Eric McDade, DO, an Assistant Professor of Neurology and Dementia Specialist at the Washington University at St. Louis School of Medicine, talks about the Dian-Tu Trial and the future of care for Alzheimer’s disease.
Interview conducted by Ivanhoe Broadcast News in March 2017.
Let’s start by asking, if you could tell us a little about the Dian-Tu Trial?
Dr. McDade: Yes, the Dian-Tu trial is a unique trial that focuses on this specific Alzheimer’s disease population, one of which that what it should have is a specific genetic cause for their Alzheimer’s disease. Alzheimer’s disease is linked to many probable genetic risk factors, but in the Dian-Tu trial we are actually focusing on a population that is associated with defects in three chromosomes. These genetic changes are actually passed in a way that each generation from somebody who has the gene has a fifty-fifty chance of getting the gene defect, and if they do inherit this genetic change they have almost a 100 percent chance of developing Alzheimer’s. And importantly, they typically develop it in their forties and fifties and sometimes as even as early as their thirties.
How prevalent is this as far as you can tell?
Dr. McDade: It is very rare actually, so we estimate that it probably makes up less than one percent of all cases of Alzheimer’s disease. When you start looking at young onset Alzheimer’s disease, it may make up of a larger proportion, but we are still talking about probably in the order of five to ten percent, so maybe five to ten out of 100 people who have Alzheimer’s in their fifties may carry one of these genes.
This early onset?
Dr. McDade: We have rough estimates right now as part of leading into the Dian-Tu trial, we have an ongoing study called the Dian Observational study and that started in 2008, and that has been following these families who are at risk for having the genes. Currently from the start of the trial in 2008 up until now we have had nearly 500 people enrolled in that trial. Now, that does involve sites outside of the US. With some of the estimates that we have recently done worldwide; we think that as far as those who would be eligible for the Dian-Tu trial, we are talking about numbers in the range of three to four thousand, so we are talking about relatively small numbers. But this population we think actually holds the key or one of the major keys in understanding the disease particularly when we talk about prevention.
Why is this so important to researchers to be able to determine the mechanism of this happening and then what happens from there?
Dr. McDade: One of the reasons that the decisions were made to focus on this disease is that it is incredibly tragic to see these families pass this disease on from generation to generation. When you meet these families who are getting this disease in their thirties, forties and fifties; I think almost all people involved with this are impelled to really do something and to try and have an impact on these families. One of the unique things about this is that although there is a number of different specific mutations, these gene mutations, that are associated with the disease, they all converge on a similar pathway; and it has to do with an abnormal processing of this protein called amyloid. A lot of people know of the amyloid plaques, they hear about them being associated with Alzheimer’s disease. It is one of the core pathologies of the disease; so we know or we understand the many ways of the mechanism. We know that a one point or another there is an alteration in the genes that causes this amyloid protein to build up in the brain; so it allows us to understand mechanistically where we are intervening. The other key thing is that with this disease, because of this strong genetic predisposition, there has been a lot of evidence and we have recently done studies to look at this, that the time that someone gets the disease actually is somewhat predictable as well, based on the family history and based on this specific gene that they inherent. The reason this becomes really critical is that one of the problems and one of the biggest hurdles we have had with prevention in Alzheimer’s, is predicting who is going to get the disease. Then if you can predict who is going to get it, when do you start to sort of study them. Within this population we know that within a family, say typically people develop symptoms at about fifty, for about ten, twenty, thirty years back, we start to track these families and we can actually start to see sort of step by step how the pathology and how the changes associated with the onset of memory problems start to develop. It allows us to really track smaller numbers of people, but we take a really wide angle at the disease. That prevention strategy, in this population for instance, although it is difficult to find these families, once you have identified the families who has these mutations it actually becomes much easier to predict. Once they get the disease and then track the disease from the earliest system onset or the earliest changes in pathology till when they get it.
You talked about early prevention and obviously no cure for Alzheimer’s?
Dr. McDade: Right.
Identifying early becomes important, why so?
Dr. McDade: Many of the studies that have been done, the clinical trials that have been done on Alzheimer’s disease have unfortunately, we used the term failed in meaning that they have not shown to be effective; they have not been identified as being effective therapies. We have not had a new drug approved for Alzheimer’s disease in over fifteen years actually; so it has been some time. One of the concerns is that not only in our therapies it may not be affective, we are actually making many advances in identifying more effective therapies, but part of the problem might be that we are intervening far too late in the disease; and so by the time somebody develops Alzheimer’s disease if you are to look at their brain there is a number of different changes that have occurred beyond just these amyloid plaques. There are inflammatory changes and vascular changes; the brain in many ways has been ravaged by the disease. We think if we are able to identify when the changes really start to happen and in particularly when to start to isolate a single pathway, like amyloid. If you can say at this point in the disease, say twenty years before we expect people to get symptoms; at that time the only identifiable abnormality that we can really see is the amyloid pathway, if we have good drugs that can really target that abnormal amyloid protein, we think it would be a lot easier to stop the disease from progressing rather than trying to catch up and prevent all of these sort of downstream effects that happen after the disease is really sort of set forth.
Could you tell me what Dian-Tu stands for?
Dr. McDade: Dian-Tu stands for the Dominantly Inherited Alzheimer Network Trials Unit.
There are some drugs that you or your fellow researchers are looking at here, can you walk me through some of them and I understand there is a third you are about to take a look at?
