What should people living with dementia and their families take away from the recent data published on lecanemab, the Alzheimer’s drug developed by Biogen and the Japanese firm Eisai?
The drugmakers’ announcement of their Phase 3 trial results got lots of attention in the popular press. Some stories heralded the drug as a “breakthough.” But even experts disagree about the drug’s benefits. While many researchers see the study results as an important step forward, many clinical physicians who treat patients with Alzheimer’s Disease remain skeptical about the drug’s real-world benefits and worried about its side effects.
What is lecanemab?
Lecanemab is a monoclonal antibody, a drug that stimulates the immune system to attack a specific substance in our bodies. It is directed at a protein called amyloid beta, which is found at high levels in the brains of people with Alzheimer’s. One problem: While this protein is associated with Alzheimer’s, there has been little evidence that it causes the disease. Or that reducing it benefits patients with Alzheimer’s in a significant way.
At the same time, other researchers believe that buildup of a different protein, called tau, may be a cause of Alzheimer’s. Still others think it may be some combination of both beta and tau.
Optimists are excited about lecanemab because the trial suggests drugs that reduce the levels of amyloid beta also could slow the progression of Alzheimer’s. In addition, the recent trials suggest lecanemab also may lower tau levels. For patients with the disease, it seems to buy time. How much remains highly uncertain.
But there are many caveats.
First, this drug, which has yet to be approved by the FDA, shows promise only for those with mild, early-stage Alzheimer’s Disease. There is no evidence it helps those with moderate or advanced Alzheimer’s or with any of the many other forms of dementia. And even for those with mild Alzheimer’s, it is no cure. It will not stop progression of Alzheimer’s nor will it reverse any brain damage.
Second, we don’t know how the drugmakers will price the drug and whether Medicare or private insurance will pay for it. And if they do, under what circumstances.
We don’t know if Medicare will pay for lecanemab. And without knowing its cost to consumers, there is no way to judge its real-world value. And keep in mind, it is an infusion therapy that must be administered for life, or at least for as long as it shows benefits. And the longer it works, the more it will cost.
Some will say, “Alzheimer’s is so terrible, I’ll try anything.” But for people with limited resources, there is an opportunity cost that comes with spending thousands of dollars a year on a drug that may have minimal benefits. For example, would spending money on a drug reduce the funds available to pay for a personal care aide or for regular rides to the doctor? What about those who cannot afford the drug at all?
The results of the Phase 3 trial, which followed about 1800 people for 18 months, suggests it might slow cognitive decline, perhaps by several months. But because the trial ran for only 18 months, it is impossible to know what happens in the long run. Do the benefits continue or fade away? The study suggests the drug’s ability to slow cognitive decline seems to wane after a period of time.
We also don’t know why some patients benefit and others don’t. Increasingly, researchers believe that Alzheimer’s may be many diseases, much like cancer. As a result, therapies may benefit those with some forms of Alzheimer’s but not others.
There is another big problem with trying to understand the potential benefits: Experts can’t measure cognitive decline very well, especially in its early stages.
They use two measures, the Clinical Dementia Rating and the Alzheimer’s Disease Assessment Scale (ADAS). On a combined scale, the study scored cognitive decline at 1.21 for those taking the drug and 1.66 for those on the placebo. That sounds significant, but the actual math means it is relatively small. One expert, who generally is positive about the drug’s potential, calls the result, “minimally clinically important.”
But more concerning, many neuroscientists doubt the value of the scales themselves. These measures underestimate cognitive impairment, especially in early stages. So while the trial results are quite precise–an improvement of exactly 0.45 points–they may not be very reliable measures of real-world benefits.
Then there are the side effects. Adverse events include brain swelling and bleeding (known as ARIA). On one hand, while brain bleeds sound scary, they had little clinical impact on study participants. But on the other, these patients were watched much more closely than the public at large would be. An older adult taking a blood thinner for heart disease, for instance, might be at greater risk without close observation.
Studies of the drug also found some shrinking in brain volume among trial participants. This is worrisome because shrinking brain volume is itself a symptom of dementia.
The trial that Eisai and Biogen announced is not the only study of lecanemab. The National Institute on Aging, part of NIH, is funding two others—one looking at how the drug affects people with varying levels of amyloid protein but no diagnosis of dementia. The second is exploring the use of lecanemab in combination with a second drug aimed at reducing levels of tau.
Paradoxically, these studies suggest another potential risk to patients if lecanemab becomes widely available: Taking this drug would disqualify you from participating in trials for newer, potentially better drugs. If you or a loved one has mild cognitive impairment now, does it make sense to wait for something better?
If FDA approves lecanemab, and it probably will, people with early stage Alzheimer’s will have to make some tough choices.