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Podcast Library > NextGen Advisors Podcasts > FDA Approves Alzheimer’s Treatment, Controversy Ensues

July 20, 2021

FDA Approves Alzheimer’s Treatment, Controversy Ensues

Alzheimer’s disease affects 6.2 million Americans each year so the recent approval by the FDA of Biogen’s drug Aduhelm was met with hope by many patients and their advocates. The approval process used by the FDA, the efficacy data compiled to date, and the expected annual cost of the drug have created a swirl of controversy around the decision.  In this episode of the NextGen Advisors podcast, Graham Brown and Dr. Betty Rabinowitz discuss the drug’s approval and the concerns, hopes and implications it has raised.

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Transcript

Graham Brown:

Hello, this is Graham Brown, principal with the NextGen Advisors. Welcome to our podcast. Today, I'm joined by my colleague, Dr. Betty Rabinowitz, NextGen Healthcare's chief medical officer and a principal with NextGen Advisors. Welcome, Betty.

Dr. Betty Rabinowitz:

Hey Graham. Good to be her.

Graham Brown:

Last month, the FDA made a somewhat controversial decision to approve the Biogen drug Aduhelm developed to treat Alzheimer's. As we know, Alzheimer's is a really debilitating disease affecting 6.2 million Americans. The FDA use what's called the accelerated approval pathway for this drug, meaning they allowed the drug to be approved for use without determining in advance if a true positive therapeutic effect that is clinically meaningful will be achieved, therefore demonstrating an actual clinical benefit.

Graham Brown:

The accelerated pathway allows drugs for serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint. The day after the approval was announced, the FDA narrowed the indication for this drug to patients with mild cognitive impairment or mild dementia due to Alzheimer's disease according to a statement made from Biogen, the developer. A week later, three members of the FDA's advisory committee that recommended against the approval of Aduhelm resigned in protest. Betty, talk a little bit about what this drug is meant to do.

Graham Brown:

I understand it's to help clear amyloid plaques in the brain. What are amyloid plaques and what do we know about their connection to Alzheimer's or the progression of that disease in patients?

Dr. Betty Rabinowitz:

Amyloid plaques are the collection of the product of breakdown of proteins that naturally occur in the brain that accumulate in a kind of areas that can be seen on electron microscopy of brains of patients who succumbed to Alzheimer's disease or die of other causes, but are discovered to have Alzheimer's disease.

Dr. Betty Rabinowitz:

You can imagine that in a brain where the pathways and connection between millions and millions and billions of neurons is so delicate and so fine tuned that the collections of these tufts or plaques of protein disrupt very basic activities of these neurons, including the communication between neurons, the metabolism that occurs within neurons, and the natural repair activities that neurons are able to undertake on an ongoing basis throughout our lives.

Dr. Betty Rabinowitz:

Think of it as a collection of byproducts of proteins occurring in the brain that accumulate abnormally and disrupt the function of the brain. What's very confusing about this... And this drug was shown the surrogate end point was that the plaques reduced in frequency and existence. What's so tricky about this is that there are studies that show that there are patients with severe symptoms of Alzheimer's, deep dementia who have a very low burden of plaques in the brain.

Dr. Betty Rabinowitz:

And vice versa, there are those patients with very heavy burden of plaques, amyloid 42 plaques, which is the most toxic form of amyloid that don't have very severe symptoms. There's something else that we don't completely understand about the relationship between the advancement, the progression of the disease, and the severity of the plaques, hence some of the controversy around this medication.

Graham Brown:

Very interesting. Clearly the members of this FDA advisory panel in aggregate at least determined that there was some beneficial clinical value here and went forward with the narrow approval. Tell us a little bit about what's unique about this drug and what might have led to its approval.

Dr. Betty Rabinowitz:

I think what's unique about it is... The first thing is that there hasn't been another for 17 years. The level of expectation, hope, anticipation associated with its launch is significant, and there's a community of patients and caregivers who are desperate for a ray of hope and good news. The second is that it's a monoclonal antibody platform that was demonstrated to clear these amyloid plaques in the brain, which is different than the mechanism of action of the drugs approved prior to it many years ago.

Dr. Betty Rabinowitz:

I in practice was treating patients when those older drugs were launched, and I remember the excitement and hope that we had and, frankly, the somewhat disappointing outcomes of those. I think the agency was impacted by the human need and the human crisis and probably the hope that because the mechanism was different and that they had measurable surrogate outcome, that this would be different, that this drug warranted this early approval.

Graham Brown:

As I understand it, part of the controversy is that it's gone through this more rapid approval processing. It may not have necessarily the end points that we'd be seeking. But at the same time, the annual treatment costs for this drug Aduhelm is expected to be about $56,000 a year. That's really significant cost and certainly much higher than the drugs that are on the market now to treat Alzheimer's.

