25.4 Deadly Alzheimer's Drugs: Lecanemab... Different Drug Same Story, with Michael Shuman, PharmD

[00:00:00] It's like ripping off a scab. Exactly. When you do this, at its worst, you create an opening between the blood vessel and the stuff that is outside of the blood vessel. That is where you get these risks and these realities of micro hemorrhages or bleeding in the brain. And if there's enough of those, and if they are large enough or significant enough, they're going to cause, at the worst, death and at the best, accelerated functional decline.

[00:00:33] Somebody get this guy some help!

[00:01:10] Well, maybe it had to do with Lecanemab, which in January of 2023, the FDA granted accelerated approval. And by July, they had granted full approval, despite stage two clinical trials of 856 patients not meeting their 12 month primary endpoint. So what did they do? They got a lot of medical advice.

[00:01:38] They extended the study to 18 months, and it got approved based on biomarkers and secondary outcome measures, AKA moving the goalposts again. Again, the term a priori matters is you should establish your goalposts, do the study, is I'm going to throw darts at the board, but halfway through when I realized I missed the board is I'm going to say, hey, can I go two steps closer? Okay. So now I'm throwing darts two steps closer and you've changed the entire competition.

[00:02:06] Absolutely. And what I will say about Lecanemab in terms of its risk is that it does appear that the risk of aria or brain swelling or brain bleeding is a little bit less. Their data, roughly 13%. A bit better, yeah. It's a bit better. I don't know that I fully believe that, especially when you take the actual patient population into consideration.

[00:02:31] But the thing that I think is important to know about the risk is that Lecanemab targets soluble forms of beta amyloid. It doesn't just bind to that, though. It also binds to these aggregates of extracellular beta amyloid plaques. Now, half of Alzheimer's disease patients have a condition called cerebral amyloid angiopathy.

[00:02:55] This is where you can see the deposits on imaging on the insides of blood vessels and what we were talking about earlier. And so when those plaques deposit and they replace smooth muscle cells of a blood vessel, which are integral to that blood vessel wall functioning appropriately in an artery to squeeze to get blood through and then to release.

[00:03:20] When you have that on the blood vessel wall now, and then you remove it, it's like pulling that bug out of the spider web. You're going to take elements of the integrity of the wall of the blood vessel with you, and you're going to cause at best an inflamed wall of your blood vessel, which will lead to brain inflammation or swelling, which is the lesser form of evil that can come from this.

[00:03:46] And at the worst, you can cause a really weak blood vessel, or you could even imagine taking that beta amyloid plaque out may rip the entire blood vessel wall with it. Similar to if you, you know, glued something onto a wall, and then when you take it off, you take the paint with it. Yeah, which is like ripping off a scab. Exactly.

[00:04:10] When you do this, at its worst, you create an opening between the blood vessel and the stuff that is outside of the blood vessel. That is where you get these risks and these realities of micro hemorrhages or bleeding in the brain. And if there's enough of those, and if they are large enough or significant enough, they're going to cause, at the worst, death and at the best, accelerated functional decline.

[00:04:37] And again, then it's incumbent that we are actually doing the monitoring that was established in those studies. And that goes back to the idea about how do we take the intense amount of investigation and monitoring that's in a clinical trial and say that we're going to do that exact same level of rigor in clinical practice. Yeah. And it, you know, it'd be great if we had independent verification of this 12 or 13%, you know, brain swelling number. We don't have that.

[00:05:06] Notably, there were three clinical trial deaths all in the Likambi or the Canumab arm. And there's an open label extension study with a total of about 20 deaths. Again, these are, we're talking about Alzheimer's. We're talking about older folks, but they don't have the comorbidities. They're not expected to die in the next, you know, 12 to 18 months, the length of the study.

[00:05:31] What I didn't realize in what we have seen happen so often in antidepressants, specifically SSRI clinical trials and the risk of suicide, which is very real. And again, kind of like smoking and lung cancer, the industry tries to create a seed of doubt and then hold onto that doubt for dear life.

[00:05:56] But in open label extensions of antidepressant clinical trials, participants are able or allowed to go from getting the placebo. And in the extended phase, they can enter into the drug treatment arm. Because you assume that if they were depressed and they didn't get any sort of treatment, then they may still be depressed and opt into the other side of the trial. If in those trials, we'll talk about this later, more at length.

[00:06:22] But in those trials, if they then become suicidal, it's very easy for the company and the paper itself to keep that data in the placebo group. Because they were originally in the placebo group, even though obviously they never became suicidal until they were given the experimental drug after the study was up. Same thing happened in the Lakanumab clinical trials.

