Narrator: Coming up on Mayo Clinic Q&A,
David S. Knopman, M.D.: But it's trying to maintain function and
daily life and maintain as much independence as possible.
Alzheimer's disease is a devastating illness that can
impact the lives of those diagnosed and their loved ones.
Recently, the FDA granted approval of a new Alzheimer's
drug to fight this illness. Our experts weigh in on the
effectiveness of the new drug.
Ronald Petersen, M.D.: I believe that part of the FDA's response
here was that this is a fatal disease. People will progress,
they will die from this disorder, and we do not have
anything else right now to offer them.
Jacob Strand, M.D.: Welcome everyone to Mayo Clinic Q&A. I'm
Dr. Jake strand sitting in for Dr. Halena Gazelka. Earlier this
week, the Food and Drug Administration approved
Aducanumab to treat Alzheimer's disease. Aducanumab, targets
amyloid plaques in the brain that are believed to be an
essential component of Alzheimer's disease. But 6
million people in the United States and 30 million people
worldwide are currently living with Alzheimer's disease, a
progressive brain disorder that is the most common cause of
dementia. What does this news mean for Alzheimer's patients?
Here to discuss is Mayo Clinic neurologist and director of Mayo
Clinic's Alzheimer's Disease Research Center, Dr. Ronald
Peterson, and Mayo Clinic neurologist, Dr. David Knopman.
Well, let's start with you Dr. Peterson. Can you just tell us a
little bit about what this drug is designed to do to help
patients with Alzheimer's disease?
Ronald Petersen, M.D.: Sure, Jake. So, Aducanumab is a
monoclonal antibody that is designed to be infused into the
bloodstream, get into the brain, and remove amyloid plaques from
the brain. Two of the defining features of Alzheimer's disease
are the presence of amyloid plaques, and tau base tangles.
This drug is designed to get the amyloid plaque out of the brain
or at least reduce the amount of amyloid in the brain.
Jacob Strand, M.D.: That's really helpful. I imagine a lot
of patients when they first heard the news that there was a
new treatment for Alzheimer's may have been envisioning a pill
or some other pills that are used for Alzheimer's symptoms
that some may be aware of. You mentioned this as an infusion.
What does it look like for a patient as they might be
available for a treatment regimen? What does that mean for
their treatment course?
Ronald Petersen, M.D.: So, if a patient were to receive this
drug, he or she would come into a medical facility, have an
intravenous line put in the arm, and then sit there in the chair
while the drug is infused for about an hour, and then watched
for a little while and then dismissed. So, it does require
an infusion, usually at a medical center. Occasionally,
there are these home infusion services. So, conceivably, it
could be done at home. But generally, it's done in a
medical center to monitor it for safety.
Jacob Strand, M.D.: That's really helpful, and I think
maybe just turning a little bit to some of the news recently,
because I imagine there's a lot of questions, and I know you all
have been fielding lots of questions. You know, this was
subject to a pretty intense debate. I work with a lot of
patients who have already asked some of my colleague's
questions. I have family members who have Alzheimer's disease,
and they're calling with questions. And so maybe Dr.
Knopman, I could ask you, can you talk to us a little bit
about some of the debate around this? I know it's hard to put
into words, but maybe we can talk about it and how you will
talk to your patients about the risks and benefits.
David S. Knopman, M.D.: Right. Thanks, Jake. Well, it's been a
very contentious discussion that's been going on for two
years. And it would take hours to describe all of that. But
briefly, the studies on which this approval was based were
terminated prematurely, or terminated back in March of
2019, when the company initially concluded that the drug did not
show benefits, they then changed their mind. They presented it to
an FDA advisory committee with the approval of the FDA
leadership in November of 2020. The Advisory Committee roundly
rejected the idea that it had clinical benefits, to be very
blunt. And then the FDA leadership took this under
advisement. And then with their report on Monday, they approved
it in what's called an accelerated approval, in which
they based the approval on the fact that it lowered brain
amyloid, even though the clinical benefits were, let's
say, uncertain. And that then is that segue to what I would say
to patients. Even though my opinion might be clear from what
I just said, I will offer it to patients and will discuss it
with them if the patient and family brings it up. But I will
present both sides. What its possibilities might be for
slowing decline of disease, never bringing about
improvement, by the way, and the possibility that it may have
minimal benefits and let them decide.
Jacob Strand, M.D.: Well, I think that's really a helpful
piece as we think about, you know, maybe this next step,
which sounds like there's even going to be because of all this
disagreement, another clinical trial, and maybe Dr. Petersen,
can you tell us a little bit about this additional clinical
trial, since it wasn't approved based on efficacy, they're gonna
do another trial about efficacy. What is that going to mean for
patients?
