A closely watched clinical trial of a potential Alzheimer’s drug has failed to prevent or slow cognitive decline, another disappointment in a long and challenging effort to find solutions for the disease.
The decade-long trial was the first time that people who were genetically destined to develop the disease but did not yet have any symptoms were given a drug intended to stop or slow deterioration. The participants were members of an extended family of 6,000 people in Colombia, about 1,200 of whom have a genetic mutation that practically guarantees that they will develop Alzheimer’s disease between the ages of 40 and 50.
For many family members, who live in Medellin and remote mountain towns, the disease has quickly robbed them of the ability to work, communicate and perform basic functions. Many die in their 60s.
In the trial, 169 people with the mutation received either a placebo or the drug crenezumab, produced by Genentech, part of the Roche Group. Another 83 people without the mutation were given the placebo as a way to protect the identity of people who are likely to develop the disease, which is highly stigmatized in their communities.
Trial investigators hoped that intervening with a drug years before memory and thinking problems emerged could keep the disease at bay and provide important information for addressing the most common type of Alzheimer’s that isn’t driven by a single gene mutation.
“We are disappointed that crenezumab has not shown significant clinical benefit,” Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute, a research and treatment center in Phoenix, and leader of the research team, said at a news conference. on the results “Our hearts go out to the families in Colombia and to all others who would benefit from effective therapy for Alzheimer’s prevention as soon as possible. At the same time, we are encouraged that this study launched and continues to help shape a new era in Alzheimer’s prevention research.”
The results are also another setback for drugs that target a key protein in Alzheimer’s: amyloid, which forms sticky plaques in the brains of patients with the disease. Years of studies with various drugs that attack amyloid at different stages of the disease have failed. In 2019, Roche stopped two other trials of crenezumab, a monoclonal antibody, in people in the early stages of more typical Alzheimer’s disease, saying the studies were unlikely to show benefit.
Last year, in a highly controversial decision, the Food and Drug Administration granted its first approval of an anti-amyloid drug, Aduhelm. The FDA acknowledged that it was not clear whether Aduhelm could help patients, but authorized it under a program that allows the authorization of drugs with uncertain benefits if they are for serious conditions with few treatments and if the drugs affect a biological mechanism that is reasonably likely. help. patients The FDA said the biological mechanism was Aduhelm’s ability to target amyloid, but many Alzheimer’s experts criticized the decision because of the poor track record of anti-amyloid therapies. The results of Thursday’s trial only added to the disappointing evidence.
“I wish there was something more positive to say,” said Dr. Sam Gandy, director of the Mount Sinai Center for Cognitive Health, who was not involved in the Colombia research.
“The pathogenic mutation in the Colombian family is known to be involved in amyloid metabolism,” Dr. Gandy said, adding, “The idea was that these were the patients most likely to respond to anti-amyloid antibodies.” .
Dr. Pierre Tariot, director of the Banner Alzheimer’s Institute and leader of the Colombian research, said some of the data suggested that patients who received crenezumab did better than those who received placebo, but that the differences were not statistically significant. significant.
He also said there were no safety concerns with the drug, an important finding because many anti-amyloid therapies, including Aduhelm, have caused brain bleeding or swelling in some patients.
Additional data from the trial will be presented at a conference in August. Dr. Tariot and Dr. Reiman noted that Thursday’s results did not include more detailed information from brain imaging or blood tests of the drug’s effects on proteins and other aspects of Alzheimer’s biology. They also didn’t reflect increases in the dose of crenezumab, which the researchers started giving patients as they learned more about the drug, Dr. Tariot said. He said some patients received up to two years of the highest dose during the five to eight years they were in the clinical trial.
Dr. Francisco Lopera, a Colombian neurologist and another research leader, began working with the family members decades ago and helped determine that their condition was a genetic form of Alzheimer’s. He said the trial had convinced him that “prevention is the best way to find a solution for Alzheimer’s disease, even if we don’t have a good outcome today.”
“We know we made a big step forward in contributing to Alzheimer’s disease research,” 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, María Areiza from Medellín, said that her husband, Hernando, whose last name is withheld to protect his privacy, was one of the first patients to enroll in the trial. Hernando, 45, who worked fixing telephone wires, began developing symptoms of cognitive decline about eight years ago. He has since progressed to Alzheimer’s dementia, but can still carry on a conversation. Because his deterioration has been relatively slow, his family was hopeful that he was benefiting from the trial.
“I had pinned all my hopes on this study,” his wife said.
Jennie Erin Smith contributed reporting from Medellin, Colombia.