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

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: