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Alzheimer’s treatment: Time for a level-set?

See the success rates, risks and costs of the new Alzheimer’s treatments.

September 18, 2023 | 6-minute read

Alzheimer’s disease awareness

Each September we recognize World Alzheimer’s month, with November being  National Alzheimer’s Awareness Month in the U.S. Both occasions mark a time to show support for the millions of people who live with Alzheimer’s disease.1

  • Alzheimer’s disease leads to the progressive loss of many essential mental and physical abilities.2
  • Alzheimer’s disease is the 6th leading cause of death among U.S. adults.3
  • In 2023, Alzheimer's and other dementias will cost $345 billion in the U.S.4

More than 6 million people are living with Alzheimer's dementia in the U.S. Up to 13.8 million may be affected by 2060.5

Alzheimer’s population set to soar

Over 7 million new patients expected by 2060

The dark line shows actual numbers of Alzheimer’s patients today. The lighter line projects forward until 2060:

Actual and projected people with Alzheimer’s Dementia, 2020 to 2060 (U.S.) Actual and projected people with Alzheimer’s Dementia, 2020 to 2060 (U.S.)

[Image adapted from: Alzheimer’s Association. 2023 Alzheimer's disease facts and figures. Published 2023.]

There is currently no cure available for Alzheimer's disease. The drugs that have recently been approved may provide some improvement in patients who are in the early stages of the disease.  Still, actual progress is only relative, and much work remains.7   

In short, the situation today with Alzheimer’s treatments is confusing. In this article we will review some of the key issues in the Alzheimer’s space, including:

  1. New drugs that are currently approved or pending
  2. Risk, cost and complexity
  3. The longer-term development pipeline

1. New Alzheimer’s drugs: Early stumble, then relative success

There are currently 3 similar drugs to treat Alzheimer’s disease that are either FDA-approved, or pending approval: Aduhelm™, Leqembi® and donanemab. Each belong to a class of medications called beta-amyloid targeted monoclonal antibodies.8 When beta-amyloid accumulates in the brain (called plaques), it can disrupt communication between brain cells, and eventually cause them to die.9

This overall approach is sometimes referred to as the “the amyloid hypothesis.” These drugs function by removing amyloid plaques before they can cause harm.10  

It is important to note that amyloid-removing drugs are only indicated for people who have the early, or mild form of Alzheimer’s. But, only about 1.5 million of the 6.7 million people with Alzheimer’s have the mild cognitive impairment form of Alzheimer’s disease. In short, most patients living with Alzheimer's disease will not qualify for treatment.11

Comparing Aduhelm, Legembi and donanemab

Aduhelm was the first FDA-approved drug in this class. It was granted accelerated FDA approval in 2021. However, amid intense controversy around its clinical trial data, physicians and payers have avoided Aduhelm over concerns for its safety and efficacy.12

The clinical trial results for Leqembi and donanemab were more encouraging. While there’s no exact way to compare differently designed trials, participants taking Leqembi and donanemab saw a statistically significant slower rate of cognitive decline over 18 months.13

Accordingly, Leqembi did receive full FDA approval this past July. And scientists expect that the results for donanemab could also lead to full FDA approval — perhaps before the end of the year.14

The glass-half-full view in each case is that a slower decline can mean more time for patients. Ideally, they and their families can maintain normal life a bit longer and delay the most distressing parts of the disease.15

Those less optimistic note that it’s not clear whether the improvements shown would even be noticeable in the real world. Sadly, all of these trial participants continued to deteriorate during their studies — regardless of whether they got the drug or the placebo.16

2. Risk, cost and complexity of anti-amyloid treatments

In a recent editorial, 3 geriatric medicine specialists summed up the situation with the current group of anti-amyloid treatments:

“From a more practical standpoint, the modest benefits would likely not be questioned by patients, clinicians, or payers if amyloid antibodies were low risk, inexpensive, and simple to administer. However, they are none of these.”17[Emphasis added]

Risk, cost and complexity are a good cross-section of the various factors that will affect how many people wind up benefitting from these drugs. Let’s go through them one at a time.

Risk: The side effects

The FDA notes that there are known side effects with the entire class of antibodies targeting amyloid, the most notable of which is amyloid-related imaging abnormalities (ARIA). ARIA-related brain swelling can infrequently lead to seizures, other severe neurological symptoms, or even death.18

That said, ARIA often displays no symptoms, and usually resolves by itself over time. When symptoms do occur, they are usually mild — a headache or increased confusion.19

Certain factors, such as, timing, genetics and other brain-related conditions, may increase the risk of ARIA.20  

Anti-amyloid drugs should be used only in the early stages of Alzheimer’s disease.21 One reason is that amyloid-lowering therapies may deliver a greater benefit when used earlier in the disease progression.22

