Could the FDA’s Approval of a New Drug to Treat Alzheimer’s Disease do More Harm than Good?

Aducanumab is a new drug designed to remove amyloid in the brain. Following an accelerated process, the Food and Drug Administration approved Aducanumab as a treatment for Alzheimer’s disease despite (what many experts feel) little evidence of effectiveness. In this episode we discuss the approval of Aducanumab with Dr. Jason Karlawish from the University of Pennsylvania and talk about what it could mean for drug discovery going forward.

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Podcast Transcript

Matt Davis:

Aducanumab, Aducanumab. Pop quiz, multiple choice. Is Aducanumab A, the location of an upcoming international Formula 1 car race. B, a popular wellness activity that promotes weight loss by combining elements from Tai Chi with mindful chewing practices. C, Donovan's wifi password or D, none of the above. Answer, none of the above. Aducanumab is a new drug for treating Alzheimer's disease that was recently approved by the Food and Drug Administration. Despite you being able to pronounce it, the approval of Aducanumab has sent shock waves through the medical community. I'm Matt Davis.

Donovan Maust:

I'm Donovan Maust

Matt Davis:

You're listening to, Minding Memory. Today, we're joined by Dr. Jason Karlawish. Dr. Karlawish is a professor at the Perelman School of Medicine and a senior fellow of the Center for Bioethics at the University of Pennsylvania. He's a physician, dementia researcher and accomplished author. Dr. Karlawish's research focuses on the ethics and policies regarding Alzheimer's disease. He's written a column for Forbes and has published two books, Open Wound, and more recently The Problem of Alzheimer's. That explores the history of the science and culture regarding Alzheimer's disease in America. Jason, thanks so much for joining us.

Dr. Jason Karlawish:

Pleasure to be here, thanks so much for having me.

Matt Davis:

Ken Langa from the University of Michigan, who was a longtime collaborator with Dr. Karlawish and friend of this podcast is also with us today. Ken, welcome back.

Dr. Ken Langa:

Thanks Matt, great to be here.

Matt Davis:

To set the stage for the discussion today, we want to give a little background to listeners who might not be familiar with what's been going on. The drug, Aducanumab, is an amyloid beta directed antibody that was developed by the company Biogen. It also goes under the brand name, Aduhelm, which isn't surprising they decided to shorten the name for advertising. The drug is designed to clear amyloid from the brain, which intuitively seems like a good idea. Like any other drug being considered for human use, a series of trials were conducted to determine how well it works and its level of safety.

The Food and Drug Administration is responsible for evaluating new drugs here in the United States. Biogen applied for an accelerated approval. And in November of 2020, the FDA convened an advisory committee of 11 experts. After reviewing the findings from the trials, 10 voted not to approve the drug and one voted uncertain. In other words, no one voted to approve it. Too many people surprise in June, 2021, the drug was approved to treat Alzheimer's disease. So to start things off, I was wondering if we could talk a little bit about what we know about the Aducanumab trials, from my understanding they have not been published in any sort of peer reviewed journal. So what do we know about the trials?

Dr. Jason Karlawish:

Well, we know what Biogen presented in collaboration with the FDA because notably the presentation given at the meeting was a joint presentation by Biogen and FDA, as opposed to two separate packets, which was notable. What they reviewed with the results of two phase III trials, and one phase I trial, and a little bit of safety data from the small phase II study. Bottom line was one phase III trial showed that the drug had an effect greater than placebo in the high dose group. The other trial didn't show that. And ever since the first trial, we've known that the drug does reduce amyloid. So what the FDA was faced with and what America was faced with was a mixed set of data with a lot of need to tease out what's going on try and make sense of results. And there is as they  say, history.

Donovan Maust:

So Jason, when you say one trial had an effect greater than placebo, I think people interpret that as improvement or getting better. Can you just clarify what you mean by an effect greater than placebo?

