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A promising drug trial excites physicians and investors. The stock of the company is skyrocketing. Then, more data flows, confusion grows, actions crumble and questions begin – will this Alzheimer's drug fail like everyone else?
It is the history of treatments for neurodegenerative disease, which affects about 35 million people worldwide. There is no approved product that can slow down or stop the disease, and about 200 drugs have failed despite years and billions of dollars of effort.
A new clinical trial of a drug, called BAN2401, being developed by Biogen and Eisai, seemed to want to reverse this trend, after companies said earlier this month that their study of the compound had shown a slowing the progression of the disease.
Instead, investors who follow companies and doctors looking for a useful treatment end up with more questions than answers, even after the trial results showed that the drug was slowing down. progression of the early stages of the disease. The results added a glimmer of hope but left many reasons to doubt.
The BAN2401 trial was unusual from the beginning.
Most drug studies assign a fixed number of patients to each part of the trial. Some get a placebo. Others receive a low dose of the drug, and the rest a higher dose. This is a system for identifying whether a drug is better than a simulated treatment and, if so, which dose is the best?
Eisai and Biogen did something different, hoping to save money and time. The trial added patients to the most promising dose during the trial. It was an idea intended to help them quickly find a dosage for a larger final test without having to register as many participants.
The researchers used a new measure of progression of Alzheimer's disease in patients. The new method was designed to detect early signs of cognitive decline, a more sensitive tool than the more fuzzy measures used in previous trials.
Even with the new methods, the trial failed to achieve its main objective. In December, after calculating 12 months of patient outcomes, the drug did not clearly slow cognitive decline.
Although many studies stopped at that time, the trial was to continue so that the company could re-analyze the data in a different way with six months of additional data.
When they did, the lawsuit seems to have gone from failure to success.
A day before the results of BAN2401 are unveiled to doctors and researchers gathered at a convention center in Chicago, an Eisai executive promised certainty, which had failed many other drug manufacturers' trials .
"This will be clear," said Lynn Kramer, Eisai's Chief Medical Officer for Neurology. "You will have no ambiguity."
This was not the case.
A stock market analyst, Brian Skorney of Robert W. Baird & Co., said that there was "almost no reasonable conclusion to draw." Another, Laura Chico of Raymond James Financial, called the results "rotating head". Eisai shares plunged, cutting off much of the gains they made between when they said that they had had a good lawsuit early July, and when details were revealed on Wednesday.
The highest dose showed statistically significant results in slowing the decline of Alzheimer's disease compared to patients who received placebo. The treatment also lowered levels of amyloid in the brain, a hallmark of the disease, showing that the drug was reaching its target. But patients receiving lower doses have no cognitive benefits.
Muddying matters even more, midway through the trial, regulators – fearing side effects – ordered Eisai and Biogen to make a change. Patients with a genetic mutation associated with Alzheimer's disease were excluded from the high dose group.
This created a complication. In some previous studies, the gene is associated with the worsening of Alzheimer's disease. So was the group on the high dose of BAN2401 doing better because the drug was working? Or because there were fewer patients with a genetic mutation that accelerates the disease?
Murali Doraiswamy, director of the Neuro-Cognitive Disorders Program at the Duke University School of Medicine, was in the room watching the presentation.
"What seemed to me to be a very clean and positive essay with what appeared to be statistically significant effects on cognition and amyloid – suddenly this picture was ruined," Doraiswamy said. "This has raised all kinds of questions."
Other companies have advanced with similar results, for disappointing purposes. Eli Lilly, Pfizer and Johnson & Johnson have all tested after promising data, only to see their drugs fail in the much larger tests required for approval.
"We are now looking at everything through the lens of what has happened before," said Tamara Blutstein, an analyst at Decision Resources. "Everyone would like this to happen in a phase 3 trial. It's there that the road becomes really difficult for these drugs."
Eisai and Biogen are optimistic about their expectations, looking for ways to Accelerate the last stages of studies and obtain accelerated assessments of global agencies.More doctors say more, larger trials are needed to permanently answer if the drug works.
Even in the best case – that the results of 30 percent are not an anomaly – the drug would not be a cure – patients who received the high doses of BAN2401 still declined stably and regularly, but not as quickly as those who received the placebo.
"The magnitude of the effects is quite disappointing," said Lon Schneider, director of the California Alzheimer's Disease Center at the University of Southern California, which does not have the same effect. ;at not involved in the trial. "Is this clinically significant? I am not convinced. "
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