The FDA approved the therapy in June 2021 under its accelerated approval pathway that provides earlier access to treatments expected to benefit patients with serious diseases, and following the priority review it was given by the agency in August 2020. Aduhlem is the first Alzheimer’s treatment approved by the FDA since 2003.
Aduhelm was developed by Neurimmune and later licensed by Biogen under a collaborative development and licensing agreement. Since October 2017, Biogen and Eisai have collaborated on developing and marketing the treatment globally.
How does Aduhelm work?
Alzheimer’s disease is a progressive neurodegenerative disorder, 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 are toxic to brain cells, killing them.
Aduhelm is an antibody that targets amyloid-beta. 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, Aduhelm could reduce the number of amyloid plaques present in the brain, potentially slowing neurodegeneration and disease progression.
Aduhelm in clinical trials
Biogen sponsored several clinical trials investigating Aduhelm, under its scientific name aducanumab, in patients.
A fourth, randomized, double-blind, and placebo-controlled Phase 1 trial (NCT01677572), called 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).
Results from a long-term extension of the PRIME trial were presented at the 2017 Clinical Trials on Alzheimer’s Disease meeting. In total, 143 patients opted to continue in the long-term extension study, where all received aducanumab. This included data from patients who had been on aducanumab for up to three years. During this time, patients on aducanumab continued to experience a time- and dose-dependent reduction in amyloid plaque levels.
Based on these and other findings, 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), enrolled patients at 187 sites in North America, Australia, Europe, and Asia. The second trial, called EMERGE (NCT02484547), recruited a similar patient group at 194 sites in North America, Europe, and Asia.
Collectively, these trials enrolled nearly 3,300 people with relatively mild disease.
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 in March 2019 after an independent data monitoring committee found that they were unlikely to meet their primary objective. This was based on initial trial efficacy data and not on safety concerns.
The Phase 2 EVOLVE trial (NCT03639987), which began in late 2018, was also evaluating the safety of continued dosing of aducanumab in people with mild cognitive impairment due to Alzheimer’s disease or with mild Alzheimer’s disease dementia. This trial also was halted 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 given the treatment at high dose, up to 10 mg/kg, experienced a significant reduction in the progression of cognitive and functional impairments. ENGAGE did not meet its primary goal, but data suggested benefit to those treated at a high dose in the trial.
These and other supportive findings formed the basis of the company’s application submitted to the FDA requesting Aduhelm’s approval.
Although the Phase 3 clinical trials were not fully conclusive on the therapy’s benefits regarding cognition and function, they clearly showed that Aduhelm can reduce levels of beta-amyloid plaques, the FDA decided. These data formed the basis for its accelerated approval decision, which allows for earlier approval based on a surrogate endpoint as a marker — in this case, the reduction in beta-amyloid.
Biogen also initiated the open-label EMBARK trial (NCT04241068), which is testing Aduhelm at its high dose (up to 10 mg/kg) in people who previously took part in ENGAGE, EMERGE, or other aducanumab clinical trials that were discontinued in 2019.
Under accelerated approval, the FDA requires Phase 4 confirmatory trials to verify Aduhelm’s clinical benefit. If data from these trials fail to verify benefit, the treatment could be removed from the market.
After an initial titration period, Aduhelm is to be administered at a maintenance dose of 10 mg/kg, given as an intravenous infusion over about one hour every four weeks. According to its label, Aduhelm has been known to cause allergic reactions and ARIA-E (fluid accumulation in the brain), which should be monitored in treated patients.
Last updated: June 7, 2021
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