Dr. Jason Karlawish:

Yeah, no good point. That's doctor talk for being totally opaque. So what you're talking about with Alzheimer's disease is a slow progressive loss in cognitive abilities that overtimes translates in the losses in functional abilities. And so when you're tracking someone over say 18 month’s time, you'll find as a group, the folks with Alzheimer's disease lose more and more points if you will, on a measure their day to day function. And so what the study showed was the folks who got the drug compared to folks placebo, didn't have the same rate of change on that measure of overall function [inaudible 00:04:57], didn't decline as well over time as that.

Matt Davis:

And if you could put, say the amount of change or the reduced decline into clinical context, was it a clinically significant difference in your opinion?

Dr. Jason Karlawish:

That is an opaque question, an answer even more opaque because this is what haunts the disease and the approval so frustrating because what you're measuring is a complicated measure of functioning cognition. And what you're left with is making leaps of inference percentages of gains from baseline. Essentially it was a good example of why longer and better studies were needed to really translate that into a meaningful outcomes in day to day life. But really, I actually don't think that the effect size is the biggest problem here. It's one problem, but it's not the biggest problem. I think the more fundamental problem is just the credibility of the data to make the conclusion that the drug works.

Matt Davis:

What should we know about the study population?

Dr. Jason Karlawish:

Mostly persons who had what's called mild cognitive impairment, meaning clear cognitive impairment, measured with testing and noticed by others, but only dare I say, mild meaning causing inefficiencies in day-to-day activities, not disabilities. Person takes longer to get things done, maybe make some mistake but catches them. As opposed to someone with dementia who makes mistakes and doesn't catch them, for example, and needs someone else to help them. MCI is a legitimate recognized clinical presentation of Alzheimer's disease pathology. Starts out subtly and gets worse. And about 75% of the subjects had the MCI stage. And then another quarter had mild stage dementia.

They were talking about a population of people whose level of disability was more around, as I say, inefficiencies and troubles with higher level instrumental activities of daily living. A very worthy population to go after in an effort to try and preserve function, before they develop more disability. And they all key, they all have to have evidence of elevated amyloid done on a PET scan. So PET beta amyloid is the phrase choice. In other words, it was measured using a PET scan. And if you didn't have elevated amyloid, you could not get in the study. You had to have amyloid.

Matt Davis:

I recall that in your book, you talk about some of the history around that term, mild cognitive impairment, where it came from that I found really interesting.

Dr. Jason Karlawish:

Yeah. It's a risk factor for developing dementia.

Matt Davis:

You mentioned something about amyloid already. So how does this drug in particular compare to other drugs that are already on the market in terms of how it works?

Dr. Jason Karlawish:

Completely different than the drugs that are on the market that are advertised and labeled by FDA for the treatment of Alzheimer's. Those drugs play around with excuse the phrase, they alter level for certain neurotransmitters that possibly make neurons function better, et cetera. In contrast, this drug uses done the logic of immunotherapy techniques to bind up amyloid in a manufactured antibody and clear it for the brain. It's an elegant, mechanism that was based back to the part of the century around the year 2000. Where it's first published and studied in mouse models of Alzheimer's disease.

And it's been a very interesting mechanism to go after amyloid, as well as other protein related diseases. It started out with a bang, the immunotherapy hypothesis. I would say it remains a viable approach, but, I think the initial promise of this is going to clear the disease from the brain and make this disease like a kin to the vaccines for COVID has not played out. And here we are today.

Dr. Ken Langa:

Jason, in terms of this mechanism of action that you're just talking about in terms of amyloid and some of the things you've written, you make the comparison to cholesterol treatment. So a lot of people are thinking about Aducanumab as statin where you're reducing cholesterol in the blood. We know that lower levels of the bad cholesterol reduce your cardiovascular risk. And again, sometimes that analogy is made to the Aducanumab and treating amyloid. Just wondering if you could expand on that a comparison and some of the things that are left out in that.

