Neurimmune originally developed aducanumab. After entering into a partnership with Biogen in 2007, the company granted Biogen the license to further develop and commercialize the treatment. Biogen has been collaborating with Eisai to advance the clinical studies of aducanumab since October 2017.
How does aducanumab work?
Alzheimer’s disease is a progressive neurodegenerative disorder. It is characterized by deposits of protein structures called amyloid plaques in the brain. Amyloid-beta is normally present in the brain as a single protein or monomer. However, it aggregates into clumps in Alzheimer’s disease. Researchers think that these clumps lead to brain cell death.
Aducanumab is an antibody that targets amyloid-beta. Researchers developed it using Neurimmune’s proprietary Reverse Translational Medicine Platform. The antibody preferentially binds to the aggregated amyloid-beta. This is because it targets an epitope that is not normally accessible in the amyloid-beta monomer. Through this interaction, aducanumab could reduce the number of amyloid plaques present in the brain. This ultimately may slow neurodegeneration and disease progression.
Aducanumab in clinical trials
Biogen sponsored several clinical trials investigating aducanumab in humans.
Researchers have completed three Phase 1 trials. These were assessing aducanumab in healthy volunteers (NCT02782975) and in Alzheimer’s disease patients in the U.S. (NCT01397539) and Japan (NCT02434718).
A fourth, randomized, double-blind, and placebo-controlled Phase 1 trial (NCT01677572), PRIME, enrolled 192 prodromal (pre-dementia) and mild Alzheimer’s patients at 32 sites in the U.S. The goal was to assess the safety and effect of different aducanumab doses versus a placebo on amyloid plaques. Researchers measured this with positron emission tomography imaging.
Interim results from the first 165 patients showed that all doses of aducanumab (given as monthly infusions into the bloodstream) significantly reduced amyloid plaques in the brain in a time- and dose-dependent manner. During the first year, 40 patients from both groups discontinued treatment. Little to no change was apparent in the placebo group after one year. The greatest reduction was present at higher doses. Aducanumab also appeared to slow the rate of cognitive decline. Researchers measured this as a change in the clinical dementia rating sum of boxes (CDR-SB) and the mini-mental state examination (MMSE).
They presented results from a long-term extension of the PRIME trial at the 2017 Clinical Trials on Alzheimer’s Disease meeting. In total, 143 patients from the initial trial opted to continue in the long-term extension study, where all patients received aducanumab. This included data from patients who had been on aducanumab for up to three years. During this time, patients who received aducanumab continued to experience a time- and dose-dependent reduction in amyloid plaque levels.
Biogen also began two large-scale randomized, double-blind, and placebo-controlled Phase 3 clinical trials in people with early-stage Alzheimer’s disease. The first trial, called ENGAGE (NCT02477800), aimed to enroll 1,350 patients at 187 sites in North America, Australia, Europe, and Asia. The second trial, called EMERGE (NCT02484547), also sought to enroll the same number of patients at 194 sites in North America, Europe, and Asia.
The goal of both trials was to assess the efficacy of aducanumab, given once a month at low and high doses by infusion into the bloodstream. Researchers measured the effectiveness of the treatment by changes from the start of the study in the CDR-SB, MMSE, Alzheimer’s disease assessment scale-cognitive subscale 13 items (ADAS-Cog 13), and Alzheimer’s disease cooperative study-activities of daily living inventory mild cognitive impairment version (ADCS-ADL-MCI) scores over a 78-week period. They had expected to complete the trials in 2022.
The company halted the trials because an independent data monitoring committee found that they were unlikely to meet their primary objective. This was based on initial data from the trials and not on safety concerns. Follow-up visits and closing-out activities for both trials are now complete.
The Phase 2 EVOLVE trial (NCT03639987) began in late 2018 to evaluate the safety of continued dosing of aducanumab in participants with mild cognitive impairment due to Alzheimer’s disease or with mild Alzheimer’s disease dementia. This trial also was halted in March 2019 as a result of the committee’s findings.
However, a later analysis based on additional follow-up data, showed that EMERGE met its primary goal. Patients receiving the highest dose of aducanumab experienced a significant reduction in the progression of cognitive and functional impairments. Although ENGAGE failed to meet its primary goal, Biogen stated that data from the sub-group of patients who had sufficient exposure to the medication also showed significant benefits. These and other supportive findings formed the basis of the company’s BLA submitted to the FDA requesting the approval of aducanumab for the treatment of Alzheimer’s disease.
In August 2020, aducanumab was granted priority review by the FDA, meaning that the agency plans to expedite the review process to determine whether they will approve the medication.
Last updated: Aug. 12, 2020
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