In April, the future was looking bleak for an experimental Alzheimer's drug called valiltramiprosate, or ALZ-801.
Researchers had just released topline results of a study of more than 300 people age 50 or older, who were genetically predisposed to Alzheimer's. Overall, those who got the drug did no better than those given a placebo.
But in September, a closer look at the results revealed benefits for a subgroup of 125 people who had only mild memory problems when they started taking the drug.
Those participants, initially diagnosed with mild cognitive impairment rather than mild dementia, "showed very meaningful responses," says Dr. Susan Abushakra, chief medical officer of Alzheon, the drug's maker.
By one measure, the drug slowed cognitive decline by 52% in people with mild cognitive impairment. That result appears comparable with benefits from the two Alzheimer's drugs now on the market: lecanemab and donabemab.
But the true effect of ALZ-801 is hard to quantify because of the relatively small number of participants in the group with mild cognitive impairment.
More robust results came from measures of brain atrophy — the shrinkage that tends to come with Alzheimer's.
In the hippocampus, for example, participants who got ALZ-801 experienced about 18% less atrophy than those who got a placebo.
That's an important difference, Abushakra says, because the hippocampus is critical to memory and thinking.
The findings were published in the journal Drugs. The study was supported by a $47 million grant from the National Institutes of Health.
A drug that's different
Ordinarily, results like that would probably fall short of the evidence required for approval by the Food and Drug Administration.
But ALZ-801 may get special consideration because it has potential advantages over the two drugs already on the market.
Those drugs are both monoclonal antibodies given by intravenous infusions. That adds to the cost and requires patients to make multiple trips to an infusion center.
ALZ-801 is a twice-daily pill that can be taken at home.
Also, the monoclonal antibodies work primarily by breaking down sticky amyloid plaques. These plaques form after fragments of a misfolded protein called beta-amyloid begin to clump together.
Alzheon's product is meant to keep plaques from forming in the first place, by preventing amyloid proteins from clumping at all.
As a result, ALZ-801 doesn't cause the swelling or bleeding in the brain that often comes with monoclonal antibody treatment.
A safer treatment for a high-risk group
The availability of a safer drug like ALZ-801 could be a boon to people who carry two copies of a gene called APOE4.
Their genetic status means they have about 10 times the usual risk of developing Alzheimer's. As a result, even though APOE4/4 carriers make up only about 2% of the population, they represent about 15% of all people diagnosed with the disease.
Unfortunately, people with APOE4 genes are not only more vulnerable to Alzheimer's, they are also more likely to experience side effects from treatment with monoclonal antibodies.
"These individuals are at higher risk for inflammation in the brain that can be quite serious," says Jessica Langbaum, an Alzheimer's researcher at Banner Health in Phoenix.
Even so, Langbaum thinks people with the APOE4/4 genes can be treated safely with the current monoclonal antibodies. That could mean starting with a lower dose, she says, or beginning treatment earlier in the disease, when fewer amyloid plaques are present.
But David Watson, a scientist who carries two copies of the APOE4 gene, thinks people like him need a safer drug.
Watson, a co-author of the new study, also notes that ALZ may have benefits beyond those seen with monoclonal antibodies. For example, he says, the experimental drug appears better at reducing levels of a protein fragment associated with brain cell death.
"We're really making a difference in keeping neurons alive," he says.
More evidence of the drug's effectiveness is coming from people who have kept taking ALZ-801 after the initial 18-month study period ended, Watson says.
Despite carrying genes that usually lead to a swift decline, he says, "many of them are holding their own" in their 60s and 70s.
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