Dr. Jason Karlawish:

Well, it's a useful heuristic and it's just that it's a heuristic to help understand namely, a drug goes after what we think is a key moment in a disease's pathophysiology. And if it therefore interrupts that pathophysiology or alters that it'll alter the natural history of the disease. And certainly I think, clinical trials have borne that out with altering levels of low density lipoprotein, for example. And so that's the heuristic for what we're talking about when we talk about the same, using this approach to amyloid. But then things get more complex because, I think that at that 0.1 should just stop the analogy and just say, "Well, now what do we know about the pathophysiology that leads to dementia caused by Alzheimer's?" And it's still a work in progress. Amyloid certainly is one actor, but so it was calprotectin.

And in fact, I think some of the real encouraging data from the last few years has been the data that looks at how tau protein changes over time and its relationship to changes in amyloid. And so I think for many in the field, this, "Oh, it's like cholesterol, lower it and you'll do better." It's like, no, no, no, that's only useful to give you this idea of the other surrogate treatment. But beyond that, it's just comparing the pathophysiology of, I don't know, cancer to the pathophysiology of COVID infections. You start to lose the analogy, just breaks down. It's no longer applicable.

Matt Davis:

Most people know amyloid Alzheimer's disease, so it's like this target almost. I have a silly question, to what degree does higher levels of amyloid in the brain actually correlate with cognitive function?

Dr. Jason Karlawish:

Yeah. So this is the entry into why I think the field on one to bed on the night of June 6th thing that the amyloid hypothesis and amyloids a surrogate is a very provocative hypothesis and needed testing. And by the evening of June 7th was Heather Jaws on the floor saying, "What just happened?" Because certainly, there's provocative data that as amyloid accumulates, the Alzheimer's cascade worsens that is to stay tau spreads and you start to see cognitive decline. But what's notable by the time you have disabling cognitive impairment, you really have no further accumulation of amyloid. And a lot of the action now is tau. In fact, when we read an amyloid scan, we just say there's elevated amyloid or not once you get beyond a certain level.

And that becomes very uninteresting. And indeed, when you look at the Aducanumab data, I think the heart of the matter where everyone just again, Jaws hit the floor, was the relationship between amyloid reduction and changes on this cognitive measure, functional measure was a very poor relationship. There was not a strong correlation, not the kind of correlation to go back to Ken's point, that you see when you reduce LDL and see concomitant reduction in the risk of cardiovascular events, like a heart attack, death or stroke. And I think that's where the field is a little bit of gas, if you will. He'll make that leap of a claim that manipulating an amyloid level correlates with a clinical outcome.

And indeed FDA, I think fundamentally agreed because they said, "We're going to give this conditional approvals subject to a confirmatory trial." So already they were saying, we're not that confident about relationship, but we still think it should be put into [inaudible 00:13:00] is again, of course, we notice clinically as well as politically in policy perspective.

Matt Davis:

Is there any else we should know in terms of some of the history underpinning why the field seems to be so focused on amyloid?

Dr. Jason Karlawish:

One point that I feel very guilty of, I confess. I'm guilty, along with others, of saying this, but no new treatment for Alzheimer's in the last 20 years. It's a great rhetorical opening. Just to say, "Well, if anyone can come along with the treatment, I'll take it because it's been two decades." And that statement is factually correct. But I don't think within it is a more important and deeper story. Within that as a more important in deeper story. And that story is that in the last several years, the progress towards being able to see the disease in a living human and test drugs on that individual, and others like Heather has been really spectacular.

And I think that this notion that's had been no new treatments in 20 years. And so therefore we have to approve something, ran ragged over the fact that the last several years we've made a lot of progress and we're getting really close and this approval, which lowers the evidentiary bar for getting a drug out there now really disrupts that progress that occurring.

Matt Davis:

I sort of wonder how much imaging played into part of this too. In your book, you talk about some of the targets in terms of imaging with PET scans and stuff like that. It's like once you see something on a film, the intuition is, well, if it's in there, get rid of it. It just makes sense to go, just like osteoarthritis or something.

Dr. Jason Karlawish:

Yeah, no, and you get the logic of it. I'm not disputing it, but the prove is in the data, no amount of good hunch, supposition, belief in the end drives science. Science proceeds by open public debate and discussion of data, which back to the out the Aducanumab approval, as the hearing that was held in November was a hearing that involved whether the drug qualified for standard approval as a safe and effective therapy.

The approval on June 6th, 2021 used an entirely different regulatory mechanism was no public discussion of the evidence to support that. So it was essentially a secret process that occurred behind closed doors and down in Bethesda.

Donovan Maust:

If you think back to those earlier classes of medications that were approved, the only other FDA approved treatments, how did this process compare to that process?

Dr. Jason Karlawish:

There are weird historical parallels within the cholinesterase inhibitors and these current drugs. And the current Aducanumab store, I should say. Namely the cholinesterase inhibitors were birthed if you will, in controversy and haunted by controversy, including an initial study, that was frankly a scandal. Now, I don't think there are any scandals in any of the studies of Aducanumab. Although I do think the company cut corners with regulatory permission on doing dose finding and some other probably important intermediate steps. But studying aside those corporate decisions, almost repeating some of the aspects of the history of the cholinesterase inhibitors, namely, unclear data over interpreted and driven along by, frankly, an emotional story about desperation, the need to satiate hope. And, frankly behind that of robust business model.

The group that's clucking the loudest about this approval is pharma and the diagnostics because all of a sudden, a lot of money is going to start flowing into the system. And even the critics of the drug will ruefully in status that it's win-win if you will, for the clinics, because now money is going to start flowing into pay for all the things we wanted the last 30 years. And that was the case for the cholinesterase inhibitors, at least that was the theory. But I'll wrap up with what the cholinesterase inhibitors did for the Alzheimer's field was they did build a robust research infrastructure, a robust clinical trial infrastructure. And I think that that alone you could argue was a all right, fine. But I guess my point is that infrastructure was built. And I think now we're seeing it used yet again, more in the service of business than in the service of patient.

Donovan Maust:

Thinking about the process in one of Matt's earlier questions I asked you about the positive trial and how important the positive trial was. And I said, I think you made a comment about the minimal effect was not what really bothered you about the process. Can you fill in what did really bother you about the process?

Dr. Jason Karlawish:

Yeah. So a couple of things, number one, Biogen's skipped phase studies. So they really didn't have a good sense of what the dose of the drug should be. So when they designed the phase III studies, they had multiple doses. Turns out later on, they would figure out what the probably more effective dose was. So protocol amendments around dosing occurred. They knew going into it that eight week carrier status probably influenced both responsive of the drug as well as risk. They amended that because they hadn't really learned enough as well about that from a good phase II study. So skipping phase II in a rush to get to the answers, certainly was a cost to pick the quality data. And then they tossed in, into both trials.

Utility analysis. Utility analyses are not done for patients safety and wellbeing. Utility analyses are done for corporate wellbeing to find out whether it's time to cut your losses and run and move on to the next drug. Well, they did a utility analysis. We could debate the methodology, let alone the use of it. And the utility analysis showed that the studies were unlikely to succeed. They shut them down. Long story, short, more data rolled in. They reanalyze the data and they got the mixed result they got. And what ensued from there was just a series of data torture exercises that were certainly useful to try and better understand how to do the right next study of this drug, because there is a chance that this drug actually works. You just have to better define the population. But instead FDA frankly, went into collaboration with Biogen to figure out how we're going to tease out of a label.

Donovan Maust:

Do you think that if this had been a medication for another illness, do you think that this process would have resulted in the same outcome? Or is it something unique about dementia and Alzheimer's disease that this played out this way?

Dr. Jason Karlawish:

Well, I will make one observation, which is a slight lateral from your question. Of all the diseases of the late 20th century that have had drug development. Alzheimer's drug development has been plagued by controversy scandal and whatnot. There's got to be some underlying theme to explain that other than just independent series of events. DEMA bomb was essentially a fraud out of Russia. There was a notorious event where an investigator essentially fed information from DSMB to investors. We've talked about the cholinesterase inhibitors story. You've just run down the list and say, "What's going on here." And I wonder how much it might be, the high octane emotions that surround the disease and the desire "to do something". That leads people to make bad judgments and I'll offer this reflection.

