Was 'breakthrough' Alzheimer's drug oversold?

A lot of hype about an alleged breakthrough drug for Alzheimer’s disease may leave some families disappointed yet again. On Sept. 27, 2022, pharmaceutical company Eisai in Tokyo and biotechnology firm Biogen in Cambridge, Massachusetts, issued a press release claiming a drug called lecanemab slowed the rate of cognitive decline for adults with Alzheimer’s disease by 27%. The new findings were hailed as a significant advance. However, it is far too early to know what its true benefits and risks may be.

This agent is a monoclonal antibody designed to clear clumps of amyloid-β protein from the brain, which are thought to be a root cause of Alzheimer’s. Because it works in a different way, it may complement other therapies and be a real-game changer. Unfortunately, it may have been oversold and many people may think it can do much more than it really can.

“This is interesting and potentially good news. But the devil is in the details. They met their primary outcome in the trial but both treatment and placebo groups continued to decline. However the drug-treated group declined 27% less than the placebo group over 18 months,” said Dr. Paul Newhouse, who is the Chair in Cognitive Disorders Professor of Psychiatry, Pharmacology, and Medicine Director at Vanderbilt Alzheimer’s Disease Research Center, Nashville, Tennessee.

This is in line with the modest effect size seen previously with other agents, such as aducanumab and donenamab.

“It would be helpful to know whether the difference in decline is only seen at the 18 month endpoint or was evident at earlier time points,” Dr. Newhouse said. “In other words, does it take 18 months of administration before you see any treatment benefit compared to placebo?”

Currently available treatments work by a different mechanism, primarily affecting chemical mechanisms involved in attention and memory. It is hoped that lecanemab will work well with existing treatments as it attacks the underlying abnormal proteins associated with Alzheimer’s disease. However, Dr. Newhouse said currently it is unknown if that will happen.

“We need to see the full information on this trial. This relatively modest benefit will have to be balanced against issues of potential side effects. Brain swelling and micro-bleeds were significantly increased in volunteers treated with this agent.”

Dr. Newhouse said a big question to be answered is how significant the benefits are when weighed against the drug’s cost and the regular MRI brain scans for side effect monitoring. There are also the costs of biweekly intravenous administration.

These results are potentially a validation of the hypothesis that removing amyloid from the brain will positively influence the disease course. However it also suggests that it may be necessary to intervene even earlier in the disease process to stop it in its tracks or prevent it from occurring at all. These types of studies are ongoing now and will be critically important.

Dr. Judy Heidebrink, a professor of neurology at University of Michigan and co-leader of the Clinical Core of the Michigan Alzheimer’s Disease Research Center, Ann Arbor, Michigan, agrees with Dr. Newhouse and said many people already think this new agent will be a game-changer.

“I think it’s an important advance in demonstrating that a treatment targeting amyloid can slow the progression of Alzheimer’s disease in persons with mild symptoms. However, lecanemab doesn’t reverse or completely stop progression, and the amount of slowing appears small. So, it looks more like a ‘base hit’ than a ‘home run,’” Dr. Heidebrink said.

The recommended treatments for Alzheimer’s currently are donepezil, galantamine, rivastigmine, and memantine for treating symptoms. The U.S. Food and Drug Administration (FDA) in 2021 approved aducanumab for treating Alzheimer’s disease and it is marketed as Aduhelm by Biogen. To be eligible for this drug, individuals must have progressive weakness of memory or thinking that is mild, as determined by quantitative testing. Secondly, they must undergo a spinal tap or PET scan to show that they have amyloid in the brain.

“Another drug that targets amyloid, aducanumab, was approved by the FDA last year, but is rarely used due to uncertainty that the benefits outweigh the risks. In comparison to aducanumab, lecanemab appears to have more consistent evidence of benefit and less frequent side effects,” said Dr. Heidebrink.

If I have mild cognitive impairment should I take lecanemab?

This new agent is not being recommended for the millions of older adults who have mild cognitive impairment (MCI). That’s because MCI has many potential causes, and treatment with lecanemab would be considered only if there is evidence, such as with an amyloid PET scan, that someone has MCI due to Alzheimer’s disease.

“In addition, other health conditions need to be taken into account when considering use of lecanemab,” explained Dr. Heidebrink.

The latest study included 1,795 adults with early Alzheimer’s disease and the incidence of adverse events associated with anti-amyloid antibodies in the brain occurred in 12.5% of the lecanemab group compared to 1.7% in the placebo group. MCI can develop for multiple reasons, and individuals living with MCI may go on to develop dementia, but others will not.

Currently, there are no specific treatments for MCI. As new treatments for Alzheimer’s disease are developed, these treatments may be tested on patients with MCI. If experimental treatments help slow cognitive decline, the early diagnosis of MCI will become increasingly important. MCI refers to when there is a decline in cognitive abilities (memory, language and/or reasoning) but not to the extent that it affects routine activities, like banking, driving, managing medications, and taking care of usual responsibilities.

MCI is distinguished from dementia, a condition in which cognitive decline is significant enough to affect the ability to carry out usual daily functions. MCI can be a sign of progression to a state of dementia and is known as a risk factor for dementia. There are a number of lifestyle modifications that have been shown to help individuals with MCI and they include staying active, eating right and maintaining good sleep hygiene.

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