Narrator - Dr. Abel  00:00
Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast is

Narrator - ?  00:12
provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy.

Narrator - Dr. Abel  00:17
This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider.

Narrator - ?  00:27
And now on to the show.

Dr. Sean Kane  00:31
Welcome to HelixTalk. Episode 139 I'm your co host, Dr. Kane.

Speaker 1  00:35
I'm Dr. Patel, and today with us again, we have Dr. Rahul Deshmukh with us. Hello everyone. Welcome back, Dr. Deshmukh. Thank you for being here today. And the title of our episode, 139 is They Did What?! FDA approval of aducanumab for Alzheimer's disease? And in this episode, we're going to briefly talk about what's cooking in the world of Alzheimer's disease, but really focus on this recently approved, I would say, accelerated approval, of the new monoclonal antibody based treatment, aducanumab, or Aduhelm, by FDA. And we're going to kind of drive into the approval process briefly review the efficacy and safety data, but really kind of dive into the behind the scenes stories of like how this whole approval process was not the traditional way FDA normally approves medication, so let's dive right into it.

Dr. Sean Kane  01:35
Awesome. Well, Dr. Patel, I think it's probably worth just mentioning a little bit about the background of Alzheimer's disease, and that's what Aduhelm is FDA indicated for at this point. Alzheimer's disease is a neurodegenerative disease. It's the actually main cause of cognitive impairment and dementia in older adults, and the pathophysiology is complex, but one of the essential features is these plaques, these amyloid beta plaques, these peptides that form in the brain, and we think that that's a component of the pathophysiology, among other pathophysiology that are implicated with the disease state.

Speaker 1  02:11
And you know, we can dive and talk about the details of pathophysiology and the risk factors, but there is, there is one particular genetic mutation that is found to be somewhat of an importance, and sometimes the dosing of Aduhelm in these clinical studies were also dependent on whether the people had this mutation or not. Family history is also responsible. And then additional risk factors, such as, you know, your risk for cardiovascular disease and any other condition that can put a person at a higher risk for cardiovascular disease, medications like anticholinergic or benzodiazepine and even some environmental risk factors like, you know, second hand, hand smoking or air pollutions and pesticides are kind of implicated in causing Alzheimer's disease and then related degeneration.

Dr. Sean Kane  03:03
And you know, most of our treatments that we have basically, they're not incredibly effective. So one of the drug classes that are very commonly used are the cholinesterase inhibitors. So this is Donepezil, brand name, Aricept, Galantamine, brand name, Raza Dyne, and then rivastigmine, brand name Exelon. The way that these work is that they're inhibiting the breakdown of acetylcholine because there's a decrease in choline acetyltransferase in these patients with Alzheimer's disease, we think that that's implicated in the decline in their cortical cognitive function. So what this does is it inhibits the breakdown of acetylcholine to increase the amount of acetylcholine at the synapse and overcome some of that decrease in the enzymatic activity.

Speaker 1  03:50
To keep in mind, though, with these drugs, Dr. Kane that they're approved for kind of newly diagnosed with mild to moderate Alzheimer's disease, and provides like symptomatic, modest benefits and improvement in cognition as well as global functioning, what we call it, the activities of daily living, as well as some neuropsychiatric signs and symptoms and things like that. It doesn't really provide neural protection and does not impact the disease trajectory. So that's important to notice here. And with these drugs, as we all know it, they're cholinergic drugs. And so we're going to see some side effects that are cholinergic in nature, such as, you know, diarrhea, nausea, anorexia, the side effects can be a little bit different with the oral doses versus the patches. So patch, the Exelon patch, tends to have a little bit of less GI issues. We have bradycardia or low blood pressure issues happening, and in some cases, most likely, with the donepezil, we get to see some sleep related disturbances, such as insomnia and vivid dreams and. Nightmares, so kind of you know, chicken or the egg situation, especially when these patients have neuropsychiatric signs and symptoms of the disease themselves.