We knew that FDA and Biogen were working together so we never really spoke up about that. Number one. And then number two, we never really pressed FDA. Like, are you guys thinking about accelerated approval? And I regret that because I think this was all happening. We find out in the beginning a year ago, at least this time, and yet it just happened and we let it just happen. And I actually feel bad about the events that have unfolded. And now the consequence because of the consequences we're faced.

Donovan Maust:

Can you talk a little more about that accelerated review process and how common that is with the approval of new drugs?

Dr. Jason Karlawish:

It's not uncommon in the oncology space and other areas where there's bad diseases, need for better therapy and provocative type of physiologic mechanisms that can stand for a clinical outcome. So it's not unusual. It goes back to the HIV era when doctors were making clinical decisions based on CD4 counts, and they would track CD4 counts to track how sick someone was because that evidence was pretty darn good. And so the argument was, well, why don't we just look at change in CD4 counts to stand for effective treatment? And many said, well, no, wait a minute, does the treatment actually make people live longer and not likely to die? And people they'd said, "Well, what are you talking about? The more CD4 cells I have the healthier I am. Thank you very much." I think at the titer causal argument there.

Anyway, it gave Genesis to these regulations for the use of surrogates to approve a drug in the absence of clear clinical benefit. And they've been used in the oncology space and here now they were used for the first time in the Alzheimer's space. Again, I think these analogies are useful as for respect. So people kind of go, "Oh, I get it." But then I think trying to say the HIV story is the Alzheimer's story is a little like using physics to explain chemistry. They're just different diseases with very different pathologies, very different kinds of events. And I think the leaps of just likes CD4 so to amyloid just like LDL, that's more art and poetry than it is dying, I'm sorry.

Dr. Ken Langa:

And Jason, just to dig a little deeper on that accelerated approval process, my understanding, mainly related to the statements from the advisory board folks that resigned is, that the advisory board was specifically instructed not to consider amyloid reduction as the outcome and that [crosstalk 00:23:05]

Dr. Jason Karlawish:

Yeah, absolutely. You'll find it in the transcript. The transcript that the advisor from Washington University, his name alludes me, about the relationship between amyloid and CDOR, namely the poor relationship that was discussed by Tristan Massie, the bio statistician in his report, and Billy Dunn, who was leading the FDA's presentation, swapped the point of, and he said, " We're not considering that, the role of amyloid at the surrogate for clinical outcome here." And later on his colleague, Dr. Kelsey would reinforce that point. So that was off the table.

And I think that's what makes many people very upset. Not just upset, like,  well, you did... But very bothered about the FDA process because that's come out from staff news reporting on project Onyx, that FDA was in conversation with Biogen about a pathway towards accelerated approval before the November meeting. And so the full truth is not clear and what's coming out is disturbing. Another point in accelerated approval. It's not a consolation prize. It's not a constellation prize and what you sense, What you can read from the memos that FDA has now released is that FDA was divided. One part of FDA, Billy Dunn and his group wanted a standard approvals. Standard approval, safe and effective, market the drug. Another part of FDA did not support standard approval and probably based on their analysis, wouldn't have supported accelerated approval.

And then, Dr. Stein from the office of neuro-therapeutic says, "I don't support standard approval, but I support accelerated approval." And so essentially this decision was not a consensus. It was a compromise and accelerated approvals, not designed for, well, you want that? I want this. So let's meet in the the middle and give it accelerated approval, but that's what happened. It's utterly maddening.

Donovan Maust:

If we can just shift gears just a minute from the approval process, a couple of minutes back when Matt was asking about the trial, you explained that about three quarters were diagnosed with MCI or mild cognitive impairment and an about another quarter with mild Alzheimer's disease. But that's not what the FDA indication is for, correct? And so any thoughts about how the leap from, who was studied in the trials to who it's approved for?