[00:06:51] And one of the three clinical trial deaths was, according to the caretaker for this, I think she was a Florida woman in her mid-60s, she was in the placebo arm. She got her first infusion of Lakanumab and didn't quite feel right.

[00:07:10] And then she got her second infusion and had a rapid decline, was found to have extensive brain bleeds, confusion, word finding difficulty, and eventually started having intractable seizures and brain death eventually. Which is horrible. Yep. And her family opted to withdraw treatment.

[00:07:32] But this open label extensions, they allow for further disintegration of the data because they allow for the patient to opt in for the drug treatment. And then if I don't have access to the original data and the news articles, the investigative reports on this, they still don't know confirmatorily whether or not that patient was in the placebo group or in the drug treatment group. Because that information is not available to us.

[00:08:01] Just to be clear to any listeners or viewers is this idea about transitioning to an open label extension is not unique to this drug. That is a common thing that's done for many, many, many clinical trials. It'd be nice to have access to that data. You know, not all of these deaths are necessarily related to the treatment because you are dealing with a little bit older population. But it's just telling that there's a lot more deaths in the Lakanbe group than the placebo group.

[00:08:25] And as Gami pointed out to me when I asked him about ketamine, you know, he said, I'm not going to say that ketamine causes people to kill themselves. But when you've got, you know, a very small amount of numbers, when you're talking about something like suicide and in the extension of the study, you've got five deaths in the ketamine group.

[00:08:46] It certainly doesn't make you feel super confident that ketamine doesn't maybe have a long-term pro-suicide effect or less confidence in the assertion that ketamine is anti-suicidal. Not to mention this drug, again, is also like adecanumab. It's very expensive. It's very time intensive. I think the average MRIs per year is five of them. That's got to be close to $15,000. You've got to get a genetic workup.

[00:09:16] There's a lot of people who don't qualify for it. You know, there's some fucking back alley bullshit that goes with these drugs in the FDA approval process. The FDA, or I don't know if it was the FDA or the company, they touted this drug as a foundational advance. And they paired that with this letter to the FDA in their petition for approval. It was signed by 230 providers and researchers.

[00:09:44] Wow, that's a lot of, you know, scientists that presented to the FDA in the January 2023 original petition. Turns out the majority of those signers were either recent consultants or grant recipients of higher Biogen. Huh? Funny, funny. The game plan was already set out well in advance. And as you pointed out just a minute ago, in July of 2024, the EMA, or the European Medicines Agency,

[00:10:13] they have a CHMP, or a Committee for Medicinal Products for Human Use, that gives recommendations on market authorization for them to market their drugs to providers in Europe. And offered up one of four of their refusals for market authorization for the entire year of 2024, out of about 130 different medication petitions. And they refused to grant market authorization.

[00:10:41] They cited that the observed effect on delaying cognitive decline does not counterbalance the risk of serious side effects, including aria with brain swelling and significant brain bleeds. AKA, the benefit is too small to outweigh the risks. Well, four months later, the EMA reverses its decision and gives a positive opinion,

[00:11:04] but restricts it to specifically populations that don't have any ApoE4 genetic profile. And this is, it's unique, it's unusual, it's not, you know, unheard of, but it's unusual in that typically only about one out of five EMA appeals are successful. So, you know, it points again to, if you see all the smoke and you keep seeing smoke, There's a fire.

[00:11:33] You gotta assume there's a fire, right? You can't see it, but the confidence is totally destroyed in the institutions and in the regulatory processes. It also speaks to a direct problem with this direct-to-consumer advertising. I mean, do you want any more proof or additional credence that the U.S. mass media on both sides are just promulgating pharmaceutical interests?

[00:12:00] Are they doing their job as actual defenders of truth, defenders of the American public, or are they just promulgating these interests? The key piece here is the way that these things are presented and this idea of relative risk versus absolute risk.

[00:12:21] Relative risk will present a nice rosy number that will make a treatment sound more effective than it is because it's comparing it to a placebo. What you and I and most, if not every patient, actually probably cares about is what is the absolute risk reduction by using this medication?

[00:12:44] So you may have heard, if you've heard any of the ads about lacanumab or adacanumab, you will hear them talk about this 27% less progression of symptoms over the 18 months of the trial.

[00:12:59] This number, it's based on that CDRSB, that clinical dementia rating scale, sum of boxes, which is an 18-point scale that is meant to assess how functional somebody is that has dementia and is used in clinical trials. And it's a good scale to measure functional decline.

