25.3 Deadly Alzheimer's Drugs: Aducanumab's sketchy Accelerated Approval, with Michael Shuman, PharmD

[00:00:00] Let's rewind the clock after talking about some of the background in research around neurodegenerative diseases. And let's go back to June of 2021. The FDA grants accelerated approval of Aduhelm, or adacanumab is the generic name, by a combination of pharmaceutical interests in Biogen, which is a U.S. company, and Esai, which is a Japanese company.

[00:00:28] Interestingly, the U.S. and Japan were two of the earliest adopters approving this medicine. Well, you don't say. I want one of those hmm emojis to pop up here. Yeah, so we have Nicolas Cage doing his little... Yeah, yeah. Somebody get this guy some help!

[00:01:16] Or, put more simply... If you need help like this guy, call your own doctor. And so it was approved based on a biomarker or a surrogate marker in its ability to remove beta amyloid, despite previous clinical trials on plaque reductions not showing any clinical benefit. And the FDA cited that it is reasonably likely to predict a clinical benefit.

[00:01:46] Even though conscientious and independent scientists have stated that these drugs don't provide any clinical benefit, the use of a biomarker or a surrogate marker is nothing new. It actually goes way, way, way back in time to the use of statins that reduce cholesterol markers. Yeah, again, we're not going to test for a specific outcome, but we're going to test for something that is an indicator that is highly correlated.

[00:02:13] So one of the ones that's been used for a while today about LDL lowering as a surrogate for cardiovascular disease, or atherosclerotic cardiovascular disease, or for deaths due to MI or other cardiovascular events. And so that's something, you know, the statins, the idea was these lower LDL. LDL lowering has been shown to have these outcomes. And they actually compared it to another medication that came out around a couple, around the same time. I forget the name of it, but which raised HDL.

[00:02:43] We know raising HDL is good, but raising HDL has not been associated with improvement in mortality or these ASCVD or these outcomes. So that is not a surrogate marker. So a drug really can't be shown to have a positive cardiovascular effect, even though it raises HDL, LDL lowering. The other one was when it came out was azetamib or azetia. What it specifically worked at was looking at atherosclerotic, the thickening of the plaque.

[00:03:10] And so they worked at, I think it was the tunica intima, and they showed a thinning of the lining. And the problem though is not all the studies showed an actual LDL. A thinning of the lining of the inside of a blood vessel. Correct, yes. And so, but then actually looking at the LDL lowering of those drugs was a little bit trickier. And those actually ended up being a drug that did not show a cardiovascular benefit in terms of outcomes. And so that's one of these, the two drugs. So the statin became then the gold standard there based upon this drug lowers LDL.

[00:03:39] It's also been shown through the lowering of LDL to have these positive cardiovascular benefits. Therefore, this drug doesn't just treat an endpoint, but actually has a benefit in terms of morbidity and mortality. And you'll hear people talk about how statins are not nearly as effective as they are marketed. That the actual, you know, primary outcome, which should be how long does somebody live? Or how often do they have a major debility from something like a heart attack,

[00:04:09] which has a large association with the amount of plaque that you have lining your arteries? That's the real outcome measure that we care about. I don't know enough about it. I know there's some people who say that, you know, the statins aren't even worth the side effect risk of them. But I think there is probably better data on the statins than there is on something like the monoclonal antibodies for Alzheimer's.

[00:04:32] And we have, we found ways to mitigate some of the myalgia risk with statins, whether it's using a low dose or using resuvastatin or giving it every other day. Some of these CoQ10 or some of these vitamin D to mitigate. And so we have these certain factors that even shift the risk versus benefit a little bit more so. So, yeah, I just wanted to get a little bit of historical information about how this is not the first time that we've used a biomarker. It's a kind of out of the playbook of big pharma.

[00:05:01] And actually, to that point, the FDA, you can even go on their website and they have a listing of approved biomarkers or approved endpoints. And there's a whole bunch of them that are used. And some of them are very basic, like, you know, presence of, you know, an antigen representing that you have hepatitis or that you don't have hepatitis based upon an antigen test. And so some of them are very like, well, duh. And again, other ones are a little bit more esoteric.

