The Evolving Alzheimer Disease Treatment Landscape: Anti-Amyloid Therapies and Beyond
- Anti-amyloid antibodies have shifted the Alzheimer disease treatment paradigm by offering the first disease-modifying approach for patients with mild cognitive impairment or early Alzheimer disease, although modest clinical benefits, amyloid-related imaging abnormalities (ARIA)-related safety risks, and infusion requirements continue to influence treatment decisions.
- The pipeline remains heavily focused on improving anti-amyloid therapies, with investigational agents seeking to reduce safety concerns, simplify administration through subcutaneous formulations, and deliver more durable clinical benefits, while additional therapies target behavioral symptoms associated with Alzheimer disease.
- Long-term clinical outcomes will be the key differentiator for future therapies, as clinicians and payers look beyond amyloid plaque clearance to evidence demonstrating sustained cognitive and functional benefit, lower safety risks, and meaningful improvements in patient quality of life.
Alzheimer disease treatment is undergoing a significant transformation with the introduction of disease-modifying therapies targeting amyloid pathology. While these agents represent an important advancement for patients with early Alzheimer disease, they also raise new questions surrounding clinical value, safety, access, and long-term payer management as the therapeutic pipeline continues to evolve.
In this interview, Roy Moore of Clarivate’s market access team discusses the current Alzheimer disease treatment landscape, emerging pipeline therapies, the evolving competitive environment, and the key considerations shaping coverage and reimbursement decisions for current and future disease-modifying treatments.
Roy Moore: My name is Roy Moore. I am on the therapy team here at Clarivate. I've got 20 plus years of experience in US and global market access, including both syndicated and consulting. As it relates to Alzheimer disease, that is included in the work that I perform. Within the last year, I worked on a project where we interviewed and surveyed payers around coverage and future expectations for coverage around Alzheimer disease drugs.
Alzheimer disease treatment has evolved significantly in recent years with the emergence of disease-modifying therapies. Can you provide an overview of the current treatment landscape and discuss how anti-amyloid antibodies have changed the management of Alzheimer disease?
Roy Moore: Historically, Alzheimer disease was treated by acetylcholinesterase inhibitors like Aricept (donepezil) and Exelon (rivastigmine). The were also a N-methyl-D-aspartate (NMDA) receptor antagonists like Namenda (memantine) or combinations like Namzaric (donepezil and memantine). There have also been selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) used off-label. Auvelity (dextromethorphan and bupropion), a major depression drug, was approved a couple months ago for agitation associated with Alzheimer disease.
These treatments have been around for years, but in many cases they treated the symptoms and were not disease-modifying. There was a gap in the treatment paradigm for Alzheimer disease, which gave rise to the anti-amyloid antibodies. They offered the promise of being disease-modifying instead of treating the symptoms, which would have been a win for patients, providers, and payers, ultimately. Now, this worked on the premise that reducing AV plaques could slow down in the clinical decline of patients.
The first of these drugs that hit the market in 2021 was Aduhelm (aducanumab), which was approved via accelerated approval, although this drug was later discontinued due to lack of commercial viability. There was also some controversy surrounding the drug's approval to begin with. It has since been removed from the market. However, we did see the rise of drugs like Leqembi (lecanemab) and Kisunla (donanemab-azbt), which are being prescribed for mild cognitive impairment due to Alzheimer disease. These drugs have shown significant plaque clearance, which in theory should lead to a slower disease progression.
Now, there are drawbacks to these drugs that are worth pointing out. The clinical benefit is somewhat limited and can be applied to only a handful of patients. There are also safety risks, specifically amyloid-related imaging abnormalities such as brain swelling and brain bleeding. These drugs are typically also infused, which creates additional burden. They're also quite expensive. You can compare them to the oral therapies that have been available for decades. There are around 3 million cases of Alzheimer disease in the US, and mild cognitive impairment (MCI) due to Alzheimer disease is around 3 million—about 5 million combined. That's a pretty significant cost to payers. And that's going to shape management of this category going forward. It already has.
When we saw the launch of the first monoclonal antibodies for this disease, Centers for Medicare & Medicaid Services (CMS) changed some of its rules so that they would be covered under Medicare with certain requirements in place. So that takes us to what the payers are doing, according to surveys of payers as well as qualitative interviews that I conducted. We're finding that payers are reimbursing these drugs. Of course, the patients have to meet strict criteria or at least the criteria that are in place. Physicians must diagnose MCI or mild Alzheimer disease, and they have to confirm amyloid pathology such as whether there is biomarker evidence of amyloid positivity. Patients who meet that criteria are treated. There are also requirements in place by the payers, but that is generally how they're being managed at this point. We will see the evolution of this category as more therapies come online and more evidence is generated around the therapies themselves.