[00:13:20] I guess we said that, you know, that is ultimately what our goal is, not just simply to remove plaques, but what does that do for your ability to take care of yourself, to remember things, to live a joy-filled life? We don't just want a certain number of chocolate chips. We want the right number of chocolate chips that predicts the deliciousness of the cake, right? So let me break this down for you. The media will report this is a 27% improvement.

[00:13:47] So let's take an example of a 100-point scale. And Michael creates a drug, and he shows a two-point improvement on that 100-point scale. And I represent the placebo, and I actually improved by one point. So in terms of relative to the drug, Michael's improved two points. I've improved one point.

[00:14:11] The relative risk or the relative impact of that is going to be reported as 200%. His is twice as effective as mine. But if you look at the absolute change, you're talking about a 2% improvement for yours compared to a 1% improvement for mine.

[00:14:33] Therefore, on this 100-point scale of whatever, your drug is 1% better than not taking anything. Yeah, and that's where we have to figure out, though, is that clinically significant? And even getting into the number needed to treat, how many people do you need to then give this drug to to see one person to have this significant benefit? And then factor that in comparatively to what are the risks of harm?

[00:14:59] Yeah, and nobody would say that that is a clinically significant difference. A 1% change, probably not clinically significant. And that's assuming that your drug is completely safe. So let's take what's called the relative risk reduction with lacanumab. So over 18 months on an 18-point scale, the lacanumab group got worse by 1.21 points.

[00:15:29] The placebo group got worse by 1.66 points. So you take 1.66 minus 1.21, and you divide it by the placebo or the amount that somebody would worsen that didn't get the drug, and you get a number that sounds great, 27% better. But if you take the absolute risk reduction, you take 1.66 minus 1.21 over the total points

[00:15:57] in the scale, and I tell my patient, hey, you take this drug, you will have a 2.5% less of a progression in your Alzheimer's than if you didn't take anything. And people say, oh, that's not really that much of an impact, and maybe I don't have as much interest in that. Have you ever heard on those commercials the absolute risk? No, of course not. Or the absolute effect?

[00:16:24] And that goes back to, again, because what we look at with this is the emotional impact. And going back to the direct consumer ads, one of the ones I show in my lecture is, I forget if it was Dinepazil or Mamanthi. I think it was Dinepazil. But one of the ads was very clear. It said, give her the will to fight. And the individual with the dementia was staring right at the image. And it was, the assumption is, if you're not giving this medication, you're not giving your family member a chance to fight.

[00:16:52] And that is a manipulative way of looking at it. Oh, it's so manipulative. And that's the idea is that I want to do something. And that's, and I don't want to say we're preying on it, but if you don't do this, you're not doing enough. Even if it doesn't give them a chance. But at what cost? And again, not just dollars, but some of these adverse effects and quality of life. And what are all the alternatives there? Yeah. And the money that it costs too.

[00:17:19] You're going to pay thousands and tens of thousands of dollars for a drug that's going to lead you to die earlier. One of the headlines initially was, adacanamab will bankrupt Medicaid. Yeah. Yeah. I remember that one. If you're indiscriminately using it, you know, not that I want to put value on human life, but that if you're spending the money on this, you're not doing other things, whether it's behavioral approaches or therapy or memory groups or all the other things we can

[00:17:46] do to improve quality of life. And are we eschewing those other things to put it all into this treatment option? And again, I've got to call out the media because I've never in my life heard the media report about absolute risk reduction or absolute change. You look at historical things in the media, like the women's health initiative study, which initially came out. It was poorly stratified. The methodology was poor.

[00:18:13] And it spit out these results that women's hormones were ungodly, unsafe for everybody. And within six months, you had half of women who were taking a hormone therapy, stop their hormone medication. Well, within six months, there were other researchers who looked at the data and they said, okay, yeah, if you give women who have been out of menopause for 10 years and haven't had exposure to these

[00:18:40] hormones for 10 years, if you give them hormones, they're going to get cancer and they're going to have strokes and heart attacks and have all these thrombotic risks. That makes all the data look bad. But when you look at the women who started hormones while they were still in the transition of menopause, they had great outcomes. They had lower risks of death and mortality and morbidity, but there was no media report on the follow-up.