[00:05:27] And so the idea here about, you know, this amyloid plaque reduction as a biomarker or a surrogate endpoint for improvement in dementia. Yeah, the theory is not proven enough. So let's jump forward to Atacanumab 2021 when the approval came out. This is a drug that is $56,000 a year, not covered by insurance.

[00:05:49] They recruited early Alzheimer's disease patients, a.k.a. healthy patients without comorbidities with what's called or deemed mild neurocognitive impairment. A big question there is what percent of actual total Alzheimer's disease patients in my patient population, like we've talked about so often, have no comorbidities.

[00:06:12] That probably is not a great population to study when you want to look at the safety, especially of a particular drug class. And with that, too, is the idea about, again, to enter the study having a – the way it is diagnosed. And that's been the tricky thing about Alzheimer's. I have seen the term just thrown out there.

[00:06:32] Again, whether it's cognitive impairment or just this person is on a lot of antichlorian medications using the term Alzheimer's dementia without really having a lot of concrete reason for it. So the problem, too, becomes they had a very formalized process for inclusion into the study that, again, is are we going to the same granular level of identifying our patients in practice?

[00:06:57] Do we have access to the same level of testing and imaging and practice that we have in enrolling people in the study? Probably not. So that's the trick is are we then using it in a much wider population than in which it was originally tested? And do you trust the randomization process of the company that stands to benefit financially from their study looking good? Did they recruit slightly healthier patients to the adecanumab group?

[00:07:25] Alzheimer's is a clinical diagnosis. You don't see dysfunction on an MRI. Definitely not initially. Again, I'm not saying this has happened. I'm just, you know, positing that it is possible that you could recruit really healthy people to ensure that you're getting the most likely population to show that your drug is safe.

[00:07:52] And then maybe you recruit patients who are a little bit more, you know, clearly have the developing early kind of signs of Alzheimer's in the placebo group. If you can find the patients that are right on the cusp of starting to decline a little bit more rapidly, that's perfect for your placebo group because you're definitively going to show a difference between drug and placebo at that point.

[00:08:16] This is a drug that has a 33 to 40 plus percent risk adecanumab of what's called ARIA. And as you pointed out, ARIA sounds so nice, right? It's a songs and... Game of Thrones character that everybody loves and wants to see do well. And so ARIA stands for amyloid-related imaging abnormalities. It sounds a lot nicer than what it is. What if I said micro hemorrhage?

[00:08:46] Exactly. So Boston University neurologist and neuroscientist Andreas Chiridimow said, we need a name change because these are not just imaging abnormalities. These are things that cause brain swelling and brain bleeding. And you and I have talked about this.

[00:09:08] If you imagine beta amyloid, which aggregates into plaques, so clusters of beta amyloid. And these things can deposit in a lot of different areas. One place that they can deposit is in our blood vessels. And if you've got a drug that removes that from the wall of a blood vessel, or if you want to think of it as a hose, from the wall of a hose, it's probably when you pull that out.

[00:09:37] Just like if you tried to pull a bug out of a spider web, it's going to be really hard to pull the bug out without messing with the integrity of the web itself. That same thing happens with beta amyloid plaques that are lining blood vessel walls.

[00:09:56] So when they're pulled out, it creates a blood vessel wall that is either inflamed and contributing to inflammation, aka causes swelling, if you're lucky. Or if that wall is thin enough and you pull that plaque out of it, the drug does, then you may create a break in the wall or a very weak wall that when it gets the hit of a high amount of arterial pressure,

[00:10:23] will break open and then blood leaves your closed system and starts to spread out into the brain in what's called a micro hemorrhage. And this is exactly what we saw in the people who die in the clinical trials. So at Acanumab, there was a 75-year-old clinical trial female participant that died from aria. Again, brain bleeding from multiple micro hemorrhages.

[00:10:53] And it makes you wonder, what is the spectrum of neurological issues that don't reach the severity of death with these drugs? What are the other issues? What is the confusion or the cognitive decline that can happen because you're introducing a secondary problem even though you're claiming that you're treating the primary problem? A lot of the hypothesis now we're looking at so many conditions are predicated on inflammation.

