 and on a clock, this is Think Tech Hawaii, I'm Jay Fidel. That's Mike DeWerke, Dr. Mike DeWerke, he's our Chief Scientist here at Think Tech. And we're talking about the approval of the Alzheimer's truck. This is very important because there's a lot of people in this country that have or will have Alzheimer's and it's a very tragic experience, very hard on everybody involved. It's awful if you know anybody who has somebody in the family who has Alzheimer's, it is progressive and ultimately it gets you. Anyway, Mike, we've all been waiting for news about Alzheimer's drugs. I know so many people who follow it, they wanna know every step in the science and now we have a step in the science but it's a disappointment. Can you talk about it? Sure, sure. I happen to be the primary caregiver for a Alzheimer's patient. Alzheimer's disease affects something like five million people in the United States, two-thirds of them are women and more than two-thirds of the caregivers are women. When you talk about home health, it's daughters, sisters, wives. This is a huge problem and it affects women disproportionate. Although it affects men too. For the elderly, Alzheimer's patients, about half the caregivers are husbands and half are spouses when you look at spousal caregivers. So this affects a lot of people. It's a devastating, long-term intensive debilitating disease. Average time to death from diagnosis is like 10 years although some patients can get a point with horrible disability ongoing. So yeah, it's a serious, serious problem and it seems to be getting worse. There's some slight evidence that the incidence is starting to level off, that the incidence isn't growing exponentially the way it was. We'll see how that plays out in the coming years. Risk factors include obesity, diabetes, pollution, turns out sunlight, sun exposure. So, well, we can go through some of the slides and talk about some of these issues. Yeah, let's do that. Are the slides? Yeah, we have the first slide up is, I do Kanumab or I do Helm and it was approved and that's your first slide. Yeah, that's the title. So, I'll talk at least measurement of how you measure cognitive decline. Alzheimer's disease is a whole bunch of different ways to measure cognitive decline and you can't use just one. Well, there's several systems for measuring cognition in patients with dementia. MMSC, the many mental state exam is one of them. There's a couple of flavors of it. The original one by Dr. Fulstein, so one that the Cochrane committee looked at these tests used. There's a maximum score, it's a paper-based test, simple questions like, what day is it? What time is it? What year is it? Where are you? Can you say a complete sentence? Can you remember a few words? Can you copy a drawing? Basic test of cognitive function. The maximum score is 30 points, usual cutoff for dementia is 24, but that's very dependent upon the person in their history. If I scored 24, I'd be absolutely terrified because the cutoff should be higher for people with a higher educational level or people have received good privileged care through their lives. So it's a useful test, but it can't be used by itself to diagnose dementia, but where it's really useful is in determining the rate of cognitive decline, comparing someone from year to year and how their state is going. For people with medium onset Alzheimer's disease, it's about two MMSE points per year are lost. And it's a subtle difference. Two points can be a subtle difference. You would almost have to live with a person just to see just two points, but it's useful then. So on the next slide, I'll show you one of the problems you have with doing Alzheimer's trials. The next slide should be saying Alzheimer's seasonal variability. Turns out that you lose on an average two points per year, but the difference between summer and winter can be five years worth of decline. And these range is about two to eight years. Some people between the worst state in the winter and the best state in the summer show eight years equivalent improvement. And the overall trend over the long term is inevitably down, but that's seasonal effects pretty big, which means you have to do trials over many years to make sure you're seeing a real effect. The Adducanumab trials were six and a half years, which is about what you have to do. And the effect is really large. And this also might explain some of the anecdotes you hear about, oh, my auntie took this drug and my auntie felt better in six months. Well, when did she start taking it? It really depends. You can't just use a few months worth of data because of the seasonal effect. But is this trying to telling us that it's less of a decline in the summer, in the fall and the autumn in the winter or in the spring? So spring, you hit your bottom. It's like the weather, the climate lags the day length. So you start to go up again, let's say in March or April, you hit bottom in like March, and then you start going up again as the days get longer and longer after the equinox. And then over the summer, your cognition improves and hits top sometime like September, typically. And then start to decline again. So in the autumn, early autumn, you see a peak and the early spring, you see the nadir. So there's a big sunlight effect. And so you've got to account for the seasonality when you do the trials. And so these multi-year trials, they're expensive, they're lengthy, but that's what it takes. The next slide, I talk a little bit about the geography, geographical effects of sunlight. It turns out that the closer you are to the equator, the less likely you are to get Alzheimer's disease, at least