Dr. McDade: Our current trial was started in 2012 and actually finished enrollment in 2015, are using two different therapies, both of which are associated with these antibodies. The antibodies are against different forms of the amyloid protein, so right now we are studying people who are early in this sort of cascade; this family cascade that we talked about. You can enter the trial fifteen years before it is expected that you would start to develop symptoms to ten years afterwards, and you can also come into the trial being completely symptom-free as far as having any clear memory problems, thinking problems, or you could have mild symptoms at that time. Right now the first phase of the trial has these two drugs, both are these antibodies, they are looking at that attach to or attack different forms of the amyloid protein. We think if we can intervene early on as we talked about before, then we will have a better chance of seeing if we could really modify one disease starts or when symptoms start. We are about to enter a third phase of the trial which we call the next generation, or next gen, and in that part we would be using something called base inhibitor, which is an oral therapy or a pill. The other two are IV therapies and intramuscular injections. The current two therapies are monthly injections or infusions and the other would be a daily pill that people will be taking.
Tell me a little bit about the third phase?
Dr. McDade: The current phase is actually an international trial, so our current trial actually involves centers in North America, including Canada, the U.S. as well as Puerto Rico. We also have trials in Europe; our centers are in Europe, including the United Kingdom and Spain. Then we have centers in Australia as well, for next gen trial we anticipate there will be increasing the number of trials as well in different areas of the world. We anticipate the first phase of the study, which started in 2012 and finished enrollment in 2015, will finish in 2019, so at that time we will have the results or the read out. The current next gen study we will be starting in 2017 and likewise we anticipate that the total duration of the trial probably will be somewhere on the order of five to seven years from the point that it starts so each one of the therapies is a four year trial but it starts from the first person that entered the trial and it ends when the last person who entered the trial finished their four years of therapy.
The 2015 trial that you finish enrolling in 2015, 2019 is your profit? That is when we can anticipate the data?
Dr. McDade: Yes. That is when we anticipate the results from that to see if current two therapies are actually having an effect on the disease process.
Is there anything that you are able to tell me anything about the trial or is it too early to talk about what you have seen?
Dr. McDade: Certainly it is definitely too early. One of the things that we are currently doing with both trials is running this trial in parallel with other trials in what we call Sporadic Alzheimer’s disease. We follow those other trials to look for safety concerns that might rise or efficacy concerns, efficacy data that may come from those as well, so we follow the other trials that going on in parallel with this as well.
Tell me a little about Marty?
Dr. McDade: Marty’s part of the current trial, he has been in the one that is already been ongoing, so as part of that he would be getting either one of the monthly infusion or one of the monthly injections.
How would you characterize the search for new information and something that is going to slow the progression? How hopefully are you that there is something on the horizon?
Dr. McDade: Cautiously optimistic, I think is always sort of has to be the way you proceed when you are talking about complex brain diseases. The brain is such an unbelievable complex organ, so you always have to have some caution when, you know, making predications. I know that, and being relatively young in the field back in the late eighties and early nineties, saying that within five to ten years we are going to have this disease sort of solved and we are going to be sort of moving on and here we are almost thirty years later. But that being the case, one of the things that make it so hopeful is this incredibly dedicated population in families that we are involved with in trials like the Dian study, and then in the older population studies like the A-force study, which is again a prevention study; in people who have identified amyloid in their brain but no symptoms but don’t have these genetic causes. There is a large group in Columbia, South America too, that has actually had a similar trial to the Dian study. We have these incredibly devoted and dedicated populations, which is key to moving forward with prevention. We have recognition not only with the scientist involved, with the clinical researchers involved, but also from our advocacy outlets, like the Alzheimer’s Association. We have a recognition from government agencies, actually in the US as well as in Europe, understanding that if we don’t really start to have an effect on this disease in a way that really starts to prevent the numbers of people who are going to develop the symptoms; the estimates really indicate that this really is going to be a major, major problem and we are talking economic problem, in addition to the social problems that are associated with it. There really is this recognition, so right now I think the field is in a really good place to move forward, full steam ahead with looking at a number of different therapies, looking at a number of different pathways, looking at different unique ways that we can have these trials move forward and have the support from the pharmaceutical industry, the government, the patients and the clinical researchers. When you have all those things align; it really helps to energize everyone and move forward.
What is young onset?
Dr. McDade: Young onset Alzheimer’s disease is young onset familial in Alzheimer’s disease.
Is anything that I didn’t ask you that you want to make sure people know about this particular disease?
Dr. McDade: When people hear stories about this, one of the things is that people say is a lot of things like, hey you know I have Alzheimer’s in my family, and they want to find out about additional information and risk. What we talked about this genetic form, having it in your family indicates that maybe I have that genetic predisposed position. One of the things we all always want to be sure or clarifying is that in this form of the disease, again people typically develop symptoms in their thirties, forties and fifties as opposed to developing symptoms in their seventies and eighties. If there are people who are viewing this and have concerns though, we actually have a number of different resources in ways they can reach out and contact us. We have something through the internet called the Dian expanded registry, which provides an opportunity to actually interface with people who have concerns. Through the expanded registry it is actually one of our major ways of trying to identify people who do have this in their families, so we can get them involved with research with Dian, or get them involved in researchers that maybe looking at Alzheimer’s but they don’t carry these genes for instance.
Is there a website?
Dr. McDade: Yes, it is www.dianexr.org.
Even through that you are able to register them if this isn’t the appropriate study you guys were able to do find a possible one that it is?
Dr. McDade: Exactly.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Attn: Ellen Ziegemeier
Sign up for a free weekly e-mail on Medical Breakthroughs called First to Know by clicking here.