Ronald Petersen, M.D.: Well, it's an interesting situation,
because the drug will be available clinically, so
physicians can prescribe it and patients can receive it. But as
Dr. Knopman indicated, the FDA was uncertain as to the clinical
utility of the drugs. So, they're requiring the sponsor,
to do a phase 4 study, another study using the drug and seeing
if it produces a clinical benefit. And if it does not, the
FDA will remove the drug from the market. But during the
interim, the drug will be available to patients. So, it'll
be incumbent upon the clinicians then to really describe the
pluses and minuses of this situation. And hopefully, the
patients and families will make an informed decision as to
whether they want to undertake the treatment with the drug or
not.
Jacob Strand, M.D.: Yeah. And maybe we can put within that,
that kind of back and forth and these pros and cons. I know,
there's been certainly as a person, not an expert in the
field of Alzheimer's disease, but again, taking care of a lot
of patients where that's really a key facet in our life. There's
a great deal of fear about this diagnosis, and certainly a
significant societal impact. And there's also been, you know,
hopes before of other drugs and even sounds like other drugs
that have impacted these amyloid plaques. Dr. Knopman, what does
this mean for kind of the history of these drugs? And can
you talk a little bit about this idea that amyloid plaques, we
haven't shown there to be benefit yet? And so, what does
that mean for patients who are hoping for something that may
help even if it's uncertain?
David S. Knopman, M.D.: Well Jake, that's a really good
question. And I think that this FDA approval, has made the
situation actually even more complex, because it raises the
possibility of what I think psychiatrists call therapeutic
misunderstandings. In the lay press, one might have the sense
that this drug brought about improvement. And there's no
question that it never improved patients. At the best, it
delayed progression. And we have experience with that in our
field. It's with the existing very modest cholinesterase
inhibitor drugs, that it's very difficult to see, delay, and
justify or understand, or appreciate delay in progression.
And the other issue, which we don't have hours to talk about,
is whether the lowering of amyloid realistically has any
prospect of eventually bringing about clinical benefit. We
recall that these studies were 18 months in duration, and they
didn't see clinical benefit. Yet the FDA approval was on the
expectation that at some point in the future, it would. But to
me, that seems like a real promise that is going to be
difficult to fulfill.
Jacob Strand, M.D.: And maybe that's a really important
question I could ask Dr. Petersen as a follow-up, you
know, this idea of these short duration, we know that patients
live for many, many years with Alzheimer's disease. You
mentioned a little bit about this additional clinical trial
that will take place, and the fact that that will be a
challenge because there'll be people also able to instead of
you know getting the drug or maybe a placebo, they can go to
somewhere where they can get the drug prescribed potentially.
What sort of surveillance is the FDA and the companies and the
healthcare systems going to do to see if 36 months you know,
five years down the line, if this has shown benefit? Do we
have any information about that yet?
Ronald Petersen, M.D.: Yeah, it's an interesting situation
Jake as to how the FDA will make the decision ultimately. They
base it on the the outcome of the phase 4 trial, but clearly,
there'll be a lot of data generated by the clinical
community over the timeframe. And I think it's incumbent upon
medical systems, Mayo being one of them, to generate reliable
and valid data. So, I think we are going to develop a program
that is designed to determine which patients might be most
eligible for the treatment, and then we will follow them very
closely clinically to determine what, if anything, is happening
with the drug clearly from a safety perspective, but also
from an efficacy point of view, that is the drug stabilizing
their clinical condition. Now, keeping in mind, we'll just have
to use historical controls, like how would people have progressed
over this timeframe if they were not treated with the drug. So,
that will be a challenge. The company is also establishing
registries around the country to follow patients in a more
organized fashion, whether that's going to produce useful
data, I think, remains to be seen.
Jacob Strand, M.D.: I think the hope, of course, for a lot of
patients, I heard an interview with members of the public and
members of societies advocating for patients and their
caregivers with Alzheimer disease, that, you know, we
don't really feel like we have anything and so something is
better than nothing. And we can argue about that and the cost of
that, both to the patient in terms of time and also from a
cost perspective of the drug itself. But what I hear in those
comments is this hope that this is just the beginning, that
maybe this will help spur other types of therapies. And I wonder
if you could share, Dr. Peterson, I'll ask both of you
this question. What else is on the horizon? And kind of taking
from this the lesson of this kind of very complicated issue?