Graham Brown:

I know as a result of that, that both the Centers for Medicare & Medicaid Services, as well as different health plans, profit and not-for-profit health plans, are really debating whether they should cover this drug and put it on to their pharmacy schedule. What are some of the considerations that health plans would be looking at to decide if this should be covered?

Dr. Betty Rabinowitz:

From a health plan perspective, this is a very complex decision. On the one hand, their members are in the huge need for some assistance and relief from their symptoms. The burden and the costs associated with treatment of Alzheimer's disease are enormous. The need is completely clear, both on a human suffering perspective and also from a cost and healthcare system burden on the one hand. On the other hand, how risky is it for a health plan to approve payment for a drug where the end point hasn't been proven?

Dr. Betty Rabinowitz:

What precedent has been set where next week a cancer treatment drug is approved that costs $300,000 a year that is shown to impact certain cancer cells, but not change morbidity or mortality of the patients? This is a slippery slope in this regard. I assume, A, the commercial pairs will follow CMS and Medicare. That is usually the course that these innovative therapeutic agents follow, and it'll be interesting to see what CMS's decision is going to be.

Dr. Betty Rabinowitz:

It also depends how firmly the experts believe that reduction in plaques will ultimately be associated with reduction in morbidity, impact, disability, decline in patients with Alzheimer's.

Graham Brown:

What you raised is kind of an interesting conundrum, where there might be a drug approved by the FDA for use, but no payers are willing to pay for it.

Graham Brown:

And that creates a circumstance potentially in my mind where you really exacerbate just a disparity within healthcare: those individuals that can afford $56,000 a year for an experimental drug, or what might be considered experimental given its end points haven't been proven, can access it, and individuals, the 6.2 million that are suffering from Alzheimer's, a great cohort of them may not be able to afford that annual cost burden.

Graham Brown:

What are some of the other implications that you see if the drug is approved, but payers aren't willing to pay?

Dr. Betty Rabinowitz:

That will be very challenging. I think what will end up happening is that it will not be used enough to actually obtain the kind of data that will ultimately support its use. Because what might happen now if it gets approved and is paid for, that they will be able to very quickly because of multiple therapeutic years that will accumulate quickly because of a broad swath of patients being exposed to the drug, which will prove efficacy.

Dr. Betty Rabinowitz:

If there's very small numbers of patients using it, efficacy won't be proven and it potentially will cause a drug that has promise not to fulfill it and that we will never collect enough data to support its broad use. I must say that the FDA approval at this time prior to is going to be very complicated, and we were all be watching to see how this unfolds.

Graham Brown:

It feels a bit of Pandora's box has been opened here. I would imagine from Biogen's perspective, this is an expensive drug to develop and bring to market. If they're not able to get the revenues that support its manufacture and production, they may realize that this isn't a cost benefit that they're willing to entertain from a business perspective. They may pull the drug if there aren't enough users that can pay for it.

Dr. Betty Rabinowitz:

I think it's a great point, Graham. That would be very, very unfortunate, because it is the pharmaceutical companies willing to make the upfront investments in these newer drugs that offers the primers for these very significant illness. When you think of the burden of suffering of six million people, it's a staggering burden for families and communities and the patients themselves. We definitely need this to be successful. I hope that the process that this has gone through won't impact the actual value and outcome of this.

Graham Brown:

Normally we would have seen further phase three trials that are demonstrating a more clear connection between the end points through seeking and a large cohort study that's showing that it's really working. From a provider's perspective, what data would you want to see before you would prescribe a drug like this? If you were in practice now, would you be prescribing it to patients, or would you wait and see?

Dr. Betty Rabinowitz:

It's a great question. My approach to this would be to look at the safety profile first and foremost and to really try and understand the risk benefit ratio for the new medication. I would make any of these decisions in very close consultation both with patients who are able to participate in the decision-making and their families.

Dr. Betty Rabinowitz:

Because the unknown is present here and it needs to be a joint therapeutic decision because of the risks of the medications that aren't clear on the one hand and the second is the question of efficacy and the disappointment that would be associated with it proving to be ineffective. These are complex therapeutic decisions that have to be made in partnership with patient's families and, frankly, their Alzheimer's specialists who they invariably are seeing.

Graham Brown:

You raised an important point, because one of the challenge that I imagine is going to be placed on the provider community is this is a really unique circumstance, and there's a lot of complexity to engaging a patient and their family and their caregivers in a discussion around this, as you were just framing. Really the specialists that are providing Alzheimer's care may need to really get educated on the benefits, the risks, as you're describing, to have those conversations and guide patients and their caregivers through that decision-making process.

Graham Brown:

I imagine there's going to be more on this in the months ahead, and we may come back to this topic because it's been a pretty unique circumstance with this kind of approval, with the level of data being demonstrated so far. Thank you, Dr. Betty Rabinowitz for joining me today and our listeners for tuning in. If you'd like to listen to more episodes of the NextGen Advisors Podcast, hit the subscribe button. This is Graham Brown with NextGen Healthcare. Thanks for joining us and have a great day.