Dr. Jason Karlawish:

Yeah. So good point. So the trails had very well-defined eligibility criteria based on severity of cognitive impairment, presence of amyloid or PET amyloid imaging and indeed a very earlier trial of the drug had been done in a population with slightly greater impairment in cognition with negative. So you've got all these data swirling around, the little label comes out and it says, "Aduhelm is indicated for the treatment of Alzheimer's disease." Okay, you go on. MCI, dementia, severity, presence of amyloid, none of that, it's a very broad open-ended label.

And that means that FDA has essentially left it to the field of medicine. And frankly, the insurers to just decide, for whom is this drug reasonable and necessary. And you could argue, well, FDA is not practicing medicine. They just say, "Look, this treats Alzheimer's disease." And I get the tight conceptual logic. If you think that amyloid is Alzheimer's and changing amyloid across the entire course of the disease changes Alzheimer's. Well, these data are good to go for the spectrum of the disease. Including, I guess you could say preclinical, Alzheimer's disease, namely Alzheimer's with only amyloid and tau and no cognitive impairment.

I mean, if you look at the data, you'd think you're making leaps far beyond the data you have in front of you. And so, interesting, I will say even the most argued proponents of the approval. Stephen Salloway from Brown university, for example, will say, "But I'm only going to prescribe it for persons who fit both the trials or the ability criteria." The Alzheimer's association has endorsed that position. And even Biogen has walked, yes, do you think that that's the right way to bribe this drug? Although somewhat ironically have said that if enough patients are prescribed it there'll be able to lower the price. But, I think [crosstalk 00:27:31].

Donovan Maust:

Great logic.

Dr. Jason Karlawish:

I can't fault the company for doing what companies do. It's like wolves on sheep, that's what they do.

Dr. Ken Langa:

Jason, the health services researchers usually use the term indication creep. When there's an indication for a medication when it's in that population, the risk benefit seems good. If the creep starts happening and you start giving it to people who are lower risk, they're still at risk for the side effects, but not probably less likely to get the benefits. And it feels like they've baked in the indication creep to the approval with the way they wrote the label. But then you also brought up this thing, this entity that we've talked about for a long time preclinical Alzheimer's disease, where folks who have the amyloid in their brain, but, are still thinking normally still not any measurable or obvious decline in cognition. Talk a little bit more about what's coming with preclinical Alzheimer's disease and what this might mean for that.

Dr. Jason Karlawish:

Well, the conceptual logic of preclinical Alzheimer's disease, it makes total sense. You talk about a disease that unfolds over years before someone's got either inefficiencies or disabilities caused by cognitive impairment. And so, it makes sense to try and identify individuals who are on that do use a popular phrase cascade of neurodegeneration and intervene then. I can't quarrel with that approach. I think most reasonable people would agree conceptually, ethically it makes sense. The challenge of course, is to define who are those persons who are quote on that cascade and that's a hot and active area of research. And I hope that most would agree right now it's premature to start using Aducanumab in that population. Although I have no doubt there will be some that will do that. I think we can rest assured with that.

But, the logic would be, identify people on the basis of thumb combination of biomarkers of the disease, tau, amyloid, neurogeneration, et cetera. Intervene with the drug and slow down the natural history of decline. Make sense. Aducanumab could start to be used in that way. I have the hunch that the insurers will make every effort to try and tack that approach down because I don't think a reasonable clinician right now diagnosis preclinical Alzheimer's disease. I have the feeling that that will be a side show with a lot of heat, but not that much light. I think there's greater concern about when do you stop? And the other side of eligible namely persons who are mild to moderate, if you will, in their severity of their dementia.

Matt Davis:

So with that in mind, especially for a population of people that might not have cognitive issues yet, but have some signs of amyloid deposits in their brain. You have to really think about the side effects. The side effects are pretty bad for this new drug, right?

