🎙 Alzheimer's Disease: The Hullabaloos of Aduhelm! Ep. 12

What's all the hullabaloos about Aduhelm, the first new Alzheimer's drug approval since 2003? This month's MedEvidence guest, Dr. Steven Toenjes, MD, a board-certified neurologist, former staff neurologist in the U.S. Navy and an award-winning director of neurology residents at the Uniformed Services University of Health Sciences and decorated Navy veteran joins Dr. Michael Koren and Michelle McCormick to discuss the first new Alzheimer's drug approval since 2003 and the controversy over FDA's approval of Biogen's Aducanumab (Aduhelm). 

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Original Air Date: March 11, 2022

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Transcript

Michelle
Welcome to MedEvidence Truth Behind the Data. I'm Michelle McCormick. Today we're with Michael Koren, Dr. Michael Koren and Dr. Steven Toenjes. Just we are talking about Alzheimer's disease and now the Hubble values of Aduhelm. But first, Dr. Michael Koren is a practicing cardiologist and CEO and founder of ENCORE Research Group. He has been principal investigator of multiple trials and has been published in the most prestigious journals.

Michelle
Dr. Stephen Toenjes is a board certified neurologist and principal investigator on multiple trials at ENCORE Research Group. He is a decorated Navy veteran and has been practicing neurology in Jacksonville for over ten years. Gentlemen, quite great conversation we've been having today. If I remember correctly. I think we've really talked a lot about.

Dr. Koren
The conversation today.

Michelle
We've had a good conversation today about that. But now treatments or research trials. Dr. Koren, take us tell us a little bit about Aduhelm.

Dr. Koren
Sure. Well, I'll just start by mentioning the fact that both Dr. Toenjes and I work at Jacksonville Center Clinical Research. This is a group of physicians. It's a physician based group that runs clinical trials outside of our practices. And we have about 100 doctors in the area that participate. And we are doing studies in many different areas. My concentration would be cardiovascular.

Dr. Koren
I got very involved, of course, in the COVID 19 vaccine studies because of my expertise in running clinical trials. But Dr. Toenjes has been instrumental and has done great work for us in Alzheimer's, in migraine headache and some other areas, but about to get some Parkinson's stuff up and going so excited about that. So we've been fortunate. This physician group has developed a reputation internationally, now is doing some really good work in testing all these things, as both Dr. Toenjes and I will attest to.

Dr. Koren
It's great to talk about the theoretical elements of what should and should not work, but at the end of the day, what happens in clinical trials tells us what in fact does work, and we're never as smart as we think we are. So we have to run the clinical trials to really see whether or not our are brilliant hypotheses turn out to be actually true.

Dr. Koren
And so that's a neat thing that we do every day. And patients, you know, typically really enjoy the process and learn from the process and get very tangible benefits from the process in many cases.

Michelle
And they get to be a part of it too. So they feel like they're giving back and doing something to move medicine forward.

Dr. Koren
Yeah. And so in medicine, there are areas that make great progress fairly quickly. So Dr. Toenjes mentioned statins and we've had discussions on on this program about some of the amazing breakthroughs in lipid treatment. And they've made a huge difference. And just remind everybody. Cardiovascular death rates dropped in the U.S. by 60% between 1980 and 2010.

Michelle
That's huge.

Dr. Koren
And that was due to the fact that we we had this great research and largely due to preventative cardiovascular therapies that became prevalent.

Dr. Koren
Dr. Changes has been part of migraine studies, and we're doing a great job in migraine compared to some other areas. But Alzheimer's has been a toughie. It's been a tough area and a lot of companies have spent a lot a lot of money doing research in this area with a lot a lot of not great results. And recently it was a company called Biogen that developed a monoclonal antibody to try to prevent the development of amyloid plaques.

Dr. Koren
That had pretty mixed results. And there was a bit of a controversy about FDA approval of it. And I'll hand it off to Dr. Toenjes to give us a little bit more insight into this this particular product and the current controversy.