[00:19:10] It was this widespread campaign. And again, it just seems, I don't know, it just seems targeted to me from a psychiatry standpoint. This is around the same time that all of a sudden SSRI antidepressants became the first line treatment for menopausal depression or anxiety. They're on patent at the time. And, you know, all of the hormone treatments are more natural or, I mean, they're not totally

[00:19:38] natural, but they're much more natural than an SSRI antidepressant point being, they're not going to make as much money. It really kind of denigrates my belief in our media institutions. The other huge factor here is we're not just talking about efficacy and absolute risk reduction or the absolute change in the effectiveness. The number needed to harm. There we go. There we go. There's a number needed to treat and a number needed to harm.

[00:20:06] The number needed to treat is how many do I have to give this drug to, to get a benefit in one person? The number needed to harm is how many people do I have to give this to, to see a harm in one person? Number needed to harm should be in the double digits for any drug that you're trying to use or trying to get, you know, marketed and available and approved. The number needed to harm of lacanumab is three. That's where we have to compare the apples to apples.

[00:20:34] Part of it is what is the outcome we want versus the outcome what we don't want. And if you can critically say the, that gives you a risk versus benefit. Beyond that, there are treatments that are available that have better data than adacanumab, then lacanumab, then donanimab, donepazil or aricept. You know, they have a one year study that shows a relative risk reduction of 38%.

[00:21:00] And it has a known and a studied safety profile. It is extremely safe drug to use. You've got lithium, which, you know, I'm a huge proponent on. There are meta-analyses of the lithium dementia studies, including some clinical trials that show a relative risk reduction of 60 to 65%. You also have the data that bipolar patients who typically get dementia almost a decade earlier

[00:21:29] than the general population because they smoke more and they've got higher obesity rates. They've got higher diabetes. They've got all of these other risk factors for dementia and inflammation. The ones on lithium develop dementia at the same rate as the general population. Yeah, we were talking about this earlier is it is possible that lithium, again, they're still learning about it, but that by regulating phosphorylation,

[00:21:55] lithium can maybe even have an effect on some of these amyloid or tau. I know they're looking into what that actually does, but you said we have some treatments we can use that are dirt cheap, do some really good stuff. And do a great job of preventing this from progressing so that we're not trying to scramble to fix a process that has hundreds, if not thousands of different factors over a lifetime contributing to the development of this.

[00:22:23] And we have this hubris to think that we're just going to be able to give a drug that's going to reverse it in a few months or a couple of years. It just doesn't make sense. I mean, you've got Michael Neils, the German MD, PhD, who has put out the unified theory of Alzheimer's disease that points out, aside from the way that we're living modernly, that Alzheimer's was a rare condition back in the day. And part of that's probably due to us not living as long,

[00:22:53] but even the people who would live that long did not develop Alzheimer's at the rates that we're developing it today. So when he talks about using, you know, nutritional doses of lithium, vitamin D, paying attention to having a low inflammatory inducing diet, increased physical activity. I would really encourage people to look at Michael Neils, NEHLS, Unified Theory of Alzheimer's Disease.

[00:23:21] It is not something that is going to be propagated by mass media because it's not going to make anybody any money, but it is very sound. It's written by a MD and a molecular biologist that understands these things on a genetic and a molecular level that I couldn't possibly begin to understand like he does. And again, I have not read the book, but the idea of the same interleukins,

[00:23:48] well, I will keep beating that drum, but IL-1, IL-6, TNF, alpha, these same things that are inflamed in diabetes, which, again, I'm going to talk about insulin, and cognition, and depression. The same idea that inflammation is bad, and you find ways to modify the inflammation through diet, through exercise, that will help. Chronic inflammation is bad. Yes.

[00:24:15] Acute inflammation when you're sick is a good thing. Right. As we get ourselves to our immune fighters, we get them to the site of action. And it says, hey, Michael, I'm sick, so I'm going to stay at home and not come out, because I don't have the energy to, and not come out and infect you. Yeah. But then chronic, right, chronic inflammation is tissue destruction. Simple as that. Absolutely. So, you know, there are three deaths at minimum in this lacanumab clinical trial.

[00:24:44] I always think, what about nonfatal? I mean, you use the parallel of when we talk about the opiate epidemic and the drug epidemic, we focus on people who have died in fatal overdoses. That's a huge number, which is absolutely tragic. I mean, you're talking about 100,000 plus a year, which dwarfs any other country in the world. But what about all the people who don't die from it?