Dr. Sean Kane  05:08
And really, aside from our cholinesterase inhibitors, the other drug class that is commonly used is NMDA receptor antagonist. And there's really only one at this point. It's memantine, brand Namenda. Really clever brand name because Namenda literally has the mechanism NMDA antagonist in it. And basically, NMDA is the receptor for glutamate, and glutamate is an excitatory amino acid in your brain that will activate the NMDA receptor. So by taking the memantine or Namenda, it will block that excitation, which we think is implicated in some of the excitotoxicity of the pathophysiology in Alzheimer's disease. So the thought here is that if you block some of that glutamate activity through the MDA receptor, that you can help with that disease in terms of the symptoms

Speaker 1  05:56
and as far as the efficacy of this drug goes. You know, again, this provides small improvement in cognition and that global functioning improvement of the ADLs. Normally, it's not used by itself. It can if the cholinesterase inhibitors are intolerable for the patients, but usually this is an add on drug for moderate to severe disease. So usually, you know, if you think about this, our discussion right now, we add the cholinesterase inhibitors first, and you know, as the disease progresses, then the consideration for Namenda comes. You know, it was thought to be very well tolerated drug. If anything, they got to see some dizziness and confusion and some hallucinations with that. But other than that, it was thought to be pretty, pretty well tolerated drug,

Dr. Sean Kane  06:43
and that's basically all we have had up until this year with the new addition of aducanumab, or Aduhelm. And you know, this was indicated for Alzheimer's disease treatment under an accelerated FDA approval. And there's so much controversy around both the trials and the later FDA approval of it that we're definitely going to get into. So we've kind of glossed over the surface of a lot of Alzheimer's disease in favor of focusing on this particular drug and then the FDA approval of that drug,

Speaker 1  07:14
kind of diving further into the mechanism, aducanumab. It's a human immunoglobulin and gamma one monoclonal antibodies. So IgG one monoclonal antibodies, and that's really targeted against the aggregated, soluble and insoluble forms of those amyloid beta plaques we were talking about earlier. And so the theory is that Aduhelm reduces the beta plaques. And we're going to briefly go over the efficacy results of these trials before diving into what really happened with the FDA approval.

Dr. Sean Kane  07:51
So really, you know, September 2015 is where this story gets started. There were two phase three trials from Biogen, the manufacturer, and like any phase three trial, the intent was to assess safety and efficacy of Aduhelm for those with early Alzheimer's disease. And you know, they were primarily aimed at reducing those plaques that happen in Alzheimer's disease. And also they did look at cognition and whether there was a benefit in terms of this more clinical endpoint, as opposed to the surrogate endpoint that you can see on an MRI.

Speaker 1  08:25
One of these studies did look at the surrogate endpoints. They looked at radiographic studies to see accumulation of the beta-amyloid and stuff. However, these two studies, their primary endpoint was looking at the change from baseline in the clinical dementia rating, Sum of Boxes, we're going to shortly call it CDR-SB score at week 78 so this was a 78 week long trial. Both of these studies, if you look at literature, were Study 301 and 302 were pretty much similar in design, multi center, global, randomized, double-blind, placebo controlled, 78 week trials. Population was about the same. They had to have mild cognitive impairment and mild dementia with positive amyloid PET scan. So they had to had an evidence for these amyloid plaques in the PET scan,

Dr. Sean Kane  09:19
they studied three doses, a low dose, three or six milligrams per kilogram versus placebo. And they also studied a high dose, at 10 milligrams per kilogram versus placebo. And the primary outcome, again, this was the clinical dementia rating, some of boxes or cdrsb at week 78 the way they described that was basically the difference between drug active drug and placebo. So a negative number would be in favor of educating you Mab in terms of a benefit. So there were two studies, study 301 and 302 and the endpoint for that particular clinical outcome was negative, 0.15 Negative 0.1 meaning in favor of aducanumab. And the problem, though, is that when they looked at the high dose, the high dose was actually in favor of placebo, a positive 0.22 in Study 301, and then a negative number. So again, in favor of the active drug. Minus 0.28 instead of 302, so we kind of see some discrepant findings in terms of the higher dose that actually not outperform and to be honest, like these are really, really, really small numbers, a clinically, minimally clinically important difference is somewhere in the neighborhood of one to three points. And we're talking a difference that we observed in the clinical trials of tenths of a point being different. So really, no clinical difference here. And you know, at the time, in 2015 the manufacturer Biogen actually kind of went back to the drawing board, thinking that this was futile, that they really shouldn't continue, you know, investigating, because these were viewed at the time as negative trials.