in the Northern Hemisphere. Southern Hemisphere, there's fewer people, fewer trials. Trends are less clear. New Zealand, it's clear, but some other countries, it's less clear. But in the Northern Hemisphere, it's very clear. Farer the you are from the equator, the more likely you are to get Alzheimer's disease. And it's not mediated by vitamin D, because vitamin D supplementation seems to have very little effect unless you actually have a deficiency. So there's something else going on with sunlight or day length that's causing cognition to decline if you don't get enough of it. So if you do a clinical trial, you've got to have controls and test subjects matched geographically as well as with time of year, as well as probably racially. It turns out that because the sunlight effect, the known extra risk that African Americans have for Alzheimer's disease may partly be because of the sunlight exposure on the skin, but also may be caused by other things like poverty or healthcare pollution, other known risk factors. But the point is you've got to match geographically and you got to match season-wise and you got to match ethnicity to do these trials properly. So that makes them very expensive time-consuming trials. But lucky we live Hawaii, you have to have Alzheimer's disease. Hawaii is probably one of the best places to have it because you have a lot of sunlight, you got good personal healthcare, your decline will be a bit slower, but still inevitable. So let's, this is all background so far. So the next slide says amyloid plaque hypothesis and in my opinion, it's failure. Beta amyloid plaques are correlated with Alzheimer's disease. That's data, that's true. A risk for developing dementia is twice as great with amyloid than it is without it. But the risk of developing dementia with amyloid plaques isn't 100%. A lot of people, even in their 80s, about 40% of people without dementia in their 80s have amyloid plaques and they don't have dementia. 40% of the non-demented people have amyloid plaques without dementia. So that's an unproven hypothesis and every drug that they've tried that can actually affect the amount of amyloid that they can test for in the brain in a spinal cord has failed. It's failed to show clinical improvements in cognition even when it has cleared amyloid. And in my opinion, these adduham trials also failed or at least they have not proven what they're claimed to have proven. So- Can I have Alzheimer's without having amyloid plaques? There are people who adamantly say no. You can have dementia without Alzheimer's plaques. They will not call it Alzheimer's without amyloid plaques. So there's plenty of cases of dementia without amyloid and therefore they don't call it Alzheimer's disease, which to me it just shows how ignorant we are what the underlying real causes are. I think that underlying other hypotheses, alternate hypotheses need to be explored more and all the researchers are doing is professional Alzheimer's researchers are starting to do this. The idea that amyloid may be a reaction to some other underlying causes of disease. For example, there's just been a recent paper that pure iron and copper nanoparticles which are known to be toxic have been found in the brains of Alzheimer's patients. Hypothesis is that the amyloid plaques may be the brain's way to try to protect itself from these toxic metal nanoparticles. Hard to do the studies. So hypothesis that needs to be followed up. There are other treatments that don't attack amyloid directly that have been shown to have a modest small effect like galantamine which preserves acetylcholine which is a very important neurotransmitter has been shown to reduce the rate of Alzheimer's progression by about 10%. So you're looking at two points per year versus 1.8 points per year cognition loss. It's a very small effect, but it has proven and these acetylcholinase inhibitors are less side effects than the aducanumab that was just approved. So in the next slide, I actually talk about these trials. This drug has to be given intravenously, medical supervision of course. You can't just take it, fill it home. It's got to be done intravenously. Benefits are only seen at the highest doses in the least impaired patients. So the average many mental state examination score for patients that showed a benefit was 26. So that is sort of above the cutoff for Alzheimer's but other tests you can do can say, oh yeah, this person's starting to show Alzheimer's. And of course they also tested for amyloid. So they knew they had amyloid plaques which I could say is not necessarily going to always go to dementia. So this is an evolving story. Wikipedia article is getting updated almost daily. So that's a good place to start for the source information. 90% of the patients in these trials showed adverse effect events. Some of them were very severe like these amyloid related imaging abnormalities. They were required to do MRIs twice a year on patients getting, well, they did on both placebo and patients getting the drug. And if you showed these imaging abnormalities in your brain, which could lead to serious damage if they were allowed to progress, those seem to stop for those patients. When the FDA approved this drug, they gave no guidance at all on MRIs and testing for these aria, these amyloid related imaging abnormalities which in my view is just a gross negligence. They also gave no guidance on the stage dementia which to give this drug how to select the patients. And anyway, so there were two trials. They called them Emerge and Engage. They had about 1600 subjects each. They were identically designed. Engage, the control or placebo patients declined slower than expected. That trial showed no effect, no statistically significant effect on cognition. Engage, the control placebo effect declined faster than expected. It showed an effect, but only at the highest doses in the least impaired patients. And on top of it, they changed the high dosing regime partway through the trials. So that the patients on the high dose regime weren't exposed to the same dosage as the whole trial. Normally you would use those data and say let's do a whole new trial with the right dosing regime. And normally you would combine these two trials to get better statistics. That's not what was done. They did a sub-analysis on just the Engage patients in the high dose regime. And this has the appearance of cherry picking to get a desired result. Yeah, the results are so ambiguous. The studies so, in my opinion, poorly done that the FDA advisory committee would attend nothing to reject the approval of the drugs. They wanted them to go back and redo the trials. At the dosing regime, they were claiming had an effect. The top brass of the FDA overrode that recommendation. And that- Why is they overriding? Let's go to the next slide. Yeah. Yeah. Oh, I had to help. It should be out of helm. Sorry about that. That should have been out of helm on that slide. This drug costs $55,000 a year. So there's a big financial incentive for the company to sell it. Medicare is not allowed to negotiate drug prices thanks to our wonderful Congress. So we're on the hook for it. And they'll get that. Doctors get a percentage of the drug price. So I don't know how many doctors will prescribe the drug out of financial motive. I hope none. But there is a financial motive here and a financial motive for being counters in hospitals to try to get this drug into practice. In my opinion, it takes money away from other treatments. But people are so desperate, so desperate for anything that might help with this disease that there was a lot of lobbyists on the side of the patient advocacy side pressuring the FDA to approve it, as well as, of course, the company pressuring the FDA to approve it. What more company is this, Michael? I'm not sure. I think it's Biogen. I'll have to look that up, though. Okay. Yeah. So the benefits, even with generous interpretation of the system is because you have given them the benefit of the doubt on the one trial maybe that really high dose regime that they went to for part of the trial really will show an effect. Even with that generous interpretation, the benefits are modest. The risks are significant. And this is probably a false hope. I really think that this whole amyloid plaque hypothesis as the cause of Alzheimer's has to be questioned and other causes looked at. I mean, they've been beating this amyloid plaque hypothesis horse for decades. And so far there's been no, and it might be not even this drug has been shown to do it. There's another underlying cause for this disease that we have not yet sussed out and found a way to prevent retreat. By the way, it is Biogen. Biogen, okay. Yeah. Well, okay, I mean, this is not a pretty story. Now, of course it's really terrible to reject a 10 to zero vote of your expert advisory committee, but what's worse is that you're subjecting people to not only the cost and that's like an awful architecture, but also the risks of side effect, bad side effect, pretty serious business. And it's just, it's an awful story. You wouldn't use it, you wouldn't recommend it. And certainly from this discussion, I wouldn't either, but the problem here is this is the federal government. The federal government who did whatever it did in the case of COVID, the federal government, who has done a number of drugs that maybe weren't so good. Now we have all these protocols, all the science, all these very heavyweight guys who is there, holding the public trust and approving drugs and the problem here is public confidence, don't you think? Right, I agree, I agree. I mean, they did such a good job with the COVID vaccines, making sure those trials were tight. You know, we had like 30,000 people in each trial, very low risk of side effects, very high efficacy. It did such a good job on that emergency approval. And this was not an emergency approval, this is a full approval for a drug that shows at best modest effects, serious side effects are very expensive. The difference is astonishing between the two cases. What different organization, right? This is the FDA rather than the CDC, right? Well, I know the FDA had to give the emergency approval for the vaccines. So it's the same organization. Same organization. So I mean, yeah, it's, now the advisory committees recommended approval of the vaccines once they saw the data. And the problem with this aducanumab is that originally they were going to not bother getting the approval because when they originally did the studies, they weren't showing any benefit until they changed the protocol halfway through and then did a sub-analysis on the subset of the data. So there aren't peer-reviewed tapers out there yet for us to look at. I would love to see the actual primary source peer-reviewed paper with all the data presented as it was presented for the vaccines for COVID. I mean, it's just a very frustrating situation. Oh, I'm sure. So, you know, I mean, you're not the only one who's gone through this kind of analysis. And I really wonder what kind of pushback there has been from the scientific community, the ones who look at the protocols and look at the internal workings of the approval process. What has come out? Well, three of the members of the FDA advisor can be just resigned