A treatment that improves Alzheimer’s disease would be a great advance, but Leqembi (lecanemab), which recently received accelerated approval from the FDA, is not that drug. Yes, lecanemab slows decline to an extent detectable on a test, but not to an extent that a relative or caretaker would notice. This drug doesn’t actually make anything better. It just slows the rate that someone goes downhill over 18 months — by less than half a point on an 18 point scale. And we don’t know whether things get better or worse after that.
Leqembi is similar to Aduhelm (aducanumab), approved last year by the FDA, despite its advisory committee soundly rejecting it. Leqembi is slightly more effective — although it had no significant effect in women, those under age 65 and people who have two copies of APOE4, a gene variant that increased Alzheimer’s risk. Both Aduhelm and Leqembi cause brain bleeds, which can be fatal.
Leqembi and Aduhelm destroy amyloid plaque, a kind of protein that patients with Alzheimer’s have more of in their brains. It’s not clear whether amyloid causes Alzheimer’s, because many patients with brains full of amyloid have no symptoms of dementia. Amyloid may be a harmless marker of disease — or may even be a protective effort by the body to repair damaged cells. In any case, amyloid can fuse to blood vessel walls, and when the amyloid is attacked by a drug, the blood vessels in the brain may leak, sometimes catastrophically. Small bleeds are common; Aduhelm caused brain bleeding or swelling in 40% of patients; Leqembi is slightly less harmful, at about 21.5%, but that’s still one out of five patients.
Three people died from bleeding while taking Leqembi in studies done before the drug was approved. That’s especially concerning, because people in experimental trials tend to be healthier than people in the general population, so problems that show up in people who volunteered for a clinical trial are likely to be much greater in the general population. Bleeding is also likely be more common in those on anticoagulant drugs — blood thinners — which are given to elders with atrial fibrillation (a common condition) to reduce the risk of stroke. Two of three of the deaths during lecanemab treatment were in patients on blood thinners.
People with the APOE4 allele are more likely to have Alzheimer’s disease — and are also the most likely to bleed from amyloid-busting drugs. Black patients are more likely to have APOE4 variations, and thus more likely to have risks of bleeding. Only 2.6% of the subjects in the lecanemab trials were Black, only slightly better than the less than 1% of Black subjects in the Aduhelm studies. Nonetheless, Biogen and Eisai, collaborating companies for both Leqembi and Aduhelm, have targeted organizations of color to promote their drugs.
Biogen/Eisai have promoted a “Brain Guide” that reinforces the notion that mild memory changes must be addressed medically, unecessarily worrying elders. The companies also promoted a test for mild cognitive impairment that anyone would fail (do you ever lose your “train of thought or the thread of conversations, books, or movies”?) on a now-defunct website called “It’s Time We Know.” The website seemed designed to make anyone who misplaced their keys think that they had mild cognitive impairment (MCI), an ill-defined condition that is a risk factor for Alzheimer’s. In fact, MCI is often due to medications, fatigue or depression. And even when MCI is not caused by these factors, it often remains stable, regresses and can disappear entirely.
The Alzheimer’s Association, which takes money from Biogen, called the approval of Aduhelm a “victory for people living with Alzheimer’s and their families.” Of Leqembi, the Association claims that this treatment addresses “the underlying biology of Alzheimer’s and changes the course of the disease in a meaningful way for people in the early stage” and, again without evidence, that “individuals will have more time to participate in daily life and live independently.” UsAgainstAlzheimer’s calls the accelerated approval of Leqembi “tremendous news and a true milestone in the fight against Alzheimer’s.”
Instead of promoting drugs that don’t improve functioning, we should focus on preventing dementia through exercise, smoking cessation and treating high blood pressure, high cholesterol and diabetes — all of which reduce cognitive decline- and many other chronic diseases. Hearing aids also lower the risk of dementia.
The Alzheimer’s Association, predictably, has been pressuring the Centers for Medicare and Medicaid Services (CMS) to have Medicare cover Leqembi. There’s no reason to think that Leqembi will be marketed any more responsibly than Aduhelm. It’s up to physicians, patients, and CMS to reject an expensive drug that improves no symptoms and puts users at risk of fatal bleeds.
Adriane Fugh-Berman (firstname.lastname@example.org) is a professor in the departments of Pharmacology and Physiology and in the Department of Family Medicine at Georgetown University Medical Center, where she’s also the director of PharmedOut, a research and education project that promotes evidence-based prescribing.