Newer drugs—because they are infused—are typically covered under medical benefits, but there are prior authorization (PA) requirements or at least protocols in place for covering them. Payers are requiring disease diagnosis, stage, and confirmation (eg, patients have the plaques). Older generics go through some step therapy but in talking with payers, they aren't actively managing it beyond that because there's no head-to-head data to give them a sense of which drug is superior in this population.
Looking ahead, what are the most important investigational therapies or anticipated FDA decisions that managed care stakeholders should be monitoring over the next 12 to 24 months? Are there any emerging mechanisms of action beyond amyloid-targeting approaches that could further reshape the treatment paradigm?
Roy Moore: When it comes to Alzheimer disease, the development landscape is probably further out than 12 to 24 months, but I'll stick within that framing initially. To begin with, there is a tremendous unmet need for Alzheimer disease. This is obvious to the patients, to their family members, to physicians, and to society at large. This is a vulnerable population and very sizable. And if they aren't treated, they can end up in nursing homes, which can drive up costs. It's a clinically unfortunate disease and tough to handle.
Regarding a pipeline that's in development that's going to build upon what we've already seen, particularly around the amyloid treatments, there are 2 that stick out me. There’s from Eli Lilly called remternetug which is similar to current treatments, but it's subcutaneous (SC) dosing. So, instead of doing infused treatment, you can do SC which can allow for home injections. We're already seeing that with some of the current treatments available. So, there SC versions of the drugs already in development. The other therapy that comes to mind is one from Genentech. It's an IV, trontinemab. Since it’s an IV, it may create some challenges, but it is promising because it has a much lower ARIA rate—one of the challenges with the current therapies—than lecanemab and donanemab. It also has rapid amyloid clearing potential. With ARIA, we're talking about brain bleeding and brain swelling, so that is going to be top of mind for stakeholders going forward.
Then, of course, you'll see development outside the amyloids, although that is the main area of development that I've seen. As I mentioned before, we saw ovality. approved as label extended just relatively recently to include a population that would encompass part of AD. But we also see cobenfee in development. This is a drug that's already been approved for schizophrenia, I recall. And it's in development for psychosis and disease agitation. So, you'll see activities there. Label expansions for drugs treated for other populations that are more symptomatic. But as far as the disease-modifying ones, We're still focusing on the amyloid, currently.
As more disease-modifying therapies enter the market, how do you see the competitive landscape evolving? What differentiating factors—such as efficacy, safety, administration requirements, patient selection, or monitoring needs—may influence provider adoption and payer decision-making?
Roy Moore: With Alzheimer's disease, it simply comes down to efficacy. These are the features that resonate most with physicians and payers. Are you delaying cognitive decline? Things of that nature. One of the things that traditionally or at least recently had been a metric that had been used was, of course, the plaque clearance that's less resonant because physicians and payers at this point want to have drugs that work. They don't really care necessarily how they work. They just want to know that they work. It will come down to efficacy, primarily patient function and cognition. I mentioned the ARIA risk, which is interesting. The amyloid plaque ranked a little bit lower than you would have thought historically for physicians. Again, they're coming to a point where they just want drugs that work, not necessarily how they work.
As far as how we see things evolving, I should say that this is not a contracted category. You don't have that many drugs, and this is just not a place where manufacturers and payers are contracting. I don't believe that's necessarily going to change, but we will probably see additional competition. Maybe that will lead to contracting at some point. Payers are already managing this population. They've had help from CMS in some regards as far as what patients qualify. We will likely see them tailoring the PA to label.
There are some interesting developments that have occurred. For instance, when we surveyed physicians last year, we saw increased use of genotyping to assess the risk of ARIA for patients who are taking Lekembi Kisunla. That's not necessarily part of the restrictions, but that's something that we could see happening. If you can identify the patients who are least likely to experience ARIA, then you can direct treatment based on that, maybe give the versions of the drugs that have that lower risk.
Again, with payers, it's going to be driven by efficacy. One thing that did stand out to us was they talked a lot about real-world evidence, particularly via CMS registry. That's something that came out of CMS' coverage decision back in 2022. In talking with payers, they acknowledge these drugs do a good job at reducing plaque, but they're concerned on the clinical benefit, particularly in light of the safety concerns that I mentioned. As far as different treating factors, I mentioned the efficacy data over an extended period of time. That would actually shake up the apple cart. But if you want to reduce the risk, if you have a drug that will reduce the risk of ARIA, I think that will stand out to both physicians and payers.
