough as Neuroscientists we are taught that the immune system can’t get into the brain, and that the brain is protected from the immunity system and antibodies in particular.

So, when I suggested the vaccination approach for these mice, my colleagues pointed this out to me and said, “Interesting idea but it just won’t work because the immune system, or the antibodies won’t get into the brain and do what you want them to do”.

It turns out as a result from our previous experience on brain and working with cerebral spinal fluid that there was specific evidence that minuet tiny quantities of antibodies do get into the brain. Very, very small amounts. But I actually calculated that that small amount should have an effect.  In the end result, after a lot of convincing on the part of my colleagues we decided to just try it on a few animals; it wasn’t a big study because nobody believed it was going to work. And that’s how we finally did the first experiment. 

PDC: What was the hypothesis?

DS:  We would vaccinate them (small group of mice) for an entire year. In other words, we wanted to ask if we vaccinated them at a young age when they had no plaques, eventually when we looked at their brain tissues, when they should have a lot of plaques, what happened?

And the long and the short of it of that analyses is a year later when we looked they had almost no plaques lesions at all. Almost none. In fact, so few that we assumed something had gone wrong, we thought we had confused the cages and that we had checked the wrong set of mice.

But in the end the plaques weren’t there by any criteria that we looked at.  And over the past couple of years since that discovery, there are seven or eight laboratories around the world that have reproduced the results and they very much believe in the results.

PDC: It seems to me that really would be a real milestone –appearing that you developed the first altered disease process treatment – granted in mice – for Alzheimer’s. That only has circumstantial relationships to human Alzheimer’s disease – but, it certainly would be fuel for speculation.

DS:  Well, as a result of that success, it has opened up new areas in research and science. The brain is no longer considered totally immune privileged. It turns out that there are new approaches for Huntington disease, Mad Cow Disease and perhaps other neuro-degenerative disease, it is a matter of time before we know if they work or not, but it is great to see that this approach is being expanded beyond just Alzheimer’s disease.

PDC: So the development has already had a positive effect in disease research. What followed regarding the vaccine development for humans?

DS: As a result on our animal findings, we were encouraged to move on to patients, and began that in the late 1990’s and that continues today. So as it turns out beta amyloid peptide is a small piece of a protein that contains 42 building block amino acids. So, what we did was to do clinical trials using a synthetic form of this material in patients with Alzheimer’s disease and that is what we are in the process of doing. We have now done three clinical trials. We have done at present two safety studies and one larger study to look at more sophisticated questions. So, let me state that the safety studies do just that, they look at the safety of the compound in a small number of people.

            PDC: It seems a rather rapid pace – concept in mid nineties and clinical trials in 2000 – what was your role in this stage of the process?

DS: Aside from the extensive development of numerous second generation compounds – we decided to enter clinical trials with patients having Alzheimer’s disease using amyloid peptide – we term it AN-1792 – and, as I mentioned,  the first two studies were safety studies – what these do is ask if a drug is safe?. You must have some level of confidence that a drug is safe to administer before moving on to larger numbers of individuals. So we have done several of these safety studies – one in the United States and one in the UK. In the USA we gave a single injection to see if there was any complications.

After that we moved on to the UK safety study where we actually gave multiple injections over a long period of time – and found that AN-72 was well tolerated and safe – so much so we continued giving injections to those patients 15-18 months – much longer than we had originally anticipated.  And finally based upon good results there we moved on to a larger more sophisticated study to begin to ask more complicated questions - not so much definitive questions about whether it works or not – but whether AN-1792 is beneficial to patients.  To begin to get ready for them – we call this Phase Two – It is somewhere between testing if a drug works with a large number of patients and showing that it is safe. We call it Phase Two.

So we just now are finishing the Phase Two study – unfortunately when we initiated that study, we were two doses into that study and this was throughout the USA and Europe – at twenty-eight sites, three hundred and seventy-five patients, we ran into an unfortunate side effect. That was brain inflammation, we ran into that in about 5% of the patients that receive AN-1792. As soon as we saw the first signs of that we halted the dosing – we didn’t halt the trial and we kept the study fully blinded to the investigator and the patient and the investigators for a full year – to allow us to ask later on if indeed there might have been efficacy or that AN-1792 might have worked. But we did halt the study for safety concerns.

PDC: Does that mean the approach is dead in the water?

DS: No. We are just now beginning to access other parameters of that study – to see if there might have been any benefit to the patients. It is too soon to say, and I am obviously optimistic that it might have had benefit – but that is where we are at this moment (April 9,2003).

Now that being said, we have had several backup approaches in the laboratory – or I should say second-generation approaches that have been in the works for a number of years. AN-1792 is a forty-two amino acid protein. As it turns out the beneficial piece, the thing that seems to be working is the left handed side of it. We believe it is the anti-body production that is the beneficial piece of this possible treatment for Alzheimer’s disease – So, one of our second generation approaches uses just a fragment of this beta amyloid peptide, attached to something else - to elicit these so called “good anti-bodies”, and this is one of our second generation approaches.