Dr. Jason Karlawish:

Well, they are and they aren't. They're a good example of in a well done clinical trial with adequate monitoring done by people who this is what they do. You can detect the side effect of the micro hemorrhages and micro bleeds early on and stop the treatment early on and pretty much mitigate long lasting disability. Although certainly, some folks have to stop the drug can't tolerate. So I'm not trying to make light of the side effect, but, I'm an internist and I'm used to giving drugs that cause harm, but the flip side is they clearly have a benefit. And that's where things get contentious, I think with this drug. I think though out in wider clinical practice where people are not as healthy as a difficult clinical trial participant, they've got other diseases, particularly hypertension, blood thinners, et cetera.

I think this risk will only become more of a feature of the drugs clinical profile, because it's just going to be a more diverse in terms of disease phenotype, et cetera, a group of people. The one thing you can pick up after approval is safety signals. Once we get people enrolled in registries. For a disease like this, registries are useless to determine efficacy, but they're pretty good for determining safety signals. So we'll see. We'll see.

Matt Davis:

People are starting to roll with this and talk about what this might mean if X amount of people start taking it, in terms of costs and all these types of things. I was wondering just, I would think that brain swelling and hemorrhage as a side effect. The public might be pretty spooked out by that, but maybe not. I don't know, people that are desperate and struggling with cognitive issues. I don't know.

Dr. Jason Karlawish:

I think once you start talking about risk, if a reasonable expert says, look, there is a benefit here and it is possible for individuals to achieve that benefit. Risks become a matter of, I'll use a bad word, but I think it emphasizes the point case, phase. Namely, then it's up to the patient to decide if having you educated me about these risks and benefit, is it worth taking this drug? I think the problem with Aducanumab is we don't even know if it’s beneficial. We don't know if it's beneficial. FDA wants confirmatory trials to show that. I think it's the perfect condition for a clinical trial to enroll people who are otherwise healthy, study the drug monitor it well, really figure out whether this drug benefits really established, whether the amyloid hypothesis, in fact is a hypothesis for treatment.

But that, unfortunately, isn't the case. The drugs out there now with uncertain benefit, a documented risk. And so you're right, individuals will make that choice and some will take it. I have a few patients who want to take it and I will prescribe it to them because I have to respect their self-determination for a disease to take away their ability to self-determine their lives. Really, that's a very fundamental ethic for my practice. I have many though who after they learn about it have said not to prescribe.

Matt Davis:

So just shifting gears, we've been touching on some of this already, but  a step back. What do you think this means for the future? Both in terms of the approval process for medications in general, by the FDA and for dementia, specifically?

Dr. Jason Karlawish:

I think for the approval process for medicines with the FDA, there's a lot of big questions that need answers quickly. And I guess the biggest one is what is going on at FDA and what will be the process for the review of some of the other drugs that are similar in their mechanism in terms of targeting PET beta amyloid measures. And, are we going to see those drugs now pop out with accelerated approval mechanism. And, an evidentiary bar that's been dropped. That's extraordinarily concerning. I think the problem now that we're facing is, we'll have all these different drugs popped out there with unclear evidence about any of them. It'll take longer than if we had done well done studies to figure out whether any of them actually work, because of the inefficiency to trials, trying to be done when something's available clinically.

And that then ramifies in terms of the cost of all these drugs being used, et cetera. I'm very worried about trusting the FDA. I think it's, it's a question I don't want to answer it because I still need to learn more. But I think we need to ask ourselves, "Do you trust the FDA?" And that starts with Janet Woodcock and goes on down from there right now. I think we need to learn more, what's going on there? What are they thinking? How are they approaching drug approval now? Because what just happened doesn't seem to be the way we thought regulatory science function. Secretive, it's quiet, it was not upfront and open and, that needs to be reviewed. And then, we'll see the impact on ongoing clinical trials of other promising drugs.

Will people drop out and instead choose to take this drug. That's a very legitimate decision on the part of someone who's willing to be in research. They say, "Look, I'd rather just get a guaranteed drug. I'll take those risks rather than the risk of the clinical trial." I can't fault that. What we'll see the next six, 12 months, we'll see what the enrollment rates are, what the dropout rates are. And we'll see just how much this is going to put a kink in the ability to do the research we need to do to finally figure out a drug that's a safe and effective treatment.