[00:11:23] So anything that produces a pro-inflammatory state within the body generally can be problematic. Yeah. And this is, again, I've got to point it out for the fourth or fifth time, the patients that were recruited didn't have comorbidities. They didn't have diabetes. They didn't have high blood pressure. What happens when you throw the general public and not these kind of carefully hand-selected healthy patients into the mix?

[00:11:52] Most people with Alzheimer's are not as healthy as these clinical trial participants. This might be a good time to talk about study 301. There are several of these studies. There are study 303, which is one of the early phase two studies. Again, you go through the phases and you start to go from working with healthy individuals to small groups of your intended population to a larger, more robust study within your intended population. Study 103, the positive phase two, there was a later study 302 that was positive.

[00:12:22] But study 301 is the big one that created a lot of the controversy, which was a negative study. So what happened was they were very concerned about the risk of aria. So there was a genetic markers they looked at, and so one of them was called APOE4. And individuals positive for this APOE4 were considered at a higher risk of hemorrhaging and having bleeds. And so initially it said we're going to use lower doses of adacanamab for those individuals.

[00:12:49] So eventually, though, partway through the phase three study, they said, you know what, we can use a higher dose. And in this case, the higher dose was 10 milligrams per kilogram. And they said we can safely use 10 milligrams per kilogram in those individuals, even if they're APOE4 carriers. But they did that partway through study 301. And so they did an amendment. They said, OK, moving forward, people are going to be on this higher dose.

[00:13:12] The problem, though, is by that time they had already enrolled more people in study 301 than 302. So study 302 ended up having more people with the amended protocol, and study 301 had fewer people than were in there that benefited from that change. They said we hypothesized that that's why study 302 showed benefit, and study 301 did not. But the problem there is, again, that's just a theory.

[00:13:39] And so they came to the FDA, and they said, OK, even though study 301 was negative and 302 was positive, we can tell you why that happened. And that's why we should include that study and really only look at a certain subset of study 301. That's a somewhat unique way about looking at it. So we have one good study, one very negative study. We think there's a reason why. What should happen is you should start at square one, rerun the entire study, right?

[00:14:09] A priori, then we're going to say we're going to use 10 mix per kg in the APOE4 carriers. We're going to design a new study, and we're going to see. Because if our hypothesis is true, then that study should be a success. And if I was independently regulating you, then I would make you do that. But if you are funding me behind closed doors, then I'm going to let that slide. Yeah, they also tried to use the phase 2 study, and they said way that heavily.

[00:14:38] And so the FDA was kind of where the debate was. They said, we don't think that you can use this phase 2 study, 103, which is positive, and outweigh this negative study, 301. Because again, these later phase 3 studies are much, much more robust. And then also, again, the idea about whether or not the theory is even sound enough. Because we're saying, well, this is all predicated on, again, that the amyloid hypothesis is correct.

[00:15:03] Which even up to this point, many medications have failed to show benefit in other places. This really is the first drug even to get approved out of many, many drugs targeting different places. Some of them work at different levels of the size of the amyloid. There are so many different types of beta amyloid, specific peptides and proteins that have been identified as potential targets.

[00:15:31] That's kind of what Karen Ash was saying that co-authored some of the Lesney papers was, you know, don't throw the baby out with the bathwater that all beta amyloid is incorrect. My bigger critique is like maybe when the beta amyloid is laid down, and after it is, you know, no longer in soluble form and it forms these plaques, maybe that's where the damage has been done and is somewhat irreversible. Yeah. And so the problem, though, is again, we've got drugs that work on the oligomers, you know, monomers.

[00:16:01] So different densities of these plaques. If one of these drugs thus far, adacandib, had been approved and the others hadn't, I think what that shows us is we're still refining our theories, so we have to be very careful about using that as a biomarker for a condition until we know more about that. We haven't quite established that this is predictive of functional goals in Alzheimer's. Yeah, and it probably was kind of similar to the statins at that time, right?

[00:16:29] But now we have more evidence, definitely more evidence than the monoclonal antibodies that reducing LDL leads to a reduction in your stroke risk, leads to a reduction in your heart attack risk, and therefore an overall improvement of your morbidity, mortality. Though I would add that you probably also could just, you know, for most people who don't have genetic forms of high cholesterol, they could probably just eat better and exercise better, and they would get to the same outcomes without the risks of the side effects.