Although the Alzheimer disease market is still relatively early in its evolution, what role could future competitors, next-generation therapies, or potential biosimilars play in shaping access, pricing, and treatment selection over time?
Roy Moore: Well, you're absolutely right that it is relatively early in its evolution. We only have 2 approved disease-modifying drugs that are currently available. We have 3 that have been approved and 1 that's been removed from the market. It is still way early in the process. I’ve seen the phrase, “We know more about the surface of the moon than we know about the human brain.” And I don't know if there is any disease that highlights that more than Alzheimer disease. The market is absolutely ripe for being reshaped. If we actually had a disease-modifying drug that slowed decline to substantial levels, that would shape policy and everything going forward.
As we continue to see more drugs, we will see more contracting taking hold. This is a category that's not a protected class under Medicare where payers must cover everything, so there is some discernment needed there. But of course, I believe they would try to cover as much as possible, at least at some level, so that the patients in need can get them. As I said, it's not very common right now and is probably sometime far off because there's currently no need for it.
However, there need to be some improvements for the outcomes measured over years. For instance, with the way these trials are approved or the drugs are approved, payers—and I'm sure the physicians too at this point—want to see the efficacy and how that translates into cognitive decline. That's what's going to reshape the market more than any other factor going forward. What is the long-term data set? Can we actually discern? Is there a standard of care for this population? What actually works? And how does it work in that regard?
Given the high cost, infrastructure requirements, and ongoing questions surrounding clinical value, what are the key considerations for payers evaluating coverage of current and future Alzheimer disease therapies? How do you anticipate utilization management strategies, patient access criteria, and value-based discussions evolving as the pipeline expands?
Roy Moore: As Alzheimer drugs expand, the considerations are numerous. This is such a tricky disease. For the human brain, the endpoints are somewhat challenging to measure and they change day to day as far as patients having good or bad days. In addition to these challenging endpoints, payers also deal with the fact this patient population is sizable, which impacts Medicare reimbursements. They rely upon reimbursements from the federal government to a large extent. So, these are some things that are going to be top of mind. You have a huge population, tremendous unmet need, and the endpoints right now are murky in some regards.
The current disease-modifying therapies offer, at best, some benefit in some patients, but they carry significant safety risks such as ARIA, brain bleeding, edema, things of that nature. Stakeholders will continue to focus on those metrics. How does that affect management and access? As mentioned earlier, CMS has already shaped some of that with the coverage with evidence development rules that they laid out. These will shape a lot of who gets these drugs because patients must sign up for those programs. Beyond that, the status quo will likely continue until something comes out that changes the paradigm.
Until then, we're probably going to step through the generics that are used. These could be on-label, like inhibitors, or they can be combinations, or they can be off-label behavioral health drugs before the patients get to the monoclonal antibodies, if they meet the criteria. As far as management, I spoke before about genotyping. That could probably work its way into the PA rules because they work as biomarkers in the same way cancer drugs do. If you can identify patients who are less likely to experience safety issues, payers are probably going to put that into place, particularly if it's part of the label that would be included. It would be the same with PET scanning and things of that nature.
As far as value-based discussions, if an Alzheimer drug did emerge, the value would be immeasurable. Although it would have to be measured because payers would have to pay for it. Payers would want to understand what the cost of the drug will be and how long the drug will last. What is the rate of decline? What are the metrics that lay out 3 years, 5 years, or maybe longer?
We won't see any kind of innovative contracting. There won’t be any kind of rebates given to patients because, again, the endpoints are tricky and we're talking about extended periods of time. You would need data over many years to get signal, which payers are interested in collecting as part of any agreement. But if we did see something meaningful, the management would change. For example, there would be more aggressive management as far as directing patients to the drugs. In the same way with cancer drugs like biomarkers, if a biomarker is part of a cancer drug, they'll reimburse it tied to that biomarker. I believe there will be something similar when it comes to some of the newer drugs for Alzheimer disease if you can get some of that information out. For genotyping, you could see development along those lines in other cases as well.
This is where management is heading, but that's probably some ways off. This is not a cost concern today for payers because there aren't that many drugs and there aren't that many patients receiving it. But long term, if we do get a drug that works well, then there will be more aggressive management. This is how the discussions will be taking place going forward: How well does a drug work? How does it decline? Can you keep patients out of nursing homes, facilities, things of that nature? And what is the effect on patients' quality of life? These points are going to resonate with payers, physicians, and—most importantly—patients and their families.
