There is a new treatment for early Alzheimer’s disease that has been approved by the FDA. The trade name is Lequimbi and the generic name is Lecanemab. It is a monoclonal antibody (all of this class of medicines end in “mab) that targets the protein called amyloid-beta that accumulates in the brain of many patients with dementia due to Alzheimer’s disease. The press has been full of articles about this treatment, but it is important to understand the evidence for how well it works and in what kind of patients. I will go through that evidence in this post.
Who does Lecanemab work for?
The study that led to the FDA approval was done in people with early Alzheimer’s disease or what is called mild cognitive impairment. People with mild cognitive impairment often progress to dementia from Alzheimer’s disease. All of the people in the study had confirmed amyloid-beta deposition in the brain documented by PET scan or spinal fluid from a spinal tap. Not everyone one who has dementia has amyloid. There are many other kinds of dementia including vascular dementia, Lewy body dementia, frontotemporal dementia, mixed dementia (more than one type), dementia from Parkinson’s disease, dementia from Huntington’s disease, dementia related to alcoholism, and dementia from posterior cortical atrophy. Lecanemab only works for people who have documented excessive amyloid, not for any other type of dementia. In order to be able to take the drug, amyloid has to be documented either by a PET scan or a spinal tap. It has only been used in early Alzheimer’s disease. It does not work in people who already have more severe dementia from Alzheimer’ disease.
How well does Lecanemab work?
The study that established the effectiveness of Lecanemab was a placebo controlled double blind randomized trial. That is the gold standard for a clinical trial, so the results should be very reliable.
To measure the degree of cognitive impairment, the investigators used a test called the Clinical Dementia Rating–Sum of Boxes (CDR-SB).
The CDR-SB is measured by semistructured interviews of patients and informants, and cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The range of scores is from 0 (no cognitive impairment) to 18 (severe impairment).
Patients were randomized to be in the treatment group or the control group. There were about equal numbers in both groups. The average baseline CDR-SB score for both treatment and control groups was about 3.2. out of 18 possible, so both groups had very mild impairment at baseline.
Results of the clinical trial of Lecanemab
The trial took place over 18 months. Lecanemab has to be administered through intravenous infusion every two weeks. The control group also got intravenous infusions, but only got a placebo and not the Lecanemab. Both treatment and control groups got slightly worse over the 18 months with increasing CDR-SB scores.
At the end of the 18 months, the CDR-SB score in the control group was 4.86, an increase of 1.66. The CDR-SB score in the Lecanemab group was 4.41, an increase of 1.21. That means that people who got Lecanemab progressed in their cognitive impairment somewhat more slowly than the people who got placebo. Although the difference was modest, it was highly statistically significant. The absolute risk decrease was 9%. The formula to calculate the absolute risk reduction (ARD) is 1-(4.41/4.86)=.09. The number needed to treat to benefit one person (NNT) is 1/.09 = 11. That number means that one out of 11 people with mild cognitive impairment from amyloid deposition will benefit from taking Lecanemab.
Adverse effects
Unfortunately the major adverse effects of Lecanemab are brain swelling and bleeding in the brain. In the clinical trial 12.6% of the treatment group had brain swelling or bleeding compared to almost zero in the control group. The Lecanemab group also had 26% more infusion reactions than the control group. We can calculate the number needed to harm (NNH) for one person to get brain swelling or bleeding. That formula is 1/0.126=7.9. That means that one out of every 8 patients who get Lecanemab will have brain swelling or bleeding. When the number needed to harm is less than the number needed to treat, that is not a good thing! Fortunately most of the people who had these abnormalities on scans did not have any symptoms. Nonetheless, potentially serious adverse effects from Lecanemab are common enough to be concerning.
Because of the risk of bleeding in the brain, anyone who is on any blood thinner including aspirin is not eligible for Lecanemab, nor is anyone else who may be pre-disposed to bleeding.
Cost
A one year supply of Lecanemab costs $26,500. Your Medicare part D, which pays for medicines, or your Medicare Advantage plan may or may not cover the cost of this drug. That cost does not include the cost of the PET scan or the spinal tap that needs to be done before anyone is eligible to to take Lecanemab.
Bottom Line
Lecanemab is the first drug that shows clear benefit in slowing the progression of Alzheimers’s disease related to amyloid-beta deposition in the brain. At this point the effects of Lecanemab on the progression of early Alzheimer’s disease are modest at best, at the cost of significant side effects. This research is promising, but at this point I think that the modest benefits may be outweighed by the very significant and sometimes dangerous side effects.