Matt Davis:

Do you think this is going to perpetuate the focus still on amyloid?

Dr. Jason Karlawish:

For me it hasn't. I remained two cheers to the amyloid hypothesis, very keen to see what happens with tau in this cascade, as well as other mechanisms. To be sure in the short term companies that own anti-amyloid drugs with similar mechanism as this drug are pretty excited because all of a sudden they found a pathway to approval quicker than they thought. And again, I can't fault a company for doing that. I wish they didn't, but again, I can't tell. I keep on using carnivorous animals, but I don't know. I can't tell a rose not to bloom. Stay in your bud, don't bloom yet. If they figure out a way to bloom so be it. But boy, that's why we have FDA and I keep on going back to FDA here.

Donovan Maust:

So to what extent do you think clinicians should feel like they need to offer this thing. Before the FDA's decision, it wasn't an option. And then after it, it suddenly becomes an option, even though the evidence is no different, hasn't changed. I personally struggle with whether it's the right thing offer or not.

Dr. Jason Karlawish:

And I totally hear you and I'm on record, wrote and stat. I said, I will not prescribe it. Well now it's been approved. What are you going to do? And I've said, I'm a reluctant prescriber. And the reason why I'm a reluctant prescriber is, as much as I'm bothered by what FDA did on a number of levels of, science process and policy and the practice of regulatory science, I have to respect their authority, their decision-making. And they have allowed this drug to be out there. And now that this drug is out there, I then have to go to a core ethic of practicing being an Alzheimer's doctor, which is to do everything I can to respect the preserve and defend the autonomy of my patient.

It's really a heteronomous because they're wrapped up in the lives of others. And so, if someone, after learning about all the uncertainties, risks, benefits, as well as the process that led to approval. I think patients need to know the story behind this drug. because I think it informs, this is why it's out there. Do you trust that process? That's a question. And after all that, someone says, "Yeah, I want to do this." I'm going to have to support them in that I feel an obligation to do it. But, I'm a reluctant prescriber.

Matt Davis:

It'd be great to have you back on sometime, another episode to discuss your book, The Problem of Alzheimer's. But just briefly, what do you want our listeners to know about the book and where can they find it?

Dr. Jason Karlawish:

So The Problem of Alzheimer's: How Science, Culture, and Politics Turned a Rare Disease Into a Crisis and What We Can Do about It, is available in hardback, e-book and an audio book read by a wonderful actor. And the takeaway points is, science and culture turned a rare disease into a big disease. And then pretty quickly after that politics made it a crisis. Having said that because politics made it a crisis, actually politics is us. It's humans. And so we can actually address the crisis even right now, even without Aducanumab there's things we can do right now. Having said that though, I don't think we're going a drug our way out of this disease, but I do think we should expect to have effective drug change the natural history. Sadly, back to Aducanumab, that's not this drug.

Matt Davis:

This has been an interesting discussion, lead at night here in Ann Arbor. If you listen carefully, I think you can hear the sound of clicking keyboards among dementia researchers writing new grant proposals. Jason, Ken, thanks so much for coming on. To our listeners, make sure to check out Jason's new book. The Problem of Alzheimer's. The book does a wonderful job in portraying what people living with dementia and their loved ones go through and the history of the disease.

If you enjoyed our discussion today, please consider subscribing to our podcast. Other episodes can be found on apple podcasts, Spotify and SoundCloud, as well as directly from us at cabra.med.umich.edu where a full transcript of this episode is also available. On our website, you'll also find links to our seminars series and the data products we've created for dementia research. Music and engineering for this podcast was provided by Dan Langa more information available at www.danlanga.com. Minding Memory is part of the Michigan medicine podcast network. Find more shows at uofmhealth.org/podcast. Support for this podcast comes from the National Institute on Aging at the National Institutes of Health, as well as the Institute for Healthcare Policy and Innovation at the University of Michigan. The views expressed in this podcast do not necessarily represent the views of the NIH or the University of Michigan.

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