 In other words it is a more targeted immune response to the beta amyloid peptide. And what it nicely does is separate away what we call a cellular response to beta amyloid peptide – we believe it is this cellular response that is on the other half of the molecule that is the culprit behind the side effects that we saw. So as we move forward we hope to focus the immune system on the good antibody piece and eliminate the cellular /side effect piece of the molecule.

            PDC: In all my research, I’ve yet to find anyone who even claims to understand the disease process – but, your work seems to be operating at the molecular level of the disease process by manipulating the body’s immunity systems? Is that an accurate observation?

            DS: Well, no one knows for sure just how the Alzheimer’s disease process plays out in the human brain tissue, we believe and the hypothesis is these plaques are causing the damage. If you see the brain tissue of an unfortunate patient that has had this disease you’ll see that these plaques are wide spread – in fact they occupy a very significant part of the brain tissue. And we believe that these plaques interrupt the way neurons communicate with one another. And it is thought that if these are eliminated the neuronal connections will improve and the very health of the neuron connections will improve as well.

What the vaccination or immunization approach does is when an individual is immunized with a beta peptide they generate anti-bodies to it. A few of these anti-bodies get into the brain and they act as sentinels, they actually physically bind to the plaque lesions and the scavengers cells in the brain come along engulf and destroy the plaque lesions. We have very detailed evidence of this occurring in our mouse/animal model and there is now some evidence of this occurring at least in one of the autopsy cases of patients treated with AN-1792. So we believe the plaques are literally physically removed from the brain. It is the hope than that once these are physically removed, that the remaining neurons that are either healthy or mildly altered will improve their connection, their functionality and their health – meaning the patient will actually be able to think better. That’s the mechanism we think is operating behind the vaccination.

            PDC: So, the trials you initiated were valuable and not really finished?

            DS:  We are gaining ground everyday. Despite the side effects we ran into in Phase Two – and we have very significant compassion for those patients and individuals that suffered the side effects- there is very important reasons to be optimistic about the vaccination or immunization approach overall.

One example of that is that an individual from our late early safety study – that had been treated over a year with AN-1792 – ultimately had a pulmonary embolism and died.  The physician involved decided to an autopsy and look at the brain tissue of this diseased individual that had been treated with AN-1792.  What he found was rather remarkable.

For the most part this patient’s autopsy looked absolutely consistent with Alzheimer’s disease, there was brain shrinkage, there were what we call tangles in the neurons, but strikingly absent were plaques in most regions of the brain tissue. The neural physiologist who examined this, his name is James Nicolls said that the moment he looked at this brain tissue he was seeing something unique for the first time it had occurred.

In his experience of looking at hundreds of brain samples in autopsies he had never seen a paucity of plaques like this in his experience. Now we have to keep in mind that this is single autopsy and one individual – but it is very unusual and it is absolutely consistent with what we have seen in our animal models of the disease.

What it does suggest to us is that the fundamental idea and mechanism that we believe will happen in patients is likely occurring. And it gives us hope for the analysis of the clinical trials that just concluded as well as future approaches with our second-generation efforts.

            PDC: What is now involved in moving towards any point of validity?

            DS:  We are now at the point of having a wealth of information coming forth with regard to A-beta immune therapy in general and a good example of that is the autopsy case that was just reported in the Nature Medicine. In that report an individual who had been in the AN-1792 trials for over a year eventually died to a pulmonary embolism. An autopsy was done and to everyone’s surprise she had almost no plaques in her brain tissues. In most areas – not all areas but in most. The neuron pathologist was extremely surprised at that result – he had never seen such a thing. And the importance of that it suggests the mechanism that we hope is working in these patients is indeed working.

What we don’t yet know however, indeed from these two recent studies we don’t know from that analysis if there has been benefit to the patients – and of course I remain optimistic for the approach and anxiously await that analysis - and for all the reasons I’ve spoken about – I’m very hopeful we sill see some benefit at some level.

PDC: Is it too early to speculate about the future of the vaccine approach?

DS:  If we think about the future for a moment and the possible role for A-beta immune therapy in that future, it could be extremely important. I think therapy for Alzheimer’s disease is entering a new era. At the present, what we do for Alzheimer’s victims is bump up their cognition as much as possible, deal with their behavior problems as much as possible, but we have no real tool to alter the deteriorating ongoing pathology in their brain tissue.

My hope naturally is that A-beta immune therapy will be the first of several approaches that can actually go after the underlying causes of this disease – to get rid of the plaques or reduce them. I hope that other approaches will be developed as well – perhaps to go after the tangles for examples – or to bluster the neuronal structure itself. What this will mean is that eventually we will be at a point where people no longer die of AD.  Rather it will be a disease that has to be dealt with, it has to be controlled, it can be treated with lifestyle changes, diet changes and of course therapy and medication like we are talking about right now.

I remain very optimistic for the future of Alzheimer’s treatment in moderation. My hope is that if the A-beta immunization turns out to be of value for treatment of the disease – it would be the beginning of a way to prevent the deterioration in the brain that is occurring in the brain of these patients. What I see in the future is that the way to deal with Alzheimer’s disease would be multi-pronged.

