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 decade-long trial was the first time that people genetically destined to develop the disease — but not yet showing any symptoms — were given a drug designed to halt or slow the 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 in their 40s and 50s.
For many family members, who live in Medellín and remote mountain villages, the disease quickly robbed them of their ability to work, communicate and perform basic functions. Many die at age 60.
In the trial, 169 people with the mutation were given either a placebo or the drug crenezumab, made by Genentech, part of the Roche Group. Another 83 people without the mutation were given the placebo as a way of protecting the identities of people likely to develop the disease, which is highly stigmatized in their communities.
The study’s researchers hoped that drug intervention years before memory and thinking problems appeared would keep the disease in check and provide important information for dealing with the most common type of Alzheimer’s that isn’t caused by a single genetic mutation.
“We are disappointed that crenezumab did not show a significant clinical benefit,” 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. about the results. “Our hearts go out to the families in Colombia and everyone else who would benefit from effective Alzheimer’s prevention therapy as soon as possible. At the same time, we are heartened by the knowledge that this study has 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 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 fallen apart. In 2019, Roche stopped two other trials of crenezumab, a monoclonal antibody, in people in the early stages of the more typical Alzheimer’s disease, saying the studies are unlikely to show benefit.
Last year, in a highly controversial decision, the Food and Drug Administration granted its first approval for an anti-amyloid drug, Aduhelm. The FDA acknowledged that it was unclear whether Aduhelm could help patients, but it gave the green light to a program that allows authorization of drugs with uncertain benefits if they are for serious conditions with few treatments and if the drugs affect a biological mechanism with reasonable probability of 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 record of anti-amyloid therapies. The trial results on Thursday only added to the disappointing evidence.
“I wish there was something more positive to say,” said Dr. Sam Gandy, director of the Center for Cognitive Health at Mount Sinai, who was not involved in the research in Colombia.
“The pathogenic mutation in the Colombian family is known to be involved in amyloid metabolism,” Gandy said, adding, “The thinking 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 that some of the data suggested that patients who received crenezumab fared better than those who received the placebo, but the differences were not statistically significant.
He also said there were no safety issues with the drug, an important finding because many anti-amyloid therapies, including Aduhelm, have caused bleeding or swelling in the brain in some patients.
Additional data from the study 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 scans or blood tests of the drug’s effects on proteins and other aspects of the biology of Alzheimer’s disease. They also did not reflect increases in the dose of crenezumab, which researchers began giving patients as they learned more about the drug, 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 family members decades ago and helped determine that his disease was a genetic form of Alzheimer’s. He said the study convinced him that “prevention is the best way to find a solution for Alzheimer’s disease, even if we don’t have a good result today.”
“We know that we have taken a big step in contributing to the research of Alzheimer’s disease,” he added. “And now we are prepared to start other steps in the search for a solution to this disease.”
The wife of one of the participants, Maria Areiza, from Medellín, said her husband, Hernando, whose last name was withheld to protect his privacy, was one of the first patients to enroll in the study. Hernando, 45, who worked fixing telephone cables, began to develop symptoms of cognitive decline about eight years ago. He has since progressed to Alzheimer’s dementia but can still carry on a conversation. As his deterioration was relatively slow, his family hoped he was benefiting from the trial.
“I put all my hopes on this study,” said his wife.
Jennie Erin Smith contributed reporting from Medellín, Colombia.