Dr. Toenjes
Sure. Thank you. So Aducanumab or Adam, is an FDA approved therapy putatively a disease modifying therapy for Alzheimer's disease. It's the first Alzheimer's disease drug to gain any type of FDA approval for a long time, I think since 2003. There are some controversies that surround it. What Aduhelm is, is an antibody that very specifically identifies pathological beta amyloid.

Dr. Toenjes
And through the years of study with the drug, clearly does remove beta amyloid from brain tissue. I think that that's something that can clearly be concluded from the available evidence. The controversy comes in when we tried to determine is there clear and convincing clinical evidence, Do we actually see the outcomes that we want to see? And there were a couple of large studies that were done and historically, we won a couple, at least a couple of separate, well done randomized placebo controlled trials with corroborating results and one of biogen's trials, there did appear to be some meaningful, potentially meaningful clinical efficacy.

Dr. Toenjes
And in the other trial, there was not. And therein lies the the controversy. Now, when we dive into controversy, everyone starts to express their opinions. And in the bottom line is, is that you just have to look at the data and the science isn't controversial. The interpretation of it is what's controversial.

Michelle
How long are the trials?

Dr. Toenjes
They are generally trials that are going to go on for a year.

Dr. Koren
Okay. So I'll give you just a little research insight, a little tidbit, how you know that this is a monoclonal antibody. When you see Aducanumab, it ends with the letters MAB, which is my monoclonal antibody. So for if you want to impress your friends and look at the generic name of a drug and determine if it's an antibody or not, just look to see if ends with MAB.

Dr. Koren
And then for the advanced class, if it ends with you, maybe it's a human monoclonal antibody. So. All right, You want to impress your friends? Say, not only is it a monoclonal antibody, but it's a human monoclonal.

Michelle
Well, I think the word monoclonal antibody was kind of like a buzzword that we've had with COVID as a treatment. And that's the first time I really ever heard of that term. So I appreciate the explanation. Shannon, When something ends it, it may be totally make sense to me, but but it makes sense that you're this is what you're using for your trials, right?

Dr. Koren
And the beauty of a monoclonal antibodies is they can be developed to specifically target a protein. So they're not going to hit random things. They're going to just hit one thing. And so when we use small molecules like pills, they can have what we call off target effects. They can go into different tissues, they can do different things that may not be what's intended.

Dr. Koren
But for monoclonal antibody, they're designed just to hit one thing.

Michelle
So they will go through the system and just attack that one thing. It's like like it has like a laser focus on on where it's going.

Dr. Koren
One thing that's going to fit into the monoclonal antibody. Okay. So it's kind of like a very, very specific key.

Dr. Toenjes
And and that's exactly what advocate of MAB is. And there are other antibodies  in clinical trials in in large phase three stages for other amyloid based antibodies. And I think that it's helpful for people who are either have loved ones or are themselves living with a disease of Alzheimer's. This is a you know, this this the controversies here really hit home.

Dr. Toenjes
And it's it's not a question of whether we can remove beta amyloid out of the brains of humans with with Alzheimer's. We can do that. A number of the antibodies have been demonstrated to clearly do that. The question is, is how exactly do we do that? At what stage of the disease should we be doing that? How safe is doing that?

Dr. Toenjes
And does that translate into actually slowing down the course of disease? There are there are major controversies about whether what was seen, particularly in in Biogen's studies, were those clinically relevant. The whole the whole science of trying to evaluate someone's cognition and then evaluate how it changes is in itself difficult and and I would say controversial. When we do, I trial, there is going to be an identified primary endpoint.

Dr. Toenjes
You're going to predefined this is what we're trying to define were an effect on. And in their trials it was something called the AIDS cog some of boxes. We don't need to talk about exactly what that means, but it's just a way to assess cognition and function and the AIDS cog. Some of boxes in and of itself has some subjective interpretation to it, and therein lies some potential controversy.

Dr. Toenjes
The the reviewers in the medical literature that you'll read, I'd describe the the the Aducanumab studies. Even if you assume that the level of effect on AIDS ecog sum of boxes was actually there, that's not really what we deem a clinically relevant outcome any way. That in itself is also a controversial opinion. That would be an opinion. Who would be arguing against the approval for aducanumab for the general public?

