The word 鈥渜embi鈥� roughly translates as beautiful, elegant or healthy and was somewhat ambitiously chosen as the root for 鈥淟eqembi,鈥� the Alzheimer鈥檚 disease drug that recently made a big media splash thanks to receiving 鈥渁ccelerated approval鈥� by the U.S. Food and Drug Administration, the first regulatory agency in the world to do so.
In 1901, German physician Dr. Alois Alzheimer became intrigued by a patient who at the age of fifty-one showed signs of confusion and memory impairment. Known historically only as 鈥淎uguste D,鈥� she offered a surprisingly insightful self-diagnosis: 鈥淚 have lost myself.鈥� Dr. Alzheimer followed August D carefully for five years, wondering what was going on in that deteriorating brain. Finally, when Auguste died in 1906, he got his chance to find out. Alzheimer鈥檚 post-mortem microscopic examination revealed that his patient鈥檚 brain had undergone some very peculiar changes. A sort of sticky material had deposited in the space between the nerve cells, some of which themselves harbored tiny, twisted fibers. Just a few months after the patient鈥檚 death, at a conference of German psychiatrists, Alzheimer described the 鈥渘eurofibrillary tangles鈥� and 鈥渟enile plaques鈥� that have since become the hallmark of Alzheimer鈥檚 disease. Later analysis revealed that these were mostly composed of beta-amyloid, a type of protein. These deposits interfere with the action of the neurotransmitter acetylcholine which is involved in memory and cognition.
Alzheimer鈥檚 is a devastating disease that has basically defied treatment. Drugs such as donepezil (Aricept), that prevent the breakdown of acetylcholine by the enzyme cholinesterase were approved over two decades ago, and while such cholinesterase inhibitors can result in a small benefit in mental function over the short term, they do not change the progression of the disease. The general opinion is that they are better than nothing, but not by much. It therefore comes as no surprise that the approval of Leqembi (lecanamab) caught the media鈥檚 attention. Words like 鈥渂reakthrough鈥� were bandied about, but just how much of a breakthrough is this medication? A more apt description would be a small crack rather than a breakthrough.
First, let鈥檚 look at the process of 鈥渁ccelerated approval.鈥� This is intended for drugs that have shown some potential for serious diseases that have no significant treatment. Demonstration of clinical benefits is not required, just physiological plausibility. In the case of Leqembi, approval was based on a study that demonstrated a reduction of amyloid protein deposits in the brain as demonstrated by scans.
An experimental group of 898 subjects with mild cognitive impairment in the early stages of Alzheimer鈥檚 disease was treated every two weeks over eighteen months with an intravenous infusion of the drug while a control group of 897 subjects received a placebo. The experimental group showed a reduction in beta-amyloid deposits whereas the control group did not. That was the basis of approval. However, it should be pointed out that no studies have shown that reducing amyloid deposits results in clinical improvement.
The researchers did go on to track the cognitive status of the subjects over the eighteen-month period by interviewing them and their caregivers using questionnaires designed to evaluate memory, orientation, problem-solving, community involvement, hobbies and personal care. For each category, patients received a score of 0-3 based on their performance, with higher numbers indicating greater impairment. A total score of 18 would signify full-blown Alzheimer鈥檚 disease, while 0.5 to 6 is indicative of early stages.
At the beginning of the trial, the experimental and control groups had equal scores of 3.2 and by the end, scores increased in both groups, indicating a worsening of the disease. But the deterioration was not the same in the two groups. The experimental group's average score increased by 1.21 to 4.41, while the placebo group鈥檚 score went up by 1.66 units to 4.86. The difference between 1.21 and 1.66 is 27%, which gave rise to headlines like 鈥淣ew Alzheimer鈥檚 Drug Slows Mental Decline bqy 27%.鈥�
The difference between 4.41 and 4.86 is indeed statistically significant, meaning that it is not likely to be due to chance. Statistical significance, though is not the same as clinical significance. It is unlikely that a patient, or an objective observer, would note a difference in functional abilities based on the difference between these numbers. Of course, some people may be willing to clutch at straws and take the drug no matter how small the chance of a benefit. But there are other issues to consider, such as side effects and cost.
Yes, as with any medication, there are side effects. The major concern is about swelling and bleeding in the brain, although in most cases these resolve without further complication. Still, patients are mandated to have three brain scans during the first 14 weeks of treatment as a precautionary measure. There are also infusion-related symptoms such as flu-like effects, nausea, vomiting and blood pressure changes. Furthermore, people who carry two copies of the APOE4 gene that is recognized as a risk factor for Alzheimer鈥檚, do not benefit from Leqembi.
Then there is the cost. Quite a cost! $26,000 per patient per year! That is a lot of money for what at best is a slight slowing of the decline. If someone is willing to pay out of pocket, that is one thing. But if the drug is paid for by the government, the story is different. Then, one has to raise the question of whether paying for Leqembi is an appropriate use of limited funds. Could that money not be better directed towards the treatment of diseases with a better chance of a satisfactory outcome?
What we have here is an exorbitantly priced drug with significant side effects that may provide minimal benefits for some patients in the earliest stage of Alzheimer鈥檚 disease. Hardly a giant leap, but maybe a small step. As Eisai, the Japanese developer of the drug says, 鈥渓onger trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer鈥檚 disease.鈥� Based on what we know about Leqembi so far, can we say that it is better than nothing? Yes. But not by much.