Speaker 1  11:01
And so Dr. Kane, what you described here in in terms of these numbers, and you know which direction the studies were trending, whether placebo or the drug itself, these were futility endpoints. And then there were final results published by Biogen as well, which weren't drastically different than the fertility results. However, all of these studies, like I said earlier, looked at surrogate endpoints too. So they looked at, you know, markers for the tau path of physiology, p tau, and, you know, in the PET scan results as well. And all of those showed that Aduhelm reduced the amyloid beta plaque in a dose and time dependent manner, and all of these three studies compared to the placebo. So you know, what you discussed Dr. Kane was clinical outcomes. What I just summarized here were surrogate outcomes, and then kind of looking at safety data, we actually found something called ARIA E. This is how it's acronymized, and basically it is amyloid related imaging abnormalities. And E stands for edema, which was observed in the MRIs. And both in studies one and 240, 1% of the patients who were treated with the study drug had ARIA e positive with the higher dose, the 10 milligram per kilogram dose, compared to the 10% of those patients on the placebo. So that was something that FDA was also keeping in mind. But now, if we have all this safety data and the efficacy data. How? How do we put the whole therapy in picture, right? How do we put it in in place? And that's, that's where we bring in. Dr. Deshmukh.

Speaker 2  12:49
Look absolutely and I think you pretty much covered the broad story of this particular drug. But before we go and talk more about the controversy around this drug and its approval process. I think it may be useful for all of us to kind of go over what a clinical trial is all about. So basically, when we talk about a clinical trial and a drug company wanting to get a drug approved, they start off with what we call as phase one studies, where they test a drug in a very small amount of human subjects. Before that, they do all the basic safety studies in animals, where they show that the drug will be reasonably safe in humans, and we would like to test it in humans. So it's a very small amount of healthy individuals in which the drug is tested, where they look at different doses that they may want to test in actual studies, figure out what is called as dose ranging studies, and then once they define Okay, these are the potential doses that do not have safety issues. We would like to take this and test it in patients who actually have a particular disease or a condition, and that's where the phase two studies come in, where this drug is now administered to a larger population. These may be placebo controlled studies or they may not be placebo controlled studies, but here, what they are basically trying to establish is what we call as the pharmacokinetic pharmacodynamic effect, meaning, is there a dose response associated with it? And their goal here is to identify the most optimal dose that will produce a maximum benefit and at the same time have the lowest risk. We all know that most of the drugs carry some kind of inside effect, and the goal is to basically get the maximum benefit for the lowest amount of side effects that may be associated with the drug. And that's what phase two studies is, where they hone in basically on a set of doses. It may not be one dose, it could be multiple, but a set of doses. And finally, they go into large scale, phase three studies, where you're looking at a large number of patient population, anywhere from 300 to 3000 it really depends on the disease condition. So for this particular. Drug Alzheimer's, which affects a lot of senior population in this country and worldwide, you would want to have a big cohort of people in which this drug can be tested. And in this particular instance, though, the study is designed to define the primary endpoints, as was noted earlier. In this case, it was the improvement in cognition skills that was the intent. And in addition, there could be a lot of secondary endpoints that may be associated, but that was the one primary endpoint that was being evaluated here, the drug gets tested between patients and another set of patients who would receive placebo or basically no drug, and then you have a head on hand comparison where we see if the drug actually provides benefits to that particular cohort of the population, and if it has any effects on the disease, whether it's disease modifying or whether it is ameliorating The symptoms associated with the disease or any combination thereof. And once all that is generated, these companies take all this data package to FDA, and they apply for an MBA, a new drug application. So FDA receives all the data, and they evaluated it to decide whether this drug should be made available to patients as a spot of a treatment. So in a nutshell, that's what the drug approval process is all about.