Dr. Koren
Yeah. I'm sorry, just to jump in. Also is the other part of the controversy is really the role of the FDA.

Dr. Toenjes
Correct. That's what I yeah, I was going to go back in because you mentioned the FDA and COVID and it has been very interesting to see how COVID has influenced the general public's understanding of what happens at the FDA. They understand phase three trials. They understand safety and efficacy as main focuses in. And so I, I that is a real plus of something like our learning experience through COVID.

Dr. Toenjes
Unfortunately, when things are within the governmental realm, they are also potentially influenced by controversial behaviors. And so that that is the unfortunate part of of some of the controversy with that of cane of MAB, because patients that I see in their loved ones that I see in clinic, when you start talking about the potential risks of a medication like Aducanumab, which are very real, if there is some uncertainty with regard to our society's watchdog, which is the FDA, that really pulls the the rug out from underneath your ability to to treat patients.

Dr. Toenjes
So the controversy is is unfortunate, but we were just going to have to deal with it and move forward.

Dr. Koren
Yeah. So some people think that the FDA role should be to make sure that stuff is basically safe and the FDA shouldn't get that much involved in terms of determining how good the drug is.  And so in this particular case, this drug, everybody agrees, is, you know, it's okay. There's some potential benefits. If you look at it the right way, you get the right light at the right angle and the data look.

Dr. Koren
Okay. So it's not something that blows your mind in terms of how efficacious it is, like the COVID 19 vaccines, which was clear cut. On the other hand, the FDA determined that this basic safety was good. There's potential side effects, but typically the basic safety of monoclonal antibodies is good because they're very, very specific to the target and they don't do a whole lot outside of hitting the target.

Dr. Koren
So that that was the FDA opinion. And in this particular case, the FDA went out of their way to say that Alzheimer's research has been so difficult, that part of the reason we're approving this is so that the manufacturer can get some money to do further research, because if you keep on trying to do research and you never get a drug on the on the market, you'll never have a return on the investment and they'll never be a reason to do more studies.

Dr. Koren
And I think that was a big part of the controversy. They say that's not the FDA's role to try to support the drug companies. The FDA should be just giving us the facts and they can even decide to approve something. But just say, well, it's not that great, but it doesn't kill you, you know, that sort of thing.

Dr. Koren
And in this case, they went out of their way to say that they they were approving it because they wanted to encourage further drug development in this area and they wanted to be an income source. And then this falls on the payers and the parents of to say, okay, well, they said that the FDA is saying, no, this isn't a great drug, but they still want us to pay these outrageous sums.

Dr. Koren
How much is this drug?

Dr. Toenjes
Well, when it initially was approved, the price tag was 56,000. And then for that's the that's the administration of the drug. There are other costs. Yeah.

Michelle
But is that covered by Medicare?

Dr. Toenjes
When we talk about that, if it's not 56,000, Biogen did some recalculate the case and they lowered the price, I think, to 5550.

Michelle
Okay.

Dr. Toenjes
So they know they passed.

Michelle
All right.

Dr. Toenjes
There are sophisticated means by which we do calculations on how much a drug is worth. And those estimates were more around three or 4000 per person. And after the backlash and and publications like what I just alluded to by Biogen did lower the price of the drug. And they they chopped it in half and half. And so it is approved.

Dr. Toenjes
It is the initial statements from Centers for Medicare or Medicaid Services is that the drug will be covered with a big caveat. Patients have to be in a qualifying study. While many people would still consider the therapeutic, quote unquote experimental, it will be covered if a person's in a qualifying study.

Michelle
Yeah, I was going to say you probably had to check a lot of boxes.

Dr. Toenjes
And we have to understand it's FDA approved to reduce the load of beta amyloid in the brain of a patient with Alzheimer's. It's not FDA approved to alter the clinical course of Alzheimer's. And so you have to look at the fine print of exactly what the FDA said. What does this do? And it does do what the FDA said it does.

Dr. Koren
So the take home message for the audience is that if you forget your keys, you better save your money. That's.