to disgust. And there's been a lot of pushback from other researchers that, you know, this drug is expensive. It's not showing a benefit. The trials were not convincing. The trials should be redone with the protocol at the higher dose regime in place properly. Et cetera. There's other drugs, like I say, galantamine does show an effect, but it works differently. It works by preserving neurotransmitters instead of trying to attack amyloid. I mean, it's a horrible tragic situation that we're faced with Alzheimer's disease. But there's a saying that a drowning person will grab the blade of a sword. That's where we are. That's where we are. We're going to sword instead of a life ring to people. And they're going to be injured, you know. You think this drug takes us further down the path? I mean, your description of, you know, what we know about the disease leads me to believe that we don't know that much. I'm going to go handle on it. I would agree with you on that. I mean, I'm not a professional Alzheimer's researcher. I happen to read up on a lot because I'm a caregiver for an Alzheimer's patient and I have some skills in terms of looking at peer reviewed papers and I'm a scientist in a different field. But the thing is that we don't know a lot. I mean, there's so many different scoring regimes. There's so many different staging regimes. We don't even know how to assess the stage of Alzheimer's disease properly. There's a whole bunch of different methods for assessing how the progress of somebody and what the prognosis is. It just shows how ignorant we are of what's really going on. It's not like the periodic table where we can look at row column and say, yeah, that's the chemical property of that element. That row, that column is probably this. We just don't really understand this disease. That's what I understand from what I've read. And I think the whole amyloid plaque hypothesis. Now, they're trying to salvage the amyloid plaque hypothesis by saying, oh, there is a subset of amyloid called oligo amyloid that is particularly toxic, but we can't test for it in a living patient. It's like, okay, if you can't test for it, how do you know that any treatment you give actually has an effect on it? And then understand whether that effect shows up in the cognitive scores. So the gold standard shouldn't be amyloid in the brain or amyloid in the spinal fluid. The gold standard for this should be cognition. It's got to show a clinically significant cognitive benefit to be a treatment. And I don't think, yeah. This doesn't really take us down the path very far. In other words, my question is, is there any value in this line of research, this line of dealing with Alzheimer's or is this just a spurious bunny trail kind of exercise? I think from what I read, what I understand about the amyloid plaque hypothesis is it's a bunny trail rabbit hole that got down. And unfortunately, we're going to find out by experimenting on the population at large. If millions of people end up getting this drug on clinical practice and to start reporting back progress and side effects, we're going to find out whether this drug, when you test on millions of people has an effect. If it doesn't, then that's, I think, the death of the amyloid hypothesis. I mean, they should just shut it down, that line of investigation. Well, what about the government? You talked before about public confidence and this is certainly not a statement in favor of public confidence. If you were running the FDA, what would you do here? If you were a scientist, expert, dedicated to this field, what would you do? I guess there have been peer reviews that have criticized it, but query, what do we do when we find the FDA has made a gross error? Well, the FDA can resend their approval or they can modify it with a black box warning or they can provide more guidance on MRIs and testing to make sure that the side effects are being monitored, none of which they did. And there's been calls to the resignation of the top three people, the FDA, who are responsible for this approval. You got to really follow the science. You got to have rigorous science, especially when you're talking about something that millions of people could potentially be having to take as a drug. What about overseas, Mike? What about overseas? I don't know, I haven't looked at any overseas trials. I don't know if they've sought approval in Britain or the European Union or Japan for this drug. I would be stunned if the European regulators approved it. They are as careful as the American regulators usually. So... Very tragic story and I wonder what is ultimately going to happen here. It sounds like it's going to be a bust. And what it reveals, I think, in terms of the approval process is we have a corruption, maybe a series of corrupt phenomena that work in this area. One is that Medicare thing where you can't negotiate with the drug company. Two, the drug companies, of course, have huge lobbying resources and they play that out all the time. Three, that it works, even if the drug doesn't work. This is not a credit to Biogen, for sure. Right, right. It's not a credit to their executives for pushing this approval as opposed to starting a trial. Now, a trial is expensive, but people's lives are at stake. You could be generous with the FDA executives and they were listening to the patient advocacy groups who were demanding something to help people. You could say, oh, but it's a misplaced compassion. It's a misplaced compassion and that this is an uncontrolled experiment now that can be foisting upon these patients. Yeah. Do they ever have trials after the drug is approved? For