Ronald Petersen, M.D.: Yeah, I might just comment Jake, on your
earlier observation that this may be just the first step in
this direction. You know, Dr. Knopman mentioned that decades
ago, he and I were around when cholinesterase inhibitors were
introduced to the market. The first drug out there was
something called Tacrine, which had a relatively short shelf
life on the clinical field, because it was really not very
good. But it did open the door for other cholinesterase
inhibitors. Granted, they're just symptomatic medications,
but three others followed, have been FDA approved, and now we've
been used for many, many years to try to stabilize some of the
symptoms. I kind of view this in the same perspective. That is,
this is the first of the disease modifying therapies. I think
there will be others coming down the road, and probably better,
and then it'll remain the question of are these disease
modifying therapies actually effective at what they're doing?
So, I mean, I think it's going to be an interesting story to
follow. We're getting more sophisticated with regard to our
evaluation of appropriate patients for these studies. I
think our measurement techniques are getting better looking at
the biomarkers that categorize people. So, you know, I'm
optimistic that we're going to learn a lot more. And I believe
that part of the FDA's response here was that this is a fatal
disease, people will progress, they will die from this
disorder, and we do not have anything else right now to offer
them. And so, I think that that entered into their decision as
well.
Jacob Strand, M.D.: Yeah. And thanks for reflecting on that,
and I think this piece about these other therapies, Doctor
Knopman, maybe the same question for you. What do you see on the
horizon?
David S. Knopman, M.D.: I'm more impressed by how the need will
generate new ideas. And putting out a therapy that may have
minimal benefits, I don't think will particularly accomplish
that goal. I think the key is to find better targets for therapy
50 or 60 years where cancer chemotherapy was in the doldrums
with relatively few benefits. And then along came the
checkpoint inhibitors and other agents that were specific for
particular mutations in solid tumors, and boom, all of a
sudden, you're seeing real benefits. And I'm not sure that
the decades of treating with the traditional antineoplastic
agents really enabled that process as much as the continued
need of the failure of those agents ultimately, to bring
about real benefit. And that's how I see the situation here.
It's the need to have better therapies. And I do think that
in my capacity in reviewing grants of phase 1 and phase 2
studies in this field, that there's tremendous ferment
underneath in the biology of the disease and finding better
targets. And so, I'm hopeful in the future, that we'll get lucky
and find one that's much more potent than Aducanumab.
Ronald Petersen, M.D.: You know, Jake, if I may comment on Dave's
observation. I think he's quite right, though this might be the
first step such that ultimately, I think we're going to use
combination therapy to treat cognitive disorders and aging.
So, it may be that while amyloid modulation may not provide a
significant clinical impact, with it being on board, we might
add, say, an anti-tau or an anti-tangle agent. And that
combination may very well be effective. Whether you need the
amyloid backbone on which to treat the tau, so I think it
opens the door for a variety of other combinatorial therapies
that might be developed in the future.
Jacob Strand, M.D.: Well, maybe kind of a last question, you
know, one of the things that I think both of you have hit on,
which is so critical is this idea that we're all still
struggling to figure out what the best outcomes to look at
are, and how we take care of patients ultimately, And I think
I'm certainly believed by the idea that Mayo Clinic continues
to lead in figuring out the right biomarkers and the right
way to follow patients so that we can really target these cures
to the right patients. And something else that I just
wanted to ask about is how, maybe if this made an impact on
a specific score, or, you know, cognitive decline, it didn't
show, what does it mean for quality of life? And is that
something that will, as an outcome measure? What is the
difference it's making in people's functional status and
their quality of life over time? Do we have a sense of where the
state of research is in following a drug like Aducanumab
for those types of endpoints?
David S. Knopman, M.D.: Which I'll go first here, I think
that's really a key question. And we don't really know the
answer exactly. Personally, I think that it's how people do in
day-to-day affairs, that counts. I don't really care as much
about a mental status exam, except if it confirms what we're
hearing from the family. But ultimately, we'd like
stabilization of function at a high level of near independence.
We don't know what we would ultimately settle for if that's
the best we could do. But it's trying to maintain function in
daily life and maintain as much independence as possible. That
ultimately is the key, and we don't really know how much of
that is enough.
Ronald Petersen, M.D.: Yeah, yeah, it really it really comes
down to what's called clinical meaningfulness. So how do you
measure that? How do you measure how a person is functioning?
Actually, here at Mayo, Dave and I are involved in a study called
the Mayo Clinic Study of Aging, where we're following people who
live in the community here in Rochester and Olmsted County.
And this is a random sample of people as they're aging in
place. And we are capturing a good deal of cognitive and
functional data on them. And I think we're in a pretty good
place to offer some reflections on what constitutes a clinical
meaningful scale, and we're trying to contribute to the
field in that respect.
Jacob Strand, M.D.: Our thanks to Mayo Clinic neurologist Dr.
Ronald Petersen, and Dr. David Knopman, for joining us today on
Mayo Clinic Q&A.
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