Dr Laura Phipps, Alzheimer’s Research UK
Last month, a paper was published in Nature that demonstrated how a drug called aducanumab appears to destroy amyloid plaques in people. Now, larger studies are underway. But, several other drugs have reached this stage and have failed, so why are scientists, like Laura Phipps from Alzheimer’s Research UK, excited about aducanumab? She explained to Chris Smith...
Laura - Aducanumab is a drug; it harnesses the science of the immune system. So it’s an antibody that tags the amyloid protein in the brain and really marks it for destruction. So the mechanism through which it really works, it isn’t totally clear yet, but maybe through stimulating our body’s own immune system to help clear away that protein.
Chris - How do the antibodies get made and how do they get into the patient?
Laura - They’re given by a monthly infusion; this is what we call passive immunotherapy. So rather than giving somebody the amyloid protein themselves then letting their immune system do all the work…
Chris - Like a vaccine?
Laura - Yes. The antibody itself is made externally; it’s pre-made and it’s given by a monthly infusion, so the effects are shorter term. They’re not a one off injection so it would involve somebody going for monthly injections of that antibody treatment.
Chris - Now, the blood is kept separate from the brain, so have we any idea how this antibody given into the bloodstream can affect what goes on in the brain and get rid of this protein we don’t want?
Laura - So you’re right. The brain is a really protected area and it has what we call the blood-brain barrier that’s really selective about what goes in and what goes out. And that’s why drug development in Alzheimer’s has been such a challenge because not only have you got to find a drug that hits your target, but you’ve got to find one that goes into the brain as well. But the research suggests that this drug, and others in development, are able to do that; they are able to clear this protein out of the brain and we need to then see see whether or not that’s effective and whether that has a benefit for patients.
Chris - Now when you say “whether it’s effective,” you mean as in we know it gets the stuff out of the brain but whether that makes a difference for the outcome in the patient?
Laura - Yeah, exactly. Amyloid has been in researchers sights for many years as potentially the idea that if you could stop the buildup of amyloid, you could slow or halt the progression of Alzheimer's disease. And we’ve heard in previous interviews on the show tonight that, actually, there have been some quite high profile failures in this area where, perhaps, the drugs have been unable to look like they’re clearing the protein but hasn’t benefited patients. And so, we really need to try to understand whether or not we’re hitting the right target, whether just the timing is wrong.
Chris - What’s the evidence that it will work?
Laura - So, the study was promising, even though it was a relatively early clinical trial. It showed evidence from brain scans that the amyloid protein was being cleared out of the brain. But, obviously, they need to be taken forward into big phase three clinical trials before we can see robust statistical evidence that this makes a benefit for people.
Chris - How did the patients get on because in a previous trial, I think it was Wyeth the drug company, made a vaccine which was designed to stimulate the person’s own immune system to do something similar. A number of patients had inflammation in the nervous system; we had to stop doing that. How has this been tolerated and is the outcome better?
Laura - So, with these anti-amyloid treatments, there is this side-effect called ARIA, which stands for amyloid related imaging abnormality, and some people have this and they don’t have any symptoms at all; other people will experience confusion, or dizziness or headaches and it can bee seen on MRI scans. So it’s basically a leakage of fluid out of the blood vessels into the brain, so an oedema in the brain. Obviously, that’s not an ideal side-effect and what the researchers found is people who were on the higher dose were more likely to experience this. And this is something researchers are facing all across the anti-amyloid field.
Chris - There are two things that Louise Walker mentioned: one is that people begin to accumulate this stuff long before they actually have any symptoms, and the other is this protein tau, which Alois Alzheimer also spotted in the brains of people who have the disease. Now a) do we need to start the treatment very early in order to defer the buildup in the first place before it does damage, and two, what about the tau?
Laura - Yes, that’s a really good question. Amyloid has been the major player in drug discovery because of some of those very early discoveries, and genetic discoveries that have really implicated amyloid as driving Alzheimer’s disease. But then, in recent years, scientists have understood that, actually, amyloid may just be a trigger; it may be a judge and not an executioner and perhaps tau plays that ultimate role. But that means because the focus for a long time has been on amyloid, those anti-amyloid treatments are much further through development and so we are seeing tau treatments come through the pipeline of drug discovery, but they’re not as advanced as amyloid.
But the advantage of tau against amyloid is that we know that amyloid is one of the first changes in the brain; it’s one of the earliest changes in the brain. And so some of the clinical trials with anti-amyloids potentially have failed because they haven’t been given early enough. So, in order for them to really work, you’d have to find people in the very earliest stages of Alzheimer's disease, which then gives it a diagnostic challenge; how do we find these people?