Here, we reveal some of the actual clinical trial data about Aducanumab and Lecanamab, two Alzheimer's drugs that lowered the bar of FDA approval to an all-time low, revealing an absolute disregard for safety and efficacy of novel drugs and their potential negative impact on the American public.
Ethan: Let's talk about Aducanumab, a drug that was conditionally approved by the FDA in 2021 for the treatment of Alzheimer's Dementia, despite the FDA Scientific Advisory Board voting 8 to 1 against it, despite the fact that 3 people on that board resigned after it gained approval. This medication was approved based on what's called a ‘surrogate marker.’ What we know about Alzheimer's is that there is a buildup of a protein called Beta Amyloid. Actually the only [00:01:00] way to officially diagnose Alzheimer's is to get somebody's brain after they've passed away and do an autopsy and see these beta amyloid plaques in their brain tissue. So this medicine was approved based on the fact that it has the ability to remove beta amyloid from brain tissue. Now that may seem like, oh, it's gonna work really well. There were three studies done on it. One of them showed mild efficacy, and I would argue that data was manipulated to an extent. One of them showed no change or no improvement and the third study actually showed negative outcomes or worsening of the dementia. So the idea that we are approving a drug based on a theory that if we remove the beta amyloid, then dementia will get better. There's a lot of other potential reasons why or [00:02:00] how Alzheimer's exists and what the relationship is to beta amyloid. There may be a secondary effect when beta amyloid deposits itself that causes an irreversible change, and it doesn't matter if you take the beta amyloid out later, there may be other downstream effects, or other potential causes. These are theories of how diseases affect us. These are not always tried and true or proven entities. This drug being approved, it was taking a step beyond what we've ever done before, approving a drug that has serious side effects. 41% of the high-dose trial participants had brain swelling. 20% had ARIA, Amyloid- Related Imaging Abnormalities, 1 in 5 had micro-hemorrhages in their damn brains. Trial participants, by the way, [00:03:00] were healthy. They only had early Alzheimer's, to minimize confounding effects. So these are people who maybe had been diagnosed with Alzheimer's, but they are able to live independently. They're able to complete their activities of daily living. So you've got to anticipate that the side effects are gonna be much higher when you have patients with more comorbidities. The other factor is that the cost of Aducanumab $56,000/patient/year. I wonder why it was so high. Probably because they've spent so much money on research and development that this is one of the only ways that they can get some of their money back. Robert Wang, who is an MD PhD, had a response in July of 2021 titled, ‘FDA Perspective Article.’ And I'll just read you an excerpt; ‘the studies have shown that there is [00:04:00] no meaningful signal for clinical benefit with Aducanumab. Instead, the signal is for amyloid removal. Yet the studies for Aducanumab and for prior synthetic amyloid removing antibodies have demonstrated no significant clinical benefit with a sizeable group of recipients developing mild to severe Amyloid-Related Imaging Abnormalities leading to accelerated functional decline or worsening of outcomes. So the justification really should read that bypassing this opportunity might miss minimal improvement for a small proportion of patients at the cost of significant complications for a different larger group, although data are lacking to even prove that minimal improvement.
Michael: What they did is they changed some of their criteria partway through one of the studies, and that was the study that showed some benefit.[00:05:00] So they petitioned the FDA and said, ‘We think that one study was enough.’ And, to my knowledge, the FDA has never done what they did, which is to say, ‘Okay, we'll approve it based upon really one decent study,’ but some clear evidence from the other studies that it didn't work. Rather than make them redo the data and say, ‘All right, let's prove your hypothesis by running a study again. Okay. If you say it's because of the recruitment, then we'll approve it, but now you have to do another study while it's already on the market.’
Ethan: The whole FDA approval process was probably the scariest thing about that drug. We've never had a medicine that had that shitty efficacy, that serious of a side effect profile, that the FDA approved. It's scary for kind of what is to come in the future.