Speaker 1  16:30
What happens afterwards is a very long process of FDA to review the data. They bring in expert from the fields as part of the advisory committees to reflect on the data as well, and then they make the decision to kind of approve or reject the application. But things kind of take a juicy turn here in regards to any hum. And so what really happened is very interesting. What you explained Dr. dashmuk, was the actual process. And here what we saw with Ed home was a little bit different. Can you go ahead and kind of describe what were the differences in the approval process for any home?

Speaker 2  17:13
As you know, with Aduhelm, there were two studies that carried out, and most of the studies will have basically safety boards that will, at the interim point, check if everything is going on properly with the study, if there are any issues with the study. So they basically look at all the aspects, and it is called the independent monitoring committee. What they noticed was that the drug does not seem to be helping the patients, and the primary endpoints were not being met in the study, they also noted that a large number of patients were seeing brain swelling, or this a amyloid related imaging abnormalities. So this gave them a pause, and what we said was, we do not see any efficacy with this drug. With regards to cognition, it looks like there is a major safety signal that we should be concerned about, and as a result, we should discontinue this thing. So that was the recommendation that they gave at that particular point, and the study was discontinued. So this is where things get interesting. So the primary endpoint had failed. They went back to the drawing boards and they decided to re evaluate the whole data, and they did post hoc analysis, post meaning after study has been at least paused, not necessarily completed. In this case, it has been paused. This took FDA inputs on this, no question about it. They did work with FDA to figure out what is going on, and during this post hoc analysis, what they noticed was one of the dose was showing some kind of a small benefit, but in the other doses and the other trials, there was no benefit associated with the drug. But despite all this data and and the safety signal that was there, Biogen submitted what is called as a biological license application. Since this drug is an antibody, instead of conventional and DNA drug application, you would submit a biological license application. And they first did that. FDA look at this data that they have generated and recommend whether this drug should be approved or not

Dr. Sean Kane  19:21
so Dr. Deshmukh, up to this point, what has occurred in our story so far is actually not that unusual. So interim analyzes are almost always done with these larger phase three trials, for a couple reasons, and you mentioned in this particular case, it was for utility reasons, meaning that it seems futile to continue to pour money into a study where the primary endpoint wasn't working out, and also for safety reasons. And as you mentioned, they were concerned about this area adverse effect, this brain swelling seen on MRI, in terms of whether that would potentially cause harm in these patients or not. So interim analyzes, not unusual. Stop. Trials early for futility or safety reasons, not unusual. Doing a post hoc analysis is very commonly done. So really, those things are not that unusual. What was unusual is that after this kind of post hoc analysis that the manufacturer decided to pursue this bla the biologics license application at basically asking the FDA for approval. Generally speaking, once you stop a trial for futility, you you stop, you say, well, the data isn't good enough, and you don't even try to pursue FDA approval. So what happened at that point in terms of the manufacturer asking for FDA approval?

Speaker 2  20:38
I just went to FDA and said, We would like you to review this particular data set that we have and give us your judgment. So FDA decided to convene an advisory board. They would basically seek input from people, experts in the field, and the advisory committee members. This particular committee, they were 11 members, and all those 11 members after viewing the data that was presented, they gave an unanimous vote against approval. They said that this data in no way meets the thresholds of evidence based medicine. Finally say that we should allow this talk to be approved and marketed. However, despite all of this, FDA decided, for reasons that it will grant an accelerated approval to Aduhelm. And then some of the justifications that FDA came out for this particular trial is that the data demonstrated that the drug reduced the buildup of the amyloid beta back in pain that was well established. There was no question about according to the FDA, and this is a statement that comes from that the reduction of amyloid beta plaque, it serves as an surrogate endpoint that will reasonably likely predict the clinical efficacy of the drug. So this is a very important statement that they made in their justification that amyloid beta plaque reduction is likely to predict clinical efficacy. We know from many, many years to date that, unfortunately, there has been no correlation between amyloid beta plaques and improvement in cognition. However, FDA insisted that this is likely to happen.

