Closely monitored clinical trials of a potential Alzheimer’s drug have failed to prevent or slow cognitive decline, another frustration of the long and challenging effort to find a solution to the disease.
The decade-long trial was the first time that those who were genetically determined to develop the disease – but who still had no symptoms – were given a drug intended to stop or delay their fall. The participants were members of an extended family of 6,000 people in Colombia, of whom about 1,200 have genetic mutations that virtually guarantee that they will develop Alzheimer’s disease between the mid-40’s and mid-50’s.
For many family members, who live in Medellin and remote mountain villages, the disease quickly robs them of the ability to work, communicate, and perform basic tasks. Many died in their 60s.
In the trial, 169 people with mutations received a placebo or drug, Cranizumab, which was produced by Genentech, part of the Roche group. Another 83 people without mutations have received placebo as a way to protect the identities of people at risk for the disease, which is highly stigmatized in their community.
Trial investigators hoped that interfering with a drug a year before memory and thought problems appeared could alleviate the disease and provide important insights into tackling a more common type of Alzheimer’s that is not driven by a single genetic mutation.
“We are disappointed that Cranizumab did not show a significant clinical benefit,” said Dr. Eric Rayman, executive director of the Banner Alzheimer’s Institute, a research and treatment center in Phoenix and leader of the research team, at a news conference. Benefit from effective Alzheimer’s prevention therapy as soon as possible. At the same time, we take heart in the knowledge that this study has been launched and continues to help shape a new era in Alzheimer’s prevention research. “
The consequences for drugs that target a key protein in Alzheimer’s are another drawback: amyloid, which forms a sticky plaque in the brains of infected patients. Year after year research on various drugs that attack amyloid at different stages of the disease has become flat. In 2019, Cranizumab, in the early stages of the more common Alzheimer’s disease in Roche, discontinued two more tests for a monoclonal antibody, saying the study was unlikely to benefit.
Last year, in a highly controversial decision, the Food and Drug Administration first approved an anti-amyloid drug, Aduhelm. The FDA acknowledged that it was unclear whether Aduhelum could help patients, but said it was green light under a program that would allow certain treatments to approve drugs for serious illness with uncertain benefits and if the drugs affected a biological process that could reasonably help. Patients have been told by the FDA that the biological process was Aduhelm’s ability to attack amyloid, but many Alzheimer’s experts have criticized the decision because of the poor track record of amyloid therapy. The results of Thursday’s trial only added to the disappointing evidence.
“There would have been something more positive to say,” said Dr. Sam Gandhi, director of Mount Sinai’s Center for Cognitive Health, who was not involved in the Colombian study.
“Pathogenic mutations in the Colombian family have been implicated in amyloid metabolism,” said Dr. Gandhi.
Dr. Pierre Tariot, director of the Banner Alzheimer’s Institute and a leader in Colombian research, said some data showed that patients taking cranizumab performed better than those taking placebo, but the differences were not statistically significant.
He added that there were no safety issues with the drug, which is an important finding because many anti-amyloid therapies, including adjuvants, have caused bleeding or swelling in the brains of some patients.
Additional information on the trial will be presented at a conference in August. Dr Tariot and Dr Rayman noted that Thursday’s results did not include more detailed data from brain imaging or blood analysis of the effects of drugs on proteins and other aspects of Alzheimer’s biology. They also did not show an increase in the dose of Cranizumab, which researchers began to give patients as they learned more about the drug, Dr. Tariot said. He said some patients have received the maximum dose in five to eight years of clinical trials, up to two years.
Dr. Francisco Lopera, a Colombian neurologist and another leader in research, began working with family members decades ago to help determine if their suffering was a 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 we don’t have good results today.”
“We know we’ve taken a big step forward in contributing to the investigation of Alzheimer’s disease,” he added. “And now we are ready to take other steps to find a solution to this disease.”
One participant’s wife, Marilyn Ariza of Madeleine, said her husband, Hernando, whose name was withheld to protect his privacy, was one of the first patients to be enrolled in the trial. Hernando, 45, who worked to fix telephone wires, began developing symptoms of cognitive impairment about eight years ago. He has since developed Alzheimer’s dementia but can still hold conversations. Because his deterioration has been relatively slow, his family was optimistic that he would benefit from the trial.
“I put all my hopes into this study,” his wife said.
Jenny Erin Smith contributed to the report from Medellin, Colombia.