example, they can... Not bad. Oh, yeah, I mean, it's like with the COVID. They continued the trials after the approval of the vaccines. The problem with... So they could continue the trials. They could do a new trial. The problem is just giving it to patients is that only people who are showing symptoms, a cognitive decline will take the drugs. There's no control. There's no control group to compare to, really. I mean, because you got to do an intravenous infusion. All the circumstances are exactly the same, except one group gets a placebo, the other group gets the drug. Because if you just get intravenous infusion, that alone might give you a placebo effect that could, if you're in the early stages, help override some of the decline. Placible effect is very powerful. So, yeah, the fact that this is an IV drug, that it's very hard to do, you've got to do a real controlled trial in a clinical setting to have it work. But now that the drug's been approved, who's going to sign up for a clinical trial where they might get a placebo? I mean, that's just... That's a good point. It's just a whole mess. And it's racially... Let's assume there was negligence in the approval process. Let's assume there was a corruption in the approval or a number of them. Is this the kind of thing that could ever be subject to a class action suit by people who will have been injured? Sure. I mean, I don't know how protected the drug company is. With the FDA approval, they're more protected than they would have been. Could they sue the government for approving it? Possibly. That's hard. However, I'm not a lawyer. So not being a lawyer, I can't really state what the odds of a class action suit are if people are injured by the side effects of this drug with given how small its benefits are. Yeah. Oh, she was very interesting. So from where we stand now, last question, where do you think this is going to go? Both in terms of this drug, and the name of it is Adu Kanamab. And the street name is Adu Helm. Adu Helm. Where do you think it's going to go? And the other question is, where do you think, when all this shakes out, where do you think public confidence is going to be in the drug industry and in the FDA and the National Institutes and the CDC and the government apparatus for approving drugs? Yeah, this is a national tragedy because it will harm public confidence. Especially if in clinical practice, it really turns out that this thing has no significant clinical benefit and shows significant risk of harm. I'm not recommending it for my dementia patient. Her doctor isn't recommending it to me either. We're both appalled, but there are other doctors in Hawaii who aren't so appalled by this approval, perhaps out of desperation for anything that might help. My thought is that, no, I'm going to do what I'm doing to get my Alzheimer's patient out in the sun as much as possible, and make sure she gets good nutrition because that's known to help. Try to manage the cognitive decline as best we can because the decline right now is still inevitable. Now, some of these people, you put them in a home or in a nursing home where they never get outside to see the sun works no longer, no wonder they're suffering faster cognitive decline. Some of these facilities seem designed to enhance cognitive decline. So treatment managing the care is where we should be putting our resources right now until we get a better hypothesis and a better class of drugs that might actually treat the cause of the disease. We do not understand the causes of this disease. That's my takeaway. And we should really be focusing on treatment that better palliates manages the symptoms and the decline. And I'll tell you my takeaway from all of that is there are two problems that you described that are very troubling. One is that there's a disparity in the community on who gets Alzheimer's. I think that's clear, racially, economically, and so forth. And it's just another reason to be concerned that these disparities exist and we can't seem to resolve them. That's a problem for I'm sure a lot of people. And the other is, we've just had this crisis. We are having this crisis over COVID and you and I have spoken about it many times. And there's people who resist taking the vaccine. They say that they have hesitancy. Some of them have Trumpitis. But the problem is that this is not going to help in Joe Biden's efforts to get people to relax and accept the advice of government because government has been nicked on this. And I think- Yeah, I think it's been nicked. Yeah, and- I agree, I agree. The other thing is that you're a scientist and you're also a caregiver. So you're gonna delve down as obvious that you have. But what it tells us, if you're about to take a drug that you don't know about or more of the point that's a new drug with new approval after tests that you may find out are questionable or that are being questioned, you better do your research, man. If you don't do your research, you could be in the line of fire for something like this one, which I agree is tragic. So there's all kinds of fallout from this. Yeah, and I'm lucky that I have the skills to do this research, to understand the evidence. A lot of people don't. And a lot of people's caregivers, family members don't. So that's the real tragedy. They're gonna be exploiting people who can't evaluate the evidence. Well, thank you, Mike. This has been a very valuable discussion. I certainly appreciate your work and your willingness to share with us. And I look forward to our next discussion together. Mike Dworkin, our Chief Scientist. Thank you so much. Thank you, Jay. Thank you. Thank you, Aloha.