Amyloid, Tau Levels Continuing to Fall With Aduhelm’s Long-term Use
Aduhelm (aducanumab) continues to clear away amyloid plaques and tangled fibers made up of tau — two abnormal protein aggregates that build in the brain of those with Alzheimer’s disease — after nearly two and a half years of treatment, Biogen, which markets the treatment, reports.
It also announced plans to begin patient screening for ENVISION, a Phase 4 post-marketing study of Aduhelm, in May.
The updated findings come from long-term extensions of EMERGE (NCT02484547) and ENGAGE (NCT02477800), two placebo-controlled Phase 3 clinical trials testing how well Aduhelm works to slow Alzheimer’s progression when given monthly as an intravenous (into-the-vein) injection to a total of 3,296 patients.
People in these two and earlier Aduhelm trials were invited to enroll in EMBARK, an open-label Phase 3b trial (NCT04241068) of the therapy’s long-term use that opened in March 2020 and is due to run into October 2023.
Patients on long-term treatment continued to experience significant reductions in amyloid plaque levels at week 132, Biogen stated. Plasma levels of p-tau181, which is tau phosphorylated at residue 181 — one of the protein’s building blocks — also continued to decline beyond two years, with data out to week 128.
Those with more effective clearance of amyloid plaques at week 78, the close of EMERGE and ENGAGE’s placebo phase, also experienced greater reductions in plasma p-tau181 levels at week 128, a finding that adds further evidence to amyloid plaques being used as a surrogate biomarker to predict how well Aduhelm works.
An effective clearance was defined as a standardized uptake value ratio (SUVR) of 1.1 or less on a brain positron emission tomography (PET) scan.
“These are meaningful findings, which further our understanding of amyloid and downstream biomarkers, such as p-tau 181, in Alzheimer’s disease and can help inform how long patients may benefit from treatment to reduce amyloid beta plaque,” Samantha Budd Haeberlein, PhD, vice president and head of neurodegeneration development at Biogen, said in a press release.
“These data demonstrate that long-term treatment with Aduhelm continues to reduce the underlying pathologies of Alzheimer’s disease beyond two years,” she added.
Haeberlein detailed these findings in the presentation, “Key milestones in Alzheimer’s disease,” at the International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD 2022) held March 15–20 in Barcelona and virtually.
The company noted in its presentation that “accumulation of Aβ [amyloid-beta] is believed to initiate a cascade of pathological changes that lead to neurodegeneration.”
Aduhelm, by Biogen and Eisai, is an antibody designed to remove toxic clumps of that protein, thought to drive the death of nerve cells (neurons) in the brain of people with Alzheimer’s. The therapy received accelerated approval from the U.S. Food and Drug Administration (FDA) in June 2021 — becoming the first Alzheimer’s medicine in almost 18 years to be approved by the agency.
Data from the two Phase 3 clinical trials also showed that the antibody results in lower plasma p-tau181 levels and lesser clinical decline.
Newly presented data now further show a slower clinical decline in patients with lower plasma p-tau181 levels at week 78 than in those whose plasma p-tau181 levels had not fallen.
In other words, people with lower plasma p-tau181 levels had slower increases in Clinical Dementia Rating–Sum of Boxes (CDR-SB) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (13 Items) (ADAS-Cog 13) scores, indicating less severe disease. They also had less negative scores in the Mini Mental State Examination (MMSE) and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL-MCI) questionnaires.
Of note, plasma p-tau181 was an exploratory endpoint for the clinical trials, meaning that it was initially thought to be less likely to show an effect.
Findings of abnormalities suggestive of swelling or bleeding on brain scans of some Aduhelm-treated patients were a safety concern, and are continuing to be monitored by magnetic resonance imaging (MRI), the company reported. This side effect, called amyloid-related imaging abnormalities (ARIA), does not usually cause symptoms but could potentially cause harm.
In the trials’ placebo-controlled phase, swelling (ARIA-E) occurred in 35.2% of patients treated with Aduhelm at its highest and approved dose of 10 mg/kg. ARIA-E was more common among those carrying a form of the APOE gene called APOE E4 (43.0%) than among non-carriers (20.3%). Carrying APOE E4 is known to increase the risk of developing Alzheimer’s.
Serious ARIA-E symptoms were experienced by 0.3% of patients on Aduhelm 10 mg/kg, but most (98.2%) resolved during the course of the study, with the majority resolving within three to four months. Most ARIA-E findings occurred prior to a patient’s eighth treatment at the 10 mg/kg dose, the presentation noted.
After the placebo-controlled phase, the probability of ARIA-E remained relatively stable beyond two years, with data out to longer than 192 weeks.
EMBARK is testing Aduhelm’s safety and tolerability in 1,696 patients who went through a wash-out period imposed when EMERGE and ENGAGE were halted in 2019 after an analysis indicated futility.
During the wash-out period, which lasted a mean 1.6 years, the reduction in amyloid plaque levels was maintained in patients previously receiving Aduhelm, Biogen reported, noting the finding points to a continued reduction of amyloid plaques after treatment stops.
Similarly, patients randomized to Aduhelm in those two trials had slower increases in the CDR-SB dementia measure compared with those given placebo, indicating its effect on clinical decline is also maintained — at least for some months — after stopping treatment.