Speaker 1  22:26
So basically what I'm understanding here Dr. dashmuk Is that just looking at amyloid plaque reduction, FDA said that this drug will provide clinical benefit as well, which is exactly the opposite of what we try to tell students and utilize, you know, evidence based medicine, and say, if a blood pressure reducing, medication just reduces the blood pressure and doesn't improve morbidity and mortality. Okay, big deal. We got to use the drug that has this clinical outcomes affiliated with them, right? Not, not just looking at whether it reduced the beta plots or not. And I think the things kind of get even more serious is that the committee who weighed in, the advisory committee who weighed in, had no idea that FDA was even considering accelerated approval. Am I right?

Speaker 2  23:19
Yes, that's absolutely correct. So they made their decision based on what was presented to them, and then FDA decided to approve and using this particular pathway, and none of the members of that committee had any clue. And that was the concern that many of them raised, that we never discussed this question of accelerated drug approval, you never asked a strain on this particular topic, really.

Dr. Sean Kane  23:46
You know, at this point, it kind of leaves your head scratching of why did the FDA go ahead and approve the drug despite the advisory board unanimously voting to not do it? And, of course, the cost is one of the biggest things that has come up in the news. You know, this is a $50,000 plus medication per year, and we don't really even know that it works, works in the sense of improving a cognitive outcome for a patient. You know, you can't even conduct a cost effective analysis for this medication, because literally, is no effectiveness to be seen, there's no clinical benefit. Even if you looked at a surrogate marker, it wouldn't make sense that that for every $50,000 you spend, you decrease beta amyloid plaque by 30% that doesn't mean anything. What you're looking for is to say, by spending $50,000 per year per patient, you can improve cognitive outcomes by X amount. And as we said, the X is really not there. There is no clear clinical benefit for this medication.

Speaker 1  24:47
Few controversy that followed this approval process was some of the advisory members actually resigned, three of them and said they had nothing to do with this process. They did not agree with this approval to the point. Were now a couple of congressional committees are set that are investigating FDA approval of this of this drug, especially with the price tag that's attached. And you know, usually, as we talked about the approval process and the submission of data as part of the nd application, it's all companies doing. And what was interesting is that FDA really joined hands with Biogen in looking at the data, and they kind of CO presented the data that kind of put a label that there is something of interest, there is some efficacy that we are looking at, and usually that that's not what happens with drug approval.

Speaker 2  25:39
So another interesting thing that happened with this is Dr. Kane, you pointed about the safety, where there is the brain swelling and the ARIA type of issue with this drug that is seen in majority of the population. When FDA approved this drug, for every new drug, a label is issued to see what is the indication for which the drug is used, what is the patient population? And FDA did not put any kind of restrictions on this. Yes, they did have that safety warning on it, but did not put any kind of restrictions to guide physicians or doctors who may want to consider this therapy as to how they should use it. What is the population they should target? So none of this, it was basically a free for all type of a thing. And given the cost of the drug, given the population we are dealing with, it's a massive number of people, and we do not know if this drug works, and we do not know how we will react to these drugs in terms of safety, and will there be major problems at hospitalizations and so on.

Dr. Sean Kane  26:43
You know, historically, an FDA approval meant something in the sense that the FDA has put their stamp on the safety of a drug, the efficacy of a drug, and that they're putting their seal of approval on that medication. And you know, something like this really calls into question both conflict of interest, but also, how much can patients in the United States in general trust the process of an FDA approval if something like this occurs? In my mind, this is pretty flagrant in terms of how bad the approval was, but for future drugs, maybe it's not as flagrant. And are we going to be able to catch other monkey business that happens in terms of drugs that shouldn't be approved if it isn't as obvious or as flagrant as this particular one.

