A closely watched clinical trial of a potential Alzheimer’s drug failed to prevent or slow cognitive decline, another disappointment in the long and challenging effort to find solutions to the disease.
The 10-year trial marked the first time people who were genetically predisposed to develop the disease — but who had no symptoms yet — were given a drug meant to stop or slow its decline. The participants were members of an extended family of 6,000 people in Colombia, about 1,200 of whom have a genetic mutation that virtually guarantees they will develop Alzheimer’s disease in their mid-40s to mid-50s.
For many members of the family, who live in Medellín and remote mountain villages, the disease quickly stole their ability to work, communicate and perform basic functions. Many die in their sixties.
In the study, 169 people with the mutation were given 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 identities of people who could get the disease, which is highly stigmatized in their communities.
The study’s researchers had hoped that intervening with a drug years before memory and thinking problems arose could keep the disease at bay and provide important insights into tackling the more common type of Alzheimer’s not caused by a single disease. genetic mutation.
“We are disappointed that crenezumab has not shown a significant clinical benefit,” said Dr. Eric Reiman, executive director of Banner Alzheimer’s Institute, a Phoenix research and treatment center, and leader of the research team, at a news conference. about the results. “Our hearts go out to the families in Colombia and to all others who would benefit as soon as possible from an effective prevention therapy against Alzheimer’s disease. At the same time, we take heart in the knowledge that this study has started 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 disease: amyloid, which forms sticky plaques in the brains of patients with the disease. Years of studies of various drugs that attack amyloid at different stages of the disease have failed. In 2019, Roche stopped two other studies of crenezumab, a monoclonal antibody, in people in the early stages of the more typical Alzheimer’s disease, saying the studies were unlikely to show any 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 unclear whether Aduhelm could help patients, but gave the green light to a program that would allow the approval of drugs of uncertain benefit if they are for serious illnesses with few treatments and if the drugs affect a biological mechanism that can reasonably help patients. The FDA said the biological mechanism was Aduhelm’s ability to attack amyloid, but many Alzheimer’s experts criticized the decision for the poor track record of anti-amyloid therapies. Thursday’s study results only added to the disappointing evidence.
“I wish there was something positive to say,” said Dr. Sam Gandy, the director of the Mount Sinai Center for Cognitive Health, who was not involved in the Colombia investigation.
“The pathogenic mutation in the Colombian family is known to be involved in amyloid metabolism,” said Dr. Gandy, adding, “The thinking was that these were the patients most likely to respond to anti-amyloid antibodies.”
dr. Pierre Tariot, the director of the Banner Alzheimer’s Institute and a leader of the Colombian study, said some data indicated that patients who received crenezumab did better than those who received the placebo, but the differences were not statistically 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 hemorrhage 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 do not include more detailed information from brain imaging or blood analysis of the drug’s effects on proteins and other aspects of Alzheimer’s disease biology. They also did not reflect increases in the dose of crenezumab, which researchers began giving to patients as they learned more about the drug, said Dr. tariot. 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 disease. He said the trial convinced him that “prevention is the best way to look for the solution to Alzheimer’s disease, even if we don’t have a good result today.”
“We know we’ve made a big step in contributing to Alzheimer’s research,” he added. “And now we’re willing to take other steps to look at the solution to this disease.”
The wife of one participant, Maria Areiza of Medellín, said her husband, Hernando, whose last name is being withheld to protect his privacy, was one of the first patients to enroll in the study. Hernando, 45, who worked repairing telephone cables, began developing symptoms of cognitive decline about eight years ago. He has since progressed to Alzheimer’s disease, but can still carry on a conversation. Because his decline was relatively slow, his family had been hopeful that he would benefit from the process.
“I had pinned all my hopes on this study,” his wife said.
Jennie Erin Smith reported from Medellín, Colombia.
