Still No Success Worthy of the Name in Anti-Amyloid Immunotherapies to Treat Alzheimer's Disease

Work on immunotherapies that can clear amyloid-β from the brain, an approach to treating Alzheimer's disease, continues to slowly grind out incremental benefits. First, the prospective treatments failed to clear amyloid-β, then they failed to show any degree of patient benefits, and now the latest trial data indicates a minor slowing of progression in Alzheimer's patients. It is unclear where the ceiling lies in this slow and painful process. Amyloid-β clearance is in principle a good idea, and implementations may become useful, given time and better understanding. It is certainly the case that an expensive therapy that merely slows the progression of Alzheimer's by 27% is not much of a therapy, however.

Sadly, the incentives operating on the leadership of pharmaceutical companies working with therapies targeted to large patient populations tend to favor efforts to spin mediocre outcomes into a success story. Medical regulation makes it so expensive to deploy new therapies that only very large organizations can carry work forward into late stage clinical trials, where the costs rise into the hundreds of millions of dollars. These organizations are beholden first and foremost to their shareholders, not to the patient community. Not that it would be any better were large governmental agencies to do the same thing.

Finally: Big Win on All Outcomes for Lecanemab in Phase 3 Topline Results

Eisai and Biogen yesterday announced positive topline results from the Phase 3 Clarity trial of their anti-amyloid antibody lecanemab. The drug slowed decline on the primary endpoint, CDR-SB, by 27 percent over 18 months, and also nudged down decline on all secondary clinical endpoints. The incidence of the brain edema known as ARIA-E was 12.5 percent, about one-third of that seen with Biogen's approved anti-amyloid antibody Aduhelm. That said, researchers also noted the absolute difference in CDR-SB scores was small, at 0.45, with some questioning how clinically meaningful this is. In the bigger picture, researchers said the data strengthen the amyloid cascade hypothesis. "This confirms the importance of Aβ in disease pathogenesis. This is the first time a therapeutic antibody has clearly changed the course of Alzheimer's disease. It is a pivotal moment in the history of Alzheimer's therapy."

Five big questions about the new Alzheimer's treatment

In the study, people getting lecanemab still had cognitive decline, but it progressed 27% slower than in those on a placebo. That translates to 0.45 points on the 18-point CDR-SB. Although the difference is modest, it's spawning hope. "This does make us feel a little better. These drugs do work." Lecanemab had side effects, most notably certain brain abnormalities seen with other anti-amyloid therapies, including swelling and small hemorrhages in the brain. Neuroimaging turned up these concerns in about 21% of patients on lecanemab, and 9% of those on the placebo. Although these abnormalities often produce no symptoms, about 3% of those getting lecanemab did have symptoms from them.

Doctors aren't sure how the apparently gentler slope of cognitive decline would be perceived by patients and their families. "Does that mean that grandma is going to have a few better days, a few better months, a few better years? It's still an open question." Commenters hesitate to make grand pronouncements, especially after last year's flameout of aducanemab. "We're all feeling a sense of wariness and caution. We want to dig into the data before we make any large conclusions."


Are we certain that Amyloid-β isn't eaten during a 4 to 5 day water fast? Has anyone looked into it?

Posted by: Tom Schaefer at October 6th, 2022 2:47 PM

Erasmus beat me to it.

But of course the limited success will be taken as proof of the current failed hypothesis until the grey beards in white coats pushing it retire or die.

Posted by: Neal Asher at October 6th, 2022 9:42 PM
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