Alzheimer's Theory Gains Converts

"The success of Eisai Co.'s new Alzheimer's drug has helped quiet a decadeslong dispute over a leading theory of what causes the disease and how to treat it, with proponents declaring victory and some former skeptics switching sides.

Since the early 1990s, many scientists have thought that removing clumps of a sticky protein called amyloid from the brains of Alzheimer's patients could help slow the disease, if not stall or reverse it. The theory was an outgrowth of the "amyloid hypothesis," which held that an abnormal accumulation of brain amyloid was the central trigger in a complex neurodegenerative process leading to Alzheimer's.

The pharmaceutical industry seized on the idea and began developing drugs to attack amyloid. Until recently, they all failed. Between 2004 and 2021, nearly two dozen drugs flopped in clinical trials.

Late last year, Eisai's Leqembi became the first medicine to clearly show that reducing amyloid could slow down Alzheimer's, a progressive form of dementia that affects six million people in the U.S.

The drug's effectiveness is modest, but undeniable, doctors say. Patients with early-stage symptoms who were given Leqembi over 18 months had cognitive decline that was 27% less than those who received placebos, a delay equal to about five months, according to Eisai,which co-developed the drug with Biogen Inc.

"The amyloid hypothesis has essentially been proven -- it isn't really a hypothesis anymore," said Dennis Selkoe, a professor of neurologic diseases at Harvard Medical School. "The debate now drifts toward whether [Leqembi] is effective enough."

Critics remain. They say that scientists still aren't sure how amyloid removal slows down the disease, and that it might be because of secondary effects such as reducing tangled strands of a protein called tau that is also commonly found in Alzheimer's patients.

Newer drugs such as Leqembi are highly effective at reducing amyloid and yet still produce only a minor slowing of Alzheimer's, said Lon Schneider, an Alzheimer's researcher at the University of Southern California. "The clinical change is so small as to be irrelevant as to whether busting [amyloid] plaques changes the course of the disease," said Dr. Schneider. "If the idea was to bust plaque and improve function, then you really haven't demonstrated that."

In the past, big drugmakers including Pfizer Inc. have pulled back from Alzheimer's research following study failures. Some scientists say the field has focused too singularly on amyloid and needs to reassess its basic assumptions about how to treat the disease.

The amyloid debate intensified following the Food and Drug Administration approval in 2021 of Aduhelm, an anti-amyloid drug developed by Biogen, in partnership with Eisai. In two large studies, Aduhelm was effective at reducing brain amyloid, but produced mixed overall results.

The approval was criticized by some doctors and scientists, including the American Academy of Neurology, for going beyond scientific consensus that amyloid lowering would help patients. Several external experts who had recommended against approval resigned from an FDA advisory committee in protest.

Medicare took the unprecedented step of issuing a blanket denial of routine coverage for anti-amyloid drugs, citing in part continuing controversy over the amyloid hypothesis.

But the Leqembi data have made some skeptics rethink their position on anti-amyloid drugs, said Sam Gandy, a neurologist at Mount Sinai in New York who was critical of the FDA's approval of Aduhelm. "There are skeptics who have come closer to believing, who are convinced enough that they will use the drug," said Dr. Gandy.

The agency overseeing Medicare officials has said that it is open to reconsidering the coverage policy if it receives additional data to answer outstanding questions about anti-amyloid drugs.

David Holtzman, a neurologist at Washington University in St. Louis, said he was skeptical of anti-amyloid drugs because of research showing that the protein accumulates in the brain decades before someone receives an Alzheimer's diagnosis, by which point it might be too late.

"Because the whole amyloid cascade starts about 20 years before the symptoms ever begin, it wasn't clear to me whether it would be too late to remove the amyloid so far into the course of the process," said Dr. Holtzman. "But it does look such as there clearly are effects."

David Knopman, a Mayo Clinic neurologist, said he began to change his mind in early 2021, when Eli Lilly & Co. reported that its anti-amyloid drug donanemab dramatically lowered brain amyloid in Alzheimer's patients and slowed their clinical decline.

Eisai's Phase 3 Leqembi study and, ironically, the failure of a Roche Holding AG drug study late last year, confirmed that removing amyloid could help treat Alzheimer's, Dr. Knopman said. "Together, the studies gave a much clear picture of the degree of amyloid lowering needed to get into a successful zone," he said.

He said Leqembi's success is only a partial vindication of the amyloid hypothesis, which in the minds of many doctors promised to stop Alzheimer's in its tracks or even reverse certain symptoms."The hope was that amyloid removal would have the same therapeutic benefits that vitamin C has for scurvy -- you introduce a treatment and you get a cure."

"We may have reached the limit of what amyloid lowering can do," said Dr. Knopman. "We therefore need to be thinking about alternatives, such as treating people earlier, looking at combination therapies and really looking at alternative targets."" [1]

 

Poorly written article. If even one drug works as expected, then a mass of investors will rush like a mass of bison to put money into drugs that work similarly to this drug. Not always, but usually, a lot of money helps solve complex medical problems. And those problems are here. For example, why did twenty drugs not work and one does? What's the difference?

 

1. U.S. News: Alzheimer's Theory Gains Converts
Walker, Joseph.  Wall Street Journal, Eastern edition; New York, N.Y. [New York, N.Y]. 28 Feb 2023: A.3.