Also related to timing is that serious side-effects from amyloid-related imaging abnormalities may be an unintended result of removing amyloid plaques — doing so may weaken cerebral blood vessels. Therefore, since there is simply less amyloid plaque present in the early stages, the risks associated with removing it should be lower.23

The gene variant called APOE4 is linked to a higher risk for ARIA. In trials, all 3 amyloid antibody drugs saw a greater risk of ARIA among people who carried copies of this gene.24

Overall, 15% of the Alzheimer's population carries 2 copies of the APOE4 mutation and fall into a high-risk group.25 The genetic-ARIA link is serious enough that the Department of Veterans Affairs has said it won’t routinely cover anti-amyloid treatment for those with 2 copies of APOE4.26

The FDA product label for Leqembi recommends that patients undergo genetic testing for APOE4.27

Anticoagulants are often prescribed in cases of stroke, heart attack and pulmonary embolisms to break down blood clots or prevent clots from forming.28

Many drugs are incompatible with anticoagulants.29 And in trials, using anticoagulants was associated with an increased number of brain hemorrhages in patients taking Leqembi. Therefore, the prescribing information recommends caution when using Leqembi in patients taking anticoagulants.30

Cost: The daunting price of Alzheimer’s treatments 

The wholesale acquisition cost for Leqembi is $26,500 per year. Further, Eli Lilly has said it expects a similar price for donanemab when it is approved.31

Medicare will cover 80% of that $26,500. But a 20% co-pay would leave patients paying close to $5,000 out-of-pocket per year. (Different Medicare arrangements would influence these costs.)32

In addition to the cost of the drugs, patients must adhere to an extensive battery of pre-and-post treatment medical visits, brain scans, laboratory tests and infusion center appointments. That said, treatment costs may actually total approximately $90,000 per year.33

Worse, analysts warn that these new costs will be hard for the health system to absorb over the short term. The results could include other needed services being displaced, payers sharply restricting access, or that health care insurance costs could grow rapidly.34

Of course, total costs will ultimately depend on how many people take the new drugs. As noted, about 1.5 million people have the treatable form of Alzheimer’s disease.35

The makers of Leqembi (Eisai Co. and Biogen Inc.) expect 10,000 people to take the drug by March 2024, and as many as 100,000 by 2026.36 But even at this relatively modest uptake, annual costs for 100,000 treatments would still run to almost $3 billion:

Projected sales for Leqembi based on uptake

10,000 utilizers by 2024, 100,000 users by 2026

Each bar represents potential sales figures bases on number of users.

Projected annual spending on Leqembi Projected annual spending on Leqembi

[Image adapted from: KFF. New Alzheimer’s Drugs Spark Hope for Patients and Cost Concerns for Medicare. Published July 6, 2023.]

Complexity: Drug administration and access to imaging technology

In addition to being expensive, anti-amyloid drugs are very complicated to administer. Depending on utilization, they may require more resources than are currently available.

There continues to be a shortage of neurology specialists who treat Alzheimer’s. The American Academy of Neurology recently found that there may be 28,000 fewer neurologists than needed by 2025.37

Looking specifically at dementia care, a recent study showed that 47% of patients in urban areas had access to neurology care. That drops by nearly 10% for rural areas, where 38% of patients could access neurology care.38

Alzheimer’s care suffering from lack of specialists

Dementia patients struggle to access care

A shortfall of neurology specialists is affecting dementia care in general and may also slow the use of new Alzheimer’s drugs.

[Image adapted from: American Academy of Neurology. People in rural areas less likely to receive specialty care for neurologic conditions. Published December 23, 2020.]

Access to imaging technology is another issue. All potential Alzheimer’s patients will need both preliminary and frequently updated brain scans. These are required both to detect amyloid plaques and to monitor for symptoms of ARIA.39  

With potentially tens, or hundreds of thousands more patients, neuroimaging centers will need to increase their capacity to perform many more brain MRI and PET scans.40

Leqembi is administered by infusion every 2 weeks; for donanemab it is every 4 weeks. Infusion centers will need to accommodate more patients, as capacity for these specialized facilities is already tight.41, 42

In fact, even before any anti-amyloid drugs were approved, industry experts worried that adding an infusible drug for Alzheimer's disease could overwhelm the capacity of non-oncology office-based infusion centers.43

Given these capacity issues, the RAND corporation has calculated a worst-case scenario in which patients might wait over 18 months for treatment.44

3. The longer-term Alzheimer’s drug development pipeline

Since the currently approved drug treatments for Alzheimer’s seem underwhelming, this brings us to the longer-term development pipeline. Is there something much better on the horizon?

Unfortunately, the news on this front is not encouraging.

As of January 1 of this year, there were 187 clinical trials in Phases 1, 2 or 3, assessing 141 unique treatments for Alzheimer’s. Of these treatments, 25% continue to target amyloid beta or tau.45

The continued focus on amyloids is frustrating to some researchers. In fact, over recent years, many scientists have been calling for a wider range of research areas — beyond amyloid and tau.46

Why? 

