The decision was based on new analysis run by Biogen in consultation with the FDA of a larger dataset from the trials halted in March.
No one expected this. In March, Biogen and its collaboration partner, Tokyo-based Eisai, announced they were discontinuing the global Phase III clinical trials, ENGAGE and EMERGE, of aducanumab in patients with mild cognitive impairment from Alzheimer’s and mild Alzheimer’s dementia. Biogen was also discontinuing the EVOLVE Phase II trial and the long-term extension PRIME Phase Ib trial of the drug. An independent data monitoring committee indicated they probably wouldn’t hit their primary endpoint.
Many thought it was the final nail in the amyloid theory of Alzheimer’s disease. Aducanumab is an antibody targeting beta-amyloid, one of the proteins that accumulates in the brains of Alzheimer’s patients and was believed to be one of the primary causes of the disease.
Today, the two companies announced that after discussions with the U.S. Food and Drug Administration (FDA), Biogen will pursue regulatory approval for aducanumab. The Phase III EMERGE trial met its primary endpoint, showing a significant decrease in clinical decline. The company now believes that data from a subset of patients in the trial who were given a high enough dose of the drug had significant benefits on measures of cognition and function, including memory, orientation, and language. There were also benefits on activities of daily living—conducting personal finances, household chores like cleaning, shopping, and laundry, and independently traveling outside of the home.
The decision was based on new analysis run by Biogen in consultation with the FDA of a larger dataset from the trials halted in March. The larger dataset included data that became available after the independent monitoring committee’s recommendation.
“With such a devastating disease that affects tens of millions worldwide, today’s announcement is truly heartening in the fight against Alzheimer’s,” said Michel Vounatsos, Biogen’s chief executive officer. “We are hopeful about the prospect of offering patients the first therapy to reduce the clinical decline of Alzheimer’s disease and the potential implication of these results for similar approaches targeting amyloid beta.”
Biogen expects to file a Biologics License Application (BLA) in early 2020 and continue talks with regulators around the world, including Europe and Japan. The BLA will include data from the Phase I/Ib trials as well as complete data from the Phase III studies.
In addition, Biogen plans to offer access to the drug to eligible patients who were previously involved in the Phase III trials, the long-term extension trial for the Phase Ib PRIME study and the EVOLVE safety study.
The two trials, EMERGE, which evaluated 1,638 patients, and ENGAGE, which evaluated 1,647 patients, were discontinued after the futility analysis on March 21, 2019. That analysis was based on data prior to December 26, 2018 in 1,748 patients who’d completed the 18-month trial period. The analysis found the studies were not likely to meet the primary endpoint. Biogen states, “Futility analyses are common in large clinical studies and use statistical modeling to attempt to predict the outcome of the studies based on a number of pre-specified assumptions and criteria.”
After ending those studies, a larger dataset that included a total of 3,285 patients became available. Of them, 2,066 patients had completed the full 18 months of treatment. The companies analyzed the data, and found it contradicted the futility analysis.
“Specifically,” Biogen states, “the new analysis of this larger dataset showed EMERGE to be statistically significant on the pre-specified primary endpoint (P=0.01). Biogen believes that data from a subset of ENGAGE support the findings from EMERGE, though ENGAGE did not meet its primary endpoint.”
Basically, in EMERGE, patients receiving the high dose of aducanumab were observed to have a significant reduction of clinical decline from baseline in CDR-SB scores at 78 weeks of 23% compared to placebo. They also showed a consistent decrease of clinical decline for the pre-specified secondary endpoints, including the Mini-Mental State Examination, 15% compared to placebo, the AD Assessment Scale-Cognitive Subscale 13 items of 27% compared to placebo, and the AD Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version, 40% compared to placebo.
Also, imaging of amyloid plaque deposits in EMERGE showed that the plaque burden was decreased with low and high dose aducanumab compared to placebo at 26 and 78 weeks. Biomarker data of tau levels, another abnormal protein linked to Alzheimer’s disease, was also found to be reduced in the cerebrospinal fluid, which supports the clinical findings.
The most common adverse events were amyloid-related imaging abnormalities-edema (ARIA-E) and headache. But most who had the imaging abnormalities did not experience symptoms and were typically resolved within four to 16 weeks.
Biogen shares rocketed by at least 35% at the news.
The company plans to present the data at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting in December 2019.