PDC: Are you a proponent that many cases of Alzheimer’s disease can be prevented?

DS:  Yes. There will be lifestyle changes, diet changes and new treatments on the horizon that together will stave off the disease such that no one will die of Alzheimer’s disease – it will be something that has to be dealt with and dealt with aggressively. Very akin with how we deal with cardiovascular disease today. And I also see that beyond A-beta Immune therapy it will be the first of several therapies over the next ten years that will fundamentally curb the pathology in the brain.            

What A-beta immunity therapy likely means to the patients- and likely for the field overall – is it will quite possibly be the first treatment to alter the very pathology in the brain itself. The reason this is important is if we take a moment and talk about the way we treat AD today it can set the stage. Currently the way we deal with AD today, we do have some therapeutic tools. They are modest. The ones we have are  “inhibitors” and what these drugs do is – they are helpful – they boost the ability of the brain tissue to think – they boost it up a bit. And they help a patient for a period of time – but they don’t really go after the underlying problem in the disease – and so they are of reasonably short-term benefit.

If we can alter the pathology itself – we can likely stave off the final problems of the disease. In other words, people will no longer die of AD. They will live with it and they will be able to maintain a perhaps slightly altered but nearly normal lifestyle – just like we do with cardiovascular disease today.

And eventually, if we are truly successful we will from treatment, back all the way up to prevention itself.  I am often asked, “Well, if this is a vaccination approach – can you prevent Alzheimer’s disease?”. I don’t think it is that simple really.

I think we have to first deal with how we treat the disease. Can we treat the disease by altering the pathology? And then we will slowly work our way backwards depending on just how safe it is. And if it is truly safe, and our second-generation approaches turn out to be very very safe we can work backwards. We can have that as a long-term hope but it is a wonderful dream to have.

PDC: The iBHEALTH network and the End Alzheimer’s 2012 Task Force are trying organize an anti-Alzheimer’s Lifestyle demonstration project, as well as offering online meeting and forums for the researchers and professionals – what do you think the conditions of the Alzheimer’s community really are and how valuable is any group or population efforts? 

DS: We are in the midst of a revolution in terms of understanding Alzheimer’s. Obviously, a lot of my career and my colleague’s careers have been based on trying to treat the disease on understanding the pathology of the disease- and I hope we see the fruition of that in the next five to ten years. But as we are in the midst of this revolution in Alzheimer’s we are just now beginning to understand aspects of lifestyle and diet that might affect it. For example there is evidence that high cholesterol levels might contribute to the progression or incident to AD. There is belief that anti-oxidants might be helpful. We are in the middle of a great deal of research – most of it not yet confirmed but is suggestive – if you think back maybe forty years and look at cardiovascular disease – we didn’t know that diet was so critical – and now we have extremely good evidence to support that.

            I think the same phenomena will happen in Alzheimer’s disease. Now, does someone wait until all that information is obtained? I think one needs to be very aware of all the literature out there. Some of it is wrong, but a good deal of it is right. Almost daily now in the news we read about whether anti-inflammatories might reduce the risk of Alzheimer’s disease – they probably do. 

Some of this information is conflicting but it is likely they do – ibuprofen in particular. It is going to be an important and exciting time to watch over the next few years as this unfolds but like all diseases it is going to take multiple approaches to curb it. Therapy will be a piece of it, diet will probably be another, exercise and lifestyle others, and lifestyle will be part of it. It is being said that staying, and there is good evidence to support it that staying active mentally, is protective against Alzheimer’s – you might say that is too simplistic but it turns out that when you are thinking you’re developing new synapse and nerve connections – so if you like filling out crossword puzzles or playing chess – keep on doing it.

            PDC: Do you feel the research and care giving communities are acting as a community, and what about traditional opinion camps – like the “Natural” and “Medical” proponents who often discount the other’s positions?

            DS: I think we’ve made great strides in terms of research into Alzheimer’s and we have potential therapies on the horizon. But a key piece of the future for treatment of Alzheimer’s patients is the additional research efforts and research dollars into understanding the Alzheimer’s process. We’ve worked a great deal on what we call the Amyloid hypothesis. But the goal in working on these hypotheses is to develop new treatment and there is a need for additional ideas/hypothesis down the road. We will need the help of as many medical researchers and research dollars as one can have. Because we don’t know where the new ideas and treatments are going to come from. It’s not a simple process to get there.

If you look at the efforts in other areas such as cancer or cardiovascular disease the amount of money that goes into those areas is ten to a hundred times that of Alzheimer’s research. We have to change our view of Alzheimer’s from, “Gee, there is nothing we can do about it to; there is a great deal we can do about it”. So we need to have early diagnosis – we need to have techniques to do that. We need imaging and additional advances in term of treatment.

And I can see over the next ten years – a revolution taking place in terms of the way we diagnose, care for, treat the disease process – as patients, and care givers and physicians.

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First copyright 5.9.2003 - Internet Broadcasting Association - iBA.