[00:16:59] Yeah, I'm actually going to read a quote here. So this is one of those from some of the FDA reviewers. They said, there is no compelling correlation between effects on amyloid beta plaques and effects on CDRSB. And CDRSB is the clinical dementia rating sum of boxes, which is one of those big outcomes. So there's no correlation between the plaques and effects on that at the patient level. But then at the same time, when they approved this drug... It's based on the CDRSB and a 27% improvement.

[00:17:28] They said the relationship between amyloid beta plaque reduction and CDRSB for adacannabat was consistent with the relationship observed for other compounds targeting amyloid beta. However, none of those other, against me speaking, none of those other molecules made it through to approval because of safety outcomes or due to efficacy. There is insanity. We're saying this drug works because it proves the amyloid hypothesis, but it's also the first drug to prove the hypothesis. So here's another very straightforward.

[00:17:58] You don't have to be a scientist to understand this one. The FDA scientific advisory panel, an 11-person panel composed of really, really well-respected scientists, clinicians, researchers, they voted 10-0 against this drug being approved by the FDA. The FDA totally ignored their recommendation and approved it anyway.

[00:18:27] There was one person who voted... They didn't vote yes for approval. They voted uncertain. And after all this played out, people on that panel were fucking pissed. They were like, why am I doing this if my opinion in all 10 of our opinions, 10-0, 100% of people voted against, well, 10 out of 11. The other person didn't vote for.

[00:18:52] But Aaron Kesselheim was one of three individuals on that panel who resigned after this. Aaron Kesselheim is an attorney and a physician teaching at Harvard. I don't know if you've ever heard of Harvard. It's a small school. It's a small school, but apparently they do pretty good things over there. He said in his open resignation letter, criticizing the FDA and their decision,

[00:19:17] that it was probably the worst drug approval decision in recent U.S. history. I believe it. He added that accelerated approval is not supposed to be the backup that you use when your clinical trial data is not good enough. I don't know how you say it any better. But there's a couple other people who tried to. One of them is Robert Wang, private practice, MD, PhD, internist with 40 years of experience.

[00:19:46] He's worked as an average citizen, right? Exactly. Your average primary care physician that specializes in the geriatric population, has 40 years of experience as an MD, a PhD, is based in Los Angeles. He wrote a great response to some FDA perspective article on trying to convince people like you and me why it's a good thing that it got approved, even though it was 10 to zero voted against it being approved by the scientists.

[00:20:12] So Robert Wang says, studies show no meaningful signal for clinical benefit with adacanumab. The signal is for amyloid removal, but this has not demonstrated significant clinical benefit with a sizable group of recipients developing mild to severe amyloid-related imaging abnormalities, leading to accelerated functional decline.

[00:20:40] So the justification really should read, bypassing this opportunity might miss minimal improvement for a small proportion of patients at the cost of significant complications for a different group, although data are lacking to even prove that minimal improvement exists. That goes back to, I think, some of that emotional argument, which is we don't want to miss out on this.

[00:21:07] It could be helpful for people, and we'd be really afraid to miss out on this, which again goes back to being careful to bypass data and logic because of this emotional, which again, this is a really sucky condition, and we don't want it to happen. So if there's a chance that this drug could work, we want it to happen, but at the same time, should we bypass the rigors of the model we've already established?

[00:21:32] And I am all for individuals being allowed to make the decision that they think is best for them, even if I think they're making a bad decision. So if you have an individual with Alzheimer's who decides, and them or their family, they decide that they want to be in this trial with all of the data up front and in front of them, and that says, you know, this isn't likely to improve you very much, but if you want to try...

[00:22:01] The reality is that we have to have people in our society that are willing to try new drugs to get the data. But I'm not going to subject any of my patients to that through any sort of manipulation or any sort of leaving out details about what might happen to them. If they decide they want to cross that bridge with understanding of the risks, a.k.a. actual informed consent, then I am all for it.