  • First, it’s not even clear that amyloid plaques actually cause Alzheimer’s in any meaningful sense. One commonly cited objection is that up to 40% of people in their 70s have amyloid deposits in their brains, but still have normal cognition.47
  • The second glaring issue is that the results of this approach have been weak. Overall, the billions of dollars and decades of effort invested in the amyloid hypothesis have mainly yielded a spectacular failure rate.48
  • The decidedly modest results to date for drugs like Leqembi and donanemab suggest that Alzheimer’s is more complex than we thought. It may be that amyloid is not the only factor in Alzheimer disease progression.49

Therefore, many see progress in the fact that there are trials underway on approximately 20 different disease targets. These include genes and neurotransmitter receptors, plus at least 15 trials that are looking at various different approaches. 50

But consider the implication of what this new research diversity is really telling us: Basically, we still don’t know which approach will work.51

In light of these and other difficulties, one analysis recently found that it is “highly unlikely” that a breakthrough drug for memory care will emerge within the next 5 years.52

In perspective

Clearly, there continues to be tremendous activity in the Alzheimer’s space. That activity has recently yielded some advances, although skeptics insist that these successes are minor, and only relative.53

We have discussed some potential roadblocks to widespread use of the anti-amyloid drugs. While these concerns are real, for the most part they stem from the assumption that millions of people might be treated with these drugs.54 Given that only 22% of the total Alzheimer’s population could qualify for treatment, this is unlikely.55

That said, interest in these new treatments is high. We can expect many thousands of people to use them.56 The key here, it seems, is whether we can use the collective experience of these patients to learn more about how to better treat Alzheimer’s in the future. 

Finally, you can rely on Optum Rx to provide specialty pharmacy programs that are especially well-equipped with a wide range of management tools and strategies. Our independent panel of expert clinicians follows a rigorous process to evaluate the evidence supporting FDA approval. And we already have plans in place to supply the appropriate utilization strategies for your plan or your clients’ plans.

Be sure to watch for the November edition of our Drugs to Watch series, where we plan to have in-depth coverage of the next anti-amyloid drug, donanemab.

