|
 Biogen had announced in March that it would terminate two large
clinical trials of aducanumab because they were likely to fail.
Within weeks, a group of company researchers set out to understand
what went wrong.
As they studied data from a larger pool of patients who received the
drug, they began to question that conclusion.
In the months that followed, Biogen kept its own trial investigators
and committee overseeing the trial in the dark about the possibility
that some patients had benefited from high doses of the therapy,
researchers told Reuters.
The company said it brought in outside Alzheimer's experts and
statisticians to help it parse the new findings, and sought feedback
from U.S. regulators on whether it could be considered for approval.
The result, made public on Tuesday, was an astounding reversal.
Biogen will seek U.S. approval for the therapy early next year, once
again raising hopes for patients suffering from the brain-wasting
disease. Biogen shares gained 27% on investor hopes for a
multibillion-dollar blockbuster.
The risks for Biogen remain high. Wall Street analysts cast doubt on
whether Biogen's analysis would pass muster with the U.S. Food and
Drug Administration without an additional years-long trial to
confirm the findings.
Several Alzheimer's researchers questioned why one trial appeared to
succeed, while another with the same design failed.
Many experts say they are reserving judgment until Biogen presents
more detailed data in December.
Company executives are reluctant to characterize their interactions
with the FDA, but said they worked closely with the agency until
they were confident in the findings.
Biogen was only willing to move forward with seeking approval for
aducanumab after meeting twice with FDA. The final decision was made
immediately after the second of those meetings, which took place on
Monday, Biogen officials said.
For the FDA "to say it's reasonable to file an application after two
extensive discussions with them, formal meetings as well as a number
of informal discussions, I think it's significant," Biogen research
chief Al Sandrock said in an interview.
A NAIL IN THE COFFIN
Biogen's earlier decision to terminate the trials was viewed as the
final nail in the coffin for the so-called "amyloid hypothesis" -
the theory that removing a protein associated with Alzheimer's could
stave off this fatal form of dementia. Many similar drugs had
previously failed.
Globally, 131 million people are expected to be diagnosed with
Alzheimer's by 2050, up from 50 million today. Any successful
treatment could be worth $10 billion or more in annual sales,
industry analysts say.
The March announcement also raised concerns about a second therapy,
BAN2401, that works in a similar way. Biogen is partnering with
Japan's Eisai on both drugs.
Ivan Cheung, Eisai's chief executive, said in an interview that he
expects aducanumab's revival will energize enrollment in a
late-stage study of BAN2401, with results expected in 2022. Patients
taking the highest dose of BAN2401 showed some encouraging results
in a midstage trial last year.
[to top of second column] |
"That's why in the Phase III trial, we are only studying the highest
dose," Cheung said.
The two aducanumab trials - Engage and Emerge - started a month
apart in 2015. Each had about 1,640 patients. As they progressed,
the company made changes in the trial that expanded the number of
patients who received a higher dose.
As part of a planned "futility analysis," outside monitors reviewed
half of the data as of December 2018 to determine whether the drug
had a reasonable chance of success.
"So many of us felt that this might be the drug that would cross the
finish line," said Dr. Sharon Cohen, director of the Toronto Memory
program, who led one of the studies. In March, she received the
answer: the therapy looked like a dud.
However, patients continued to receive treatment in the interim.
Cohen believes the fact that some patients got a higher dose for
longer helped swing results in the Emerge study, which ultimately
showed a benefit.
A CONTRADICTION
A month after announcing the failure, Biogen began analyzing results
from both trials, including additional data from patients who later
completed treatment.
By the time Biogen had its first FDA meeting in mid-June, the
company knew that one of the studies had succeeded, and understood
that dose was important, said Samantha Budd Haeberlein, who runs
Biogen's Alzheimer's program.
"We did a great deal of analysis in close contact with the FDA to
really understand what occurred in these trials," Haeberlein said.
"It took several months to work through that."
During that entire stretch, Cohen said she and fellow investigators
were waiting to hear why the drug had failed. They expected a
presentation in July during the Alzheimer's Association annual
meeting, but none came.
"I was completely unaware of what had been discovered until last
Sunday," said Dr. Anton Porsteinsson, a principal investigator for
the trials from the University of Rochester School of Medicine and
Dentistry. Porsteinsson said Biogen asked him to sign a
non-disclosure agreement before sharing the new analysis.
Cohen said she first reviewed the new data on Monday in what she
called a "top secret" meeting. She said the company wanted a few
investigators to hear the findings ahead of Tuesday's announcement,
but had concerns about insider trading.
Many still question why only one trial succeeded.
"The signal from the positive trial was kind of convincing,” said
Mayo Clinic Alzheimer's expert Dr. Ronald Petersen, who has been a
paid adviser for Biogen. It showed a 23% reduction in a key measure
of cognitive decline.
"But the other study, which was meant to be identical, didn't show
it," he said. "That's the challenge there."
(Reporting by Julie Steenhuysen in Chicago; Editing by Michele
Gershberg and Bill Berkrot)
[© 2019 Thomson Reuters. All rights
reserved.] Copyright 2019 Reuters. All rights reserved. This material may not be published,
broadcast, rewritten or redistributed.
Thompson Reuters is solely responsible for this content. |