[00:25:09] What about the people who go from, you know, the normal 6 to 12 breaths a minute to 3 or 2 breaths a minute, who don't quite die. They don't have a fatal outcome. But they wake up in the hospital, and they're completely childlike. They're not able to communicate anymore like they were in the past. These are people that I've seen. The same type of situation must exist with people who have a certain degree of swelling

[00:25:39] that doesn't get to the point of herniating or of hemorrhaging and dying from it. But they almost certainly have to have functional impairment as a side effect of the drug. You know, it's not just deaths. That's not all we're talking. We're talking about people's livelihoods, their ability to enjoy their lives. And we're talking about a condition that people are going to live for a decade, if not two decades.

[00:26:07] We want to know what is the 5 and 10-year mortality morbidity measure for Alzheimer's disease. And we won't know that for several years. We want to see results that are verified and reproduced by another independent entity. If we're talking about creating an accelerated, that's the whole gamut here is, well, we need to have an accelerated approval process because we don't have effective treatments. Well, we've already said we do have effective preventative treatments.

[00:26:35] But compare it to something like ALS. That condition is going to kill somebody in months, maybe at best a couple of years. So if I have ALS and I understand there's risks with a new experimental drug, I may be willing to take those risks. But what people don't realize, what patients with Alzheimer's don't realize, they're being promised something that could take the rest of their life away.

[00:27:02] And a lot of that life could be very, very enjoyable. There's so many patients with Alzheimer's who, out of a 30-point cognitive test, they get a 25 or a 24 out of 30. All the points they miss are the five points that are, hey, remember these five words, and I'm going to ask you about them in five minutes. And they can't remember that. But they can still go to Pilates. They can still play with their grandkids.

[00:27:32] They can still volunteer or even work in certain capacities. You're assuming we even diagnosed the Alzheimer's correctly. Exactly. Right. There's a lot of assumptions that go into this. You know, we didn't talk about Donanamab, but I just assume it's the next in the long line of iterations. I saw something that said that it was maybe even had less effectiveness or something like that. That's good. Right. Right. All right. You want to try to give like a little bit of a summary of our discussion here tonight?

[00:28:00] I think one main story is, again, the idea that as we look at conditions, we need to be as objective as we can. Some conditions that have a lot of, whether it's negative press, a lot of emotion with it, we still need to ascribe to a rigorous scientific model of how we evaluate these drugs. We've got to be consistent in that model of how we determine what is, you know, an appropriate clinical trial. And did they follow that trial?

[00:28:30] And if there was a deviation, we still need to have the time to go back and do that study again rigorously. So in the case of 301, a repeat of it, we need to acknowledge, you know, this is a good, you know, microcosm of the issues with scientific design is, and then, you know, risk and benefit and looking at the number needed to harm versus the number needed to treat and determining is the drug more likely to harm or to help. And we need to be able to do that as objectively as we can. Some of the objectivity, again, is being willing to acknowledge that it's going to take time.

[00:28:59] And even though we really want this drug to work, if it is not going to be beneficial, or if there are some serious side effects, we need to acknowledge that. We also need to make sure that the scientific community is objective. And again, we're not giving that one person so much power to where they can manipulate slides for 20 years and build up a theory that we then have to call into question, but also then in independence of looking it up.

[00:29:24] So that we're not entirely looking at people's livelihoods or, you know, 30,000 employees of a company who are all dependent upon this drug getting approved, but we can make sure that there's an organization that can simply say, did the drug work or not? You know, and it's not tied to stock prices or it's not tied to people getting fired or not. If I had five words to guide one directive, and if I could have this over anything else,

[00:29:51] give us the original data. Five words, yes, I counted. Yes, that's five words. On everything. That's seven words. If every single study, everyone had access to the original set of data, then it would be a lot harder for companies to get away with manipulation, for the regulators to get away with not regulating,

[00:30:15] and for us to buy into the bullshit that is consistently spewed out to us, telling us what to believe about safety and efficacy of drugs that that data just doesn't support. Yeah, so you're going to give me your family's cookie recipe is what you're saying? Exactly. Yeah. Exactly. So, moral of the story, put as many chocolate chip cookies in whatever cake or pie. Thanks again for watching and or listening.

[00:30:43] If you're passionate about the subjects that I discuss on the channel, do me a favor and like, comment, subscribe. Do whatever you can to make your voice heard that these are problems that must be addressed in our society. If you have any questions, comments, or concerns, I want to hear them. Feel free to reach out on social media or email us at renegadesyke at gmail.com.

[00:31:13] And if you'd like to be a guest of the show or you have a connection to somebody that you think would be a good guest, let us know. Thanks again for listening.