[00:22:30] But otherwise, we are subjecting people to a very dangerous drug or drug class, offering them the promise that they're going to be rehabilitated, that their condition is going to change. And with that, I think it's a concern too, that again, making sure that, you know, many times the drug is approved and it goes into a market utilization far outside of what it was using. I believe they were doing PET scans to identify the amyloid plaques for these individuals.

[00:23:00] How often are you referring your patients for PET scans? Lakanumab, the protocol for that, and the reason I know this is because they tried to recruit one of my patients. They tried to recruit her for Lakanumab for the infusions, and she was going to have to go through all of these different MRIs. It's an average of five every year, which the cost of an MRI these days is about $2,500, if not more.

[00:23:28] So that alone, you're talking about $15,000 for the MRIs alone. But it's a very specific process. They've got to get all the genetic markers of ApoE. I think where we're going with it is the idea that releasing it to a market where we're going to expect you, if you're being on this drug, to spend thousands and thousands of dollars in these extra costs that you may not be aware of.

[00:23:51] Or maybe the worst thing of it is we're going to be releasing it and utilizing it in individuals where we have no idea of their ApoE4 status. We may not even know if there are signs of amyloid plaques because we're not doing the PET scans. And we're maybe not doing that REM monitoring. I think they mandate that stuff. For somebody to get the drug, they have to go through and make sure they're not double ApoE4, which is a positive thing. Like, I will grant that.

[00:24:19] But again, you're putting a lot of onus on, you know, it has to be done this way. But again, is it going to? Or are you going to, you know, like anything, are you going to release it? And then there's going to be a lot of kind of on-label, kind of off-label utilization. That's the issue with it. Is this drug going to find it into the market, the population for which it's beneficial? Or is it going to be used for a lot more? And therefore, again, from a societal cost perspective, both safety and efficacy, are we going to lose out on?

[00:24:48] Nancy Olivieri, she wrote an opinion article on this titled, Nothing is Right About the Approval of Atacanumab, dot, dot, dot. And Nothing's New. So Nancy Olivieri, the reason why she is in such a good place in terms of her experience to respond to this, is her background is in a drug called Diferaprone.

[00:25:12] And so Nancy Olivieri is a thallus or was a heme-onc specialist, a thalassemia researcher. Thalassemia is a condition where a protein doesn't function properly or the genetic variation of the copies that somebody get are not functioning properly in terms of creating blood cells.

[00:25:34] And so these people can have abnormally functioning blood cells that they don't work like they're supposed to to carry oxygen from the lungs and out to all of the other tissues of the body. And in major forms of it, they can lead to fatality within a couple of years. So she developed this drug, Diferaprone, in 1989.

[00:25:55] And she partnered with this company, Apotex, a pharmaceutical company, with the CEO, Barry Sherman, to help fund and run clinical trials in kids because it's a relatively rare disease. In 1991, just two years later, she recognized some major safety issues. And she said, we got to pull the plug. But the CEO of Apotex, Barry Sherman, he threatened her. He said, we're going to sue you.

[00:26:23] If you go public, we're going to, you know, degrade your reputation and threaten all this litigation. Which is all part of the scientific process, right? Exactly right. Nancy Olivieri said, I don't give a fuck what you do. I'm going public anyway. Did she actually say that? No, she didn't. Oh, okay. But that would be wild. That would be wild. She said she de-gapped. She de-gapped. She says, we're pulling the plug. Went public. And Sherman targeted her.

[00:26:50] Sherman said that she was falsifying trial data to make it seem like it didn't work. Like, what? That's another one of those, like, emojis. Hmm. She has all the vested interests, both monetarily and in terms of her prestige and reputation, for this thing to work. And she's probably brought the facts. I mean, you can, yeah. Absolutely. But what she realizes is, oh, I've been down this road. I've been putting years and years of my life into this, but it's going to harm my patients. So I'm not going to do it.

[00:27:19] I'm not going to subject them to that. Sherman also said that she was committing a purported thousands of protocol violations. This was a decades-long battle with multiple lawsuits by Sherman against Olivier. In 2009, this is 20 years after they first made contact with each other. Wow. Sherman applies for FDA approval.