Speaker 2  27:28
Another thing that I would actually want to add on to is that maybe you know that mindset that FDA decided to adapt, that maybe something is better than nothing, because there is no treatment for Alzheimer's, so let's just put out something and hope that it will work. I don't think that's that's the kind of a statement an agency like FDA should be sending out to the world, because this is not just about us patients and US population. It's about its global role that FDA plays across nations,

Speaker 1  28:03
and rightly said that this is going to impact the approval of future drugs, not just for Alzheimer's, for other conditions as well, and hopefully undermine or not regard the authority that FDA actually has over these pharmaceutical companies. And so we'll see what comes out of these, you know, congressional committees that are going to soon have hearings on the approval of a new home by FDA, and perhaps there will be some interesting information that we can do another episode on that itself, absolutely.

Speaker 2  28:37
And I think one, one last thing that I do want to state in process is that there are going to be these instances. There are going to be disease conditions where we do not have adequate treatments. We still want patients to try out things, and yes, there are risks associated with it, and we should, despite the risks that we give that patient an opportunity to try out these medications to see if it could help them, because it could be a situation of life and death. And FDA actually has very good programs to support that kind of a process. They have what is called as an expanded access program where FDA can allow patients to have access to drugs that are not approved. Company can tell FDA that we have this drug. We do not have all the data on it, but we are happy to work with specific cohorts of patients and allow them to try it out and basically see if it benefits them. And I think there are all these checks and balances in place that FDA can exploit in a meaningful way, so that the patients at no point feel that they do not have anything to go by and basically they are left at their own mercy to manage the disease. There is a debilitating condition for which. There is no treatment. If there is a promising treatment out there, but not adequate data to support it. By all means, they can work with FDA and these companies and still ensure that they have access and the companies, as they should rightly do, provide all the data, provide all the studies, complete the studies and seek the appropriate approval for these medications.

Dr. Sean Kane  30:21
Certainly, as Dr. Patel mentioned, there's going to be big question marks that have already been raised about why this happened and how it happened, and as we've kind of alluded to, it does really degrade the reputation of the FDA by having this happen. And I think that it's unfortunate, but something that many people are going to be looking into in the future to see what really went on here.

Speaker 1  30:45
And I think the lesson that, you know, usually, rather than concluding main points from the episode, I think the overarching lesson that our student listeners especially can get out of this is the importance of critically evaluating the literature and really critically thinking about, you know, evidence based applications, and not necessarily going with the full or, you know, just going with the FDA approval, but really looking to see what's the magnitude of benefit, as opposed to the side effects, as well as the cost and the potential benefit that patients with any condition, not just Alzheimer's, is going to have. I think that's the overarching message here, that we got to look everything under the microscope or magnifying glass.

Dr. Sean Kane  31:32
And I would second that Dr. Patel, because if you think about it, this problem of surrogate endpoints and probably too soon, FDA approval. This is not unique to Alzheimer's disease with aduhelm that we've seen this with diabetes drugs, with pioglitazone and roseglitazone, our sulfonylureas, which are very commonly used still for diabetes, have yet to show any cardiovascular benefit in those with diabetes. Historically, we've had issues with a number of dyslipidemia agents that have failed to show cardiovascular benefit. In COPD, we have a number of long acting bronchodilators that have very minimal impact on spirometry findings, likely clinically irrelevant improvements, and have very little benefit on quality of life for these patients, this is not unique to Alzheimer's disease in this particular medication. It just happened that the discrepancy of a lack of clinical benefit, and yet FDA approval was so obvious and so wrong, it's kind of brought this to the forefront, but we've seen this story many times before, just not as flagrant as it was with this particular medication. Well, Dr. deshmir, I think that wraps up today's episode quite nicely. We Dr. Patel, and I really appreciate your interest in the topic and your involvement in today's episode. For listeners, we're available at HelixTalk.com if you want to see show notes. We're also on Twitter at HelixTalk, where we release clinical pearls from previous episodes, and we love the five star reviews in iTunes. So keep those coming. So with that, I'm Dr. Kane.

Speaker 1  33:03
I'm Dr. Patel and Dr. Deshmukh. Thank you again for being here today. Thank you and to our audience. Study hard.

Narrator - Dr. Abel  33:11
If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there

Narrator - ?  33:22
to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.