A promising drug trial inspires doctors and investors. The stock of the company is increasing. Then more data pops up, confusion grows, stocks collapse, and questions begin ̵
This was the history of treatments for the neurodegenerative disease affecting about 35 million people around the world. There is no approved product that can slow or stop the disease, and about 200 medicines have failed despite billions of dollars of years of effort.
A new clinical trial of a drug called BAN2401, developed by Biogen and Eisai, seemed to reverse this trend after companies said earlier this month that their study of the compound had slowed the progression of the disease.
Instead, investors who followed companies and physicians in search of meaningful treatment left more questions than answers, even after the study results released on Wednesday showed that the drug slowed the progression of the earliest stages of the disease by 30 percent. The results gave a glimmer of hope, but left many reasons for doubt.
The BAN2401 test was unusual from the start.
Most drug trials allocate a fixed number of patients to each part of the study. Some get a placebo. Others receive a low dose of the drug and the remainder a higher dose. Is it a system to identify if a drug is better than a dummy treatment, and if so, which dose is best?
Eisai and Biogen have done something else, hoping to save money and time. In the study, patients were included in the most promising dose as the study progressed. It was an idea that should help them quickly find a dose for a larger end-stage study without having to take in so many participants.
Researchers used a new measure of how fast the patient's Alzheimer's disease progresses. The new method was developed to detect the earliest signs of cognitive decline, a more sensitive tool than the blunt measurements used in earlier studies.
Even with the new methods, the attempt failed to achieve its main objective. In December, after 12 months of patient outcomes, the drug had not noticeably slowed cognitive decline.
While many studies had stopped, the study should be continued so that the company could re-analyze the data using another method with six months more data.
When they did, the process from failure to success seemed to develop.
One day before the results for BAN2401 were presented to the doctors and researchers gathered at a congress center in Chicago, an executive from Eisai promised assurance that something the trials of a number of other drug companies had failed to offer.
"It'll be clear," said Lynn Kramer, Eisai's chief neurologist. "You will not have an ambiguity."
That was not the case.
A stock analyst, Brian Skorney of Robert W. Baird & Co., said there were "almost no reasonable conclusions". Another, Laura Chico of Raymond James Financial, described the results as "headspinning." Biogen and Eisai shares plummeted, cutting much of the gains they made between the beginning and end of July.
The highest dose showed statistically significant results in slowing Alzheimer's disease compared to patients receiving placebo. The treatment also lowered the concentration of amyloid in the brain, a hallmark of the disease, which showed that the drug hit its target. But patients receiving lower doses had no cognitive benefit.
Muddying goes further, mid-trial regulators – feared side effects – ordered Eisai and Biogen to make a change. Patients with a gene mutation associated with Alzheimer's were excluded from the high-dose group.
That created a complication. In some previous studies, the gene associated with Alzheimer's is getting worse. So was the group on the high dose of BAN2401 better because the drug worked? Or because fewer patients with a genetic mutation accelerate the disease?
Murali Doraiswamy, head of the Neuro-Cognitive Disorders Program at Duke University School of Medicine, was in the room watching the presentation.
"What looked to me like a very clean, positive study with seemingly statistically significant effects on cognition and amyloid – suddenly this image was ruined," said Doraiswamy. "That raised all sorts of questions."
Other companies have driven similar results to disappointing results. Eli Lilly, Pfizer and Johnson & Johnson all went ahead with promising data trials just to see that their medicines were missing in the much larger tests required for approval.
"We are now seeing everything through the lens of what happened before," said Tamara Blutstein, an analyst with Decision Resources. "Everyone would like to see this put into a Phase 3 trial, which is where the road for these medicines gets very rocky."
Eisai and Biogen are bullish with their expectations and looking for opportunities to accelerate the final stages of study and get accelerated assessments from global agencies. Doctors say longer, larger studies are needed to definitely answer if the drug works.
Even in the best case – the 30-percent results are not an anomaly – the drug would be hardly a cure. Patients receiving the high doses of BAN2401 were still steadily and steadily decreasing, but not as fast as those receiving placebo.
"The magnitude of the impact is quite disappointing," said Lon Schneider, director of the California Alzheimer's Disease Center at the University of Southern California, who was not involved in the study. "Is this clinically significant? I'm not convinced."