Aducanumab

Aducanumab (BIIB037) was being developed by Biogen as a possible therapy for Alzheimer’s disease. However, in March 2019, an independent data monitoring committee determined there was insufficient evidence supporting the efficiency of aducanumab in treating the disease. As a result, all clinical trials testing the treatment have been halted.

The treatment was originally developed by Neurimmune, which, after entering a partnership with Biogen in 2007, had granted Biogen the license to further develop and commercialize aducanumab. Biogen had been collaborating with Eisai to advance the clinical studies of aducanumab since October 2017.

How aducanumab works

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by deposits of protein structures called amyloid plaques and tau tangles in the brain, leading to brain cell death.

Amyloid beta (Aβ) is normally present in the brain as a single protein, or monomer. In Alzheimer’s disease, however, it aggregates into clumps that can disrupt communication between brain cells and cause their death.

Aducanumab is an antibody, a protein designed to interact with a specific target. Developed using Neurimmune’s proprietary Reverse Translational Medicine Platform, it works by targetting Aβ. It preferentially binds to the aggregated Aβ as it targets an epitope (a specific small piece of the protein recognized by the antibody) that is not normally accessible in the Aβ monomer. Through this interaction, aducanumab could reduce the number of amyloid plaques present in the brain.

It was thought that by reducing the amyloid plaques, aducanumab could slow neurodegeneration and disease progression.

Aducanumab in clinical trials

Biogen sponsored seven clinical trialsinvestigating aducanumab in humans.

Three Phase 1 trials, assessing aducanumab in healthy volunteers (NCT02782975) and in Alzheimer’s patients in the U.S. (NCT01397539) or Japan (NCT02434718), have already been completed.

A fourth, randomized, double-blind, and placebo-controlled Phase 1 trial (NCT01677572) called PRIME had 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 aducanumab compared with a placebo on amyloid plaques at different doses measured through positron emission tomography (PET) imaging.

Interim results from the first 165 patients participating in this trial have been published in the scientific journal Nature. During the first year, 40 patients discontinued treatment; however, those who stopped treatment were spread across the aducanumab and placebo groups. All doses of aducanumab (given as monthly infusions into the bloodstream) were seen to significantly reduce amyloid plaques in the brain in a time- and dose-dependent manner compared with before treatment, whereas little to no change was seen in the placebo group after one year. The greatest reduction was seen at the higher doses. Aducanumab also appeared to slow the rate of cognitive decline, measured by change in the clinical dementia rating sum of boxes(CDR-SB) and the mini-mental state examination (MMSE).

Results from a long-term extension of the PRIME trial were presented at the 2017 Clinical Trials on Alzheimer’s Disease (CTAD) 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 period, patients given aducanumab had 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, called ENGAGE (NCT02477800) and EMERGE (NCT02484547), in people with early-stage Alzheimer’s disease. ENGAGE aimed to enroll 1,350 patients at 187 sites in North America, Australia, Europe, and Asia. EMERGE also aimed to enroll the same number of patients at 194 sites in North America, Europe, and Asia.

Both trials were aimed at assessing the efficacy of aducanumab, given once a month at low and high doses by infusion into the bloodstream, in treating the symptoms of Alzheimer’s disease. Treatment efficacy was measured by changes from baseline, measurements taken at the study start, in 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) score over a 78-week period. The trials were expected to conclude in 2022.

An independent data monitoring committee found that, based on the initial data, the trials were unlikely to meet their primary objective, and they were halted. The decision was not based on safety concerns. 

A Phase 2 trial (NCT03639987) that began in August 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 was also halted in March 2019, as a result of the committee’s findings.