[00:27:43] And the FDA commissions the Department of Scientific Investigation to inspect Olivier's original clinical trial. And after a week of scrutiny around the clinical trial, they confirm her safety concerns. And they also find that Barry Sherman has submitted data that intentionally excludes 45% of the test subjects that were in the original clinical trial. Wait, who was falsifying the data? Exactly.

[00:28:13] Right? It gets better in terms of the hypocrisy of the FDA. Uh-oh. What Sherman does is he pools all of this selected data. Don't get me started on the pool data. That's right. I know. It's a trick. From older studies using surrogate markers. And what does the FDA do? Uh-oh. They granted accelerated approval anyway. That's where Olivier's title to this up-to-date article or current article,

[00:28:39] Nothing is Right About the Approval of Atacanumab and Nothing's New because her drug had gotten accelerated approval back in 2011. Olivier warns patients and providers. She asks in this recent article, What function does the FDA now serve in comparing defepirone to Atacanumab? And she says,

[00:29:02] Now, more than ever, we need regulatory agencies that don't simply conjure up profit-generating hype, but approve products as safe and effective because they are safe and effective. She also points out very appropriately that 65% of the FDA's budget, almost two-thirds, used for the drug approval process is financed by industry. But big pharmaceutical companies.

[00:29:31] Again, the conflict of interest there is massive. Even if you're trying to be as ethical as you can, if you know that your department is going to ride or die based upon some level of appeasement of a company, it's going to be hard to be objective. Yeah. And she pointed out something that was very, very telling to me because it explained to me why Atacanumab was pulled from the market earlier this year.

[00:30:00] She says accelerated approval means that Biogen and Asai have to do a post-approval trial, stage four, which takes years. That leads to them reaping in profits before it has to actually show in the long term clear benefit on cognitive decline measures.

[00:30:26] You know, I think the core of it is noble is the idea that we're willing to get this drug on the market because we think it's so important. The idea is these are unmet needs. These are conditions in which they're life-threatening or there's a huge gap in the market. Therefore, we're going to let people get in on it because it has so much benefit. But then you said that the negative of it, though, is it then allows a drug to get on the market

[00:30:54] and reap benefit even before it's finished the process. And this is where it gets – oh, this is where it really starts to grind my gears, to quote Peter Griffin. So in 2024, as Atacanamab is not gaining a lot of traction, but you know there's people who are buying into the hype and spending $50,000 a year and probably dying an early death, Adjahelm is pulled from the market and it terminates its stage four trial.

[00:31:23] And the data from the stage four trial is lost. Now, Michael, you're a smart guy. Hopefully. Let's find out. You're a good critical thinker. Can you imagine why Biogen and Asai would abandon their potential multi-million, billion-dollar drug, Aducanamab, at the beginning of 2024, when they've done all this work and they've got two and a half years into their stage four clinical trial?

[00:31:52] Why would they just abandon that? Can you imagine? Again, I'm going to guess because we might have either – if we've unbioted or revealed kind of an interim analysis and maybe it's not as favorable as we would like. Maybe they saw something that wasn't favorable and maybe they had another drug that was similar, that was newer, and they could reset the cycle in Lacanamab.

[00:32:22] Ah. Oh, yes. I noticed the same company. Interesting. The same exact two companies that make the first one that are two and a half years into their stage four clinical trial that they don't have to release about the long-term safety and efficacy. See, all of a sudden there's the newest iteration that works better. Yeah. So, AKA, they reset.

[00:32:46] And now they can continue to profit off of Lacanamab without having to acknowledge the fact that Aducanamab stage four clinical trial data may reflect on the long-term safety and efficacy of this class of drugs. And the problem is I believe the FDA will fine them $150,000 for not reporting – if the FDA enforces it, they will fine $150,000 for not publishing the results of that Aducanamab study.

[00:33:13] But I'm going to guess Lacanamab's made more than $150,000. I would bet that you are very, very accurate on that. Yeah, and that's the problem with it. Lacanamab owned by Biogen and Asai. So, why was Biogen and Asai so willing to just let go of their baby Aducanamab?

[00:33:36] Well, maybe it had to do with Lacanamab, 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. Thanks again for watching and or listening.

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