Michael: The manufacturer of the drug said that part of the issue was that midway through the negative study 301, they were originally using lower doses of the medication because of concerns about the ARIA, so partway [00:06:00] through the study, they started using a higher dose and they amended their protocol. So the argument was made that if we had gotten to give more people the higher dose, more people would've had benefit in 301. But that's not something you can prove. They try to go back and edit the data, but, the FDA said that, ‘These were not your objectives to go back and do that. You can't do a subgroup analysis. You can't all do that.’ So really the best thing would've been to just do another study to show efficacy. But rather than do that, the FDA let it go through based upon the current data. The surrogate markers piece, it's been for a number of years that kind of the move away from surrogate markers or surrogate endpoints. Zetia is an example of a medication that was approved for hyperlipidemia (based on) how much cholesterol is there around the vessels, and then that was considered a surrogate endpoint for cardiovascular disease. All the other medications, like our statins, what they really wanted [00:07:00] is let's just talk about how many people have heart attacks or strokes. So every medication moving forward, the punch line is, we don't care about whether or not it thins the lining, Does it keep you from having a heart attack or a stroke? Pretty much every blood pressure, every diabetes medication, That has come out over the last few years, and all the statins, what they're touting is prevention of cardiovascular disease. That becomes the real endpoint there, not just whether or not you have less cholesterol in the vessel. So there's just generally a push away from surrogate endpoints. To then say well, we're gonna move away from this, but for this drug, we're gonna let it slide. That's a big thing, especially because there have been many other medications working on amyloid that have failed over time. You're saying that we know it works, or we know the theory is sound… Well, again, you can't say that because all the other drugs that purportedly did, it showed no benefit.
Ethan: I think if anything, it gives us information about what we know about the underlying disease, pathophysiology and [00:08:00] progression. This helps us to realize that maybe just the deposition of beta amyloid plaques is not the cause of Alzheimer's. It may just be a secondary effect of Alzheimer's. I can design a study to say and show whatever I want. But this historical, and obviously current, method of using a biomarker or using a secondary outcome to show that something works, it's bullshit. Aducanumab, the best primary outcome is morbidity and mortality, or results on cognitive testing. How long do you live and what is your quality of life over that duration of your life versus a placebo or a standard of care treatment? This push, it is, to me, it's solely a way to get things approved to make money off of them. Maybe you are able to [00:09:00] develop more drugs, and that's the benefit of the system. If you throw a dart at a dart board a thousand times with your eyes closed, yeah, you might hit the bulls-eye a couple of times. You might find a treatment that's very effective, but that's at the cost of 998 times touting treatments that aren't effective, that are only hurting people. And here we are in 2023, in January, on to the next monoclonal antibody that removes beta-amyloid plaque and has a little bit better side effect profile than Aducanumab, called Lecanamab.
Michael: In these studies, they had a very rigid protocol for establishing that you had Alzheimer's Dementia, as you mentioned. That is not something that can be objectively defined just on a basic neurocognitive exam. And the best way to do it is to open up the brain and be like, ‘Oh yeah, there we go.’ But obviously that's not something we can do while somebody's [00:10:00] alive. So you have some batteries you can do, but as of right now, that is not the standard of care for seeing people with dementias. A lot of times it's a probable diagnosis based upon presentation history, looking at the time course of symptoms, so in practice those are the individuals that may be diagnosed with mild neurocognitive disorder, mild dementia, but those people did not get in the study. And that's the other thing to look at in many of these studies. When we diagnose a patient, is the patient in my study that I'm reading the same as the patient I'm gonna see in my clinic? And if you can't tell that for sure, you have to be extra careful about using that medication because this may not be the intended audience. They may not benefit from it. They may only get the adverse effects.
Ethan: This Lecanamab, I believe it was FDA-approved in January of 2023. 230 people signed a letter describing Lecanumab as a “foundational advance.” However, most of these people were recent [00:11:00] consultants or grant recipients of SI Biogen. The actual efficacy of Lecanamab; in 18 months, and again, this is the study that we are aware of, this is the study that we've seen, those on the drug declined 0.45 points less on an 18-point scale compared to placebo. This is not compared to the standard of care. So I looked up a study on Donepezil, Aricept, probably the most effective medication (for dementia at this time), and using this Clinical Dementia Rating Scale the CDR, the 18-point scale showed a difference of 0.5 points. So donepezil was more effective compared to this new drug, which has serious consequences and side effects. On [00:12:00] top of that, there were 3 deaths, 3 clinical trial participants with early Alzheimer's. Your life expectancy with early Alzheimer's is over 10 years. An 80-year old man in October of 2022 died in the clinical trial, then a 79-year old Florida woman, and later, a 65-year old woman. So what is it going to take for us to stop allowing industry to drive the drugs that we are being advised to take.