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Sources

  1. Alzheimer's Foundation of America. Alzheimer’s Awareness Month. Accessed July 13, 2023.
  2. Alzheimer’s Association. 2023 Alzheimer's disease facts and figures. Published 2023. Accessed August 3, 2023.
  3. Centers for Disease Control and Prevention. Alzheimer’s Disease and Related Dementias. Last Reviewed: October 26, 2020. Accessed July 12, 2023.
  4. Alzheimer’s Association. 2023 Alzheimer's disease facts and figures. Published 2023. Accessed August 3, 2023.
  5. Ibid.
  6. Association of American Medical Colleges. AAMC NEWS. Recent breakthroughs in Alzheimer’s research provide hope for patients. Published January 24, 2023.
  7. JAMA Network. Editorial: Ushering in a New Era of Alzheimer Disease Therapy. Published July 17, 2023. Accessed July 31, 2023.
  8. Alzheimer’s Association. Beta-amyloid and the amyloid hypothesis. Updated March 2017. Accessed August 3, 2023.
  9. Ibid.
  10. Ibid.
  11. Medscape Neurology[NJM1] . New Alzheimer's Drugs: Setting Realistic Expectations. Published July 25, 2023. Accessed August 8, 2023.
  12. JAMA Network. Editorial: Ushering in a New Era of Alzheimer Disease Therapy. Published July 17, 2023. Accessed July 31, 2023.
  13. Medscape Neurology. New Alzheimer's Drugs: Setting Realistic Expectations. Published July 25, 2023. Accessed August 8, 2023.
  14. JAMA Network. Editorial: Ushering in a New Era of Alzheimer Disease Therapy. Published July 17, 2023. Accessed July 31, 2023.
  15. Medscape Neurology. New Alzheimer's Drugs: Setting Realistic Expectations. Published July 25, 2023. Accessed August 8, 2023.
  16. Science. Lilly's Alzheimer's Data for Donanemab. Published July 18, 2023. Accessed August 2, 2023.
  17. JAMA Network. Editorial: Ushering in a New Era of Alzheimer Disease Therapy. Published July 17, 2023. Accessed July 31, 2023.
  18. U.S. Food and Drug Administration. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. Published July 6, 2023. Accessed July 13, 2023.
  19. JAMA Network. Donanemab in Early Symptomatic Alzheimer Disease The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. Published July 17, 2023. Accessed August 3, 2023.
  20. U.S. Food and Drug Administration. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. Published July 6, 2023. Accessed July 13, 2023.
  21. Ibid.
  22. JAMA Network. Donanemab in Early Symptomatic Alzheimer Disease The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. Published July 17, 2023. Accessed August 3, 2023.
  23. JAMA Network. Editorial: Ushering in a New Era of Alzheimer Disease Therapy. Published July 17, 2023. Accessed July 31, 2023.
  24. Frontiers in Neurology. Amyloid-Related Imaging Abnormalities With Anti-amyloid Antibodies for the Treatment of Dementia Due to Alzheimer's Disease. Published March 23, 2022. Accessed August 10, 2023.
  25. Medscape Neurology. New Alzheimer's Drugs: Setting Realistic Expectations. Published July 25, 2023. Accessed August 8, 2023.
  26. Science. Will unpredictable side effects dim the promise of new Alzheimer’s drugs? Published August 2, 2023. Accessed August 10, 2023.
  27. U.S. Food and Drug Administration. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. Published July 6, 2023. Accessed July 13, 2023.
  28. Cleveland Clinic. Anticoagulants. Last reviewed January 10, 2022. Accessed August 15, 2023.
  29. Science. Will unpredictable side effects dim the promise of new Alzheimer’s drugs? Published August 2, 2023. Accessed August 10, 2023.
  30. U.S. Food and Drug Administration. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. Published July 6, 2023. Accessed July 13, 2023.
  31. Bloomberg. The Pros and Cons of New Drugs to Treat Alzheimer’s Disease. Updated on July 7, 2023. Accessed August 11, 2023.
  32. KFF. New Alzheimer’s Drugs Spark Hope for Patients and Cost Concerns for Medicare. Published July 6, 2023. Accessed August 2, 2023.
  33. Medscape Neurology. New Alzheimer's Drugs: Setting Realistic Expectations. Published July 25, 2023. Accessed August 8, 2023.
  34. The Institute for Clinical and Economic Review (ICER). ICER Publishes Final Evidence Report on Lecanemab for Alzheimer’s Disease. Published April 17, 2023. Accessed August 11, 2023.
  35. Medscape Neurology. New Alzheimer's Drugs: Setting Realistic Expectations. Published July 25, 2023. Accessed August 8, 2023.
  36. Reuters. Major US health systems expect to offer Alzheimer's drug Leqembi in a few months. Published August 7, 2023. Accessed August 8, 2023.
  37. Neurology. A Shortage of Neurologists – We Must Act Now. Published June 15, 2021. Accessed August 11, 2023.
  38. American Academy of Neurology. People in rural areas less likely to receive specialty care for neurologic conditions. Published December 23, 2020. Accessed August 15, 2023.
  39. Medscape Neurology. New Alzheimer's Drugs: Setting Realistic Expectations. Published July 25, 2023. Accessed August 8, 2023.
  40. Ibid.
  41. Ibid.
  42. Medscape Medical News. New Drugs Could Overwhelm Infusion Centers' Capacity. Published June 25, 2019. Accessed August 17, 2023.
  43. Ibid.
  44. RAND Corporation. Assessing the Preparedness of the U.S. Health Care System Infrastructure for an Alzheimer's Treatment. Published 2017. Accessed August 11, 2023.
  45. Alzheimer’s Association. Alzheimer's disease drug development pipeline: 2023. Published May 25, 2023. Accessed July 14, 2023.
  46. Critical Reviews in Clinical Laboratory Science. Beyond the amyloid hypothesis: how current research implicates autoimmunity in Alzheimer's disease pathogenesis. Published March 20, 2023. Accessed August 3, 2023.
  47. Scientific American. Alzheimer’s, Inc.: When a Hypothesis Becomes Too Big to Fail. Published August 25, 2021. Accessed August 7, 2023.
  48. Ibid.
  49. JAMA Network. Editorial: Ushering in a New Era of Alzheimer Disease Therapy. Published July 17, 2023. Accessed July 31, 2023.
  50. Alzheimer’s Association. Alzheimer's disease drug development pipeline: 2023. Published May 25, 2023. Accessed July 14, 2023.
  51. Advisory Board. Why a breakthrough cure for memory care disorders likely isn't coming soon. Updated on March 17, 2023. Accessed July 13, 2023.
  52. Ibid.
  53. Science. Lilly's Alzheimer's Data for Donanemab. Published July 18, 2023. Accessed August 2, 2023.
  54. RAND Corporation. Assessing the Preparedness of the U.S. Health Care System Infrastructure for an Alzheimer's Treatment. Published 2017. Accessed August 11, 2023.
  55. Medscape Neurology. New Alzheimer's Drugs: Setting Realistic Expectations. Published July 25, 2023. Accessed August 8, 2023.
  56.  KFF. New Alzheimer’s Drugs Spark Hope for Patients and Cost Concerns for Medicare. Published July 6, 2023. Accessed August 2, 2023.
  57.  Note some sources (not all) in this list are italicized as they are publication names.