Testing for new Alzheimer’s drugs has yielded disappointing results

A close-up clinical trial of a potential Alzheimer’s drug failed to prevent or slow down cognitive decline, another frustration in a long and difficult effort to find solutions to the disease.

The decade-long trial was the first time people were genetically targeted to develop the disease, but had asymptomatic symptoms, the first time they were given a medicine to stop or delay its decline. Participants were members of a large family of 6,000 people in Colombia, about 1,200 of whom have a genetic mutation that almost guarantees they will develop Alzheimer’s by the mid-40s and mid-50s.

Many family members living in Medellín and remote mountain villages have been quickly robbed of their ability to work, communicate and perform basic functions. Many die at the age of 60.

In the trial, 169 people with the mutation received a placebo or crenezumab drug, produced by Genentech of the Roche Group. Another 83 people without the mutation received placebo as a way to protect the identity of people who may develop the disease, which is highly stigmatized in their communities.

Test researchers hoped that intervention with a drug years before the onset of memory and thinking problems would ward off the disease and prevent the most common type of Alzheimer’s disease that is not caused by a single genetic mutation.

“We are disappointed that crenezumab has not shown significant clinical benefits,” Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute at the Phoenix Research and Treatment Center and leader of the research team, said at a news conference about the results. “Our hearts are on the hearts of Colombian families and all those who would benefit from effective Alzheimer’s prevention therapy as soon as possible.

The results are another setback for drugs targeting a key protein in Alzheimer’s: amyloid, which forms sticky plaques in the brains of patients with the disease. The years spent with various drugs that attack amyloid at different stages of the disease have faded. In 2019, Roche stopped two more trials of crenezumab (a monoclonal antibody) in people in the early stages of a typical Alzheimer’s disease, saying research would be unlikely to show any benefit.

Last year, in a highly controversial decision, the Food and Drug Administration gave its first approval to a drug against amyloid, Aduhelm. The FDA acknowledged that it was not clear whether Aduhelm could help patients, but gave the green light to a program that would allow the licensing of uncertain drugs, if they were for serious under-treatment illnesses if the drugs affected a biological mechanism that would help patients. . The FDA said the biological mechanism was Aduhelm’s ability to attack amyloid, but many Alzheimer’s experts criticized the decision because of the poor track record of amyloid therapies. The results of Thursday’s trial have only added to disappointing evidence.

“I’d rather say something more positive,” Dr. Sam Gandy, director of the Mount Sinai Center for Cognitive Health, was not involved in the Colombian study.

“It is known that pathogenic mutations in the Colombian family are involved in amyloid metabolism,” Dr. Gandy said, adding: “It was thought that these were the most likely to respond to antibodies against amyloid patients.”

Dr. Pierre Tariot Banner, director of the Alzheimer’s Institute and leader of the Colombian study, said some data suggest that patients receiving crenezumab performed better than those receiving placebo, but the differences were not statistically significant.

He also said there was no safety issue with the drug, an important finding because many therapies for amyloid, including Aduhelm, have caused brain bleeding or inflammation in some patients.

Additional details of the trial will be presented at a conference in August. Dr. Tariot and Dr. Reiman said Thursday’s results did not include more detailed information on brain imaging or blood tests on the effects of the medication on protein and other aspects of Alzheimer’s biology. They did not even see an increase in the dose of Crenezumab, as researchers began to learn more about the medicine they were starting to give patients. said Tariot. He said some patients received the highest dose within two years of being in a clinical trial for five to eight years.

Dr. Francisco Lopera, a Colombian neurologist and other research leader, began working with family members a few decades ago and helped determine if their disease was the genetic form of Alzheimer’s. He said the trial convinced him that “prevention is the best way to find a solution to Alzheimer’s disease, even if it does not have a good outcome today.”

“We know that we have made great strides in our contribution to research into Alzheimer’s disease,” he added. “And now we are ready to take other steps to find a solution to this disease.”

The wife of one of the participants, Maria Areiza from Medellín, said that her husband, Hernando, whose last name is reserved to protect her privacy, was one of the first patients to register for the trial. Hernando, 45, who worked on fixing the phone, began developing symptoms of cognitive decline about eight years ago. He has since gone into Alzheimer’s dementia, but may still have a conversation. As his deterioration was relatively slow, his family was hopeful of benefiting from the trial.

“I put all my hopes in this exam,” his wife said.

Jennie Erin Smith contributed to the report in Medellin, Colombia.

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