Combination of Aducanumab Infusion and Focused Ultrasound Accelerates Reduction of Amyloid-ß Plaques


The use of focused ultrasound-mediated blood-brain barrier opening has the potential to advance neurotherapeutics in the treatment of Alzheimer disease and other progreesive neurological disorder impacted by that barrier.

Ali Rezai, MD, director of the Rockefeller Neuroscience Institute at West Virginia University School of Medicine

Ali Rezai, MD

Initial findings from a first-in-human, proof-of-concept study showed that aducanumab (Aduhelm; Biogen) used in combination with a focused ultrasound (FUS)-mediated blood-brain barrier opening (BBBO) approach was found to be safe, with accelerated and greater reduction in amyloid-ß observed among treated patients.1

These data were presented by Ali Rezai, MD, director of the Rockefeller Neuroscience Institute at West Virginia University School of Medicine, at the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts. In the small-scale analysis, when comparing those with FUS-BBBO, patients with mild Alzheimer disease (AD) who received the combination approach demonstrated a progressive and significant decrease in amyloid-ß levels.

The trial featured patients who underwent the standard on-label dose escalation monthly infusion of aducanumab. Two hours after each of the first 6 monthly infusion cycles, low intensity MRI-guided FUS sonication using the ExAblate Neuro Type 2 system was delivered at 220 kHz to open the BBB in brain regions with amyloid-ß as determined by 18F-florobetaben amyloid-ß PET scan. The analysis comprised of the first 3 treated patients: 2 males, aged 77 and 60 years, respectively, with baseline Mini Mental State Examination scores of 25 and 28 at baseline, and ADAS-Cog11 scores of 13 and 7, as well as a third female patient, who had baseline MMSE scores of 27 and baseline ADASCog11 of 5.

In the study, FUS-BBB opening was limited to 1 hemisphere and compared with the contralateral homologous brain regions with no BBBO. To the point of analysis, each patient had completed 5 monthly cycles of aducanumab infusion with concomitant FUS BBBO. At baseline, investigators reported amyloid-ß plaque loads of 203, 139, and 285 units, across the signature brain regions of the 3 participants. With the combination approach, patients BBB was opened in the frontal, parietal, and temporal lobes, as well as in the hippocampus.

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At the conclusion of the analysis, all 17 BBBO procedures across multiple brain regions were well tolerated with no procedure related serious adverse events (AEs). Additionally, treated patients showed no serious neurological, cognitive, or imaging adverse events and no reports of amyloid-related imaging abnormalities. Notably, BBBO was demonstrated in each instance by focal parenchymal gadolinium contrast enhancement followed by BBB closure within 24-48 hours.

Investigators concluded that "additional studies with a larger number of patients, larger volume of BBBO, and a long-term follow-up are needed to establish the full potential of this combined approach to rapidly reduce brain amyloid-ß and impact cognitive function."1

Aducanumab, a high-affinity, fully human immunoglobulin-1 monoclonal antibody, was approved under the accelerated pathway in June 2021 as a medication for patients with early AD, but has since been met with controversy since the approval. Data from the phase 3 EMERGE (NCT02484547) and ENGAGE (NCT02477800), 1 of which met its primary end point and 1 that did not, served as the basis for the approval. Earlier this year, the FDA updated its safety-related labeling for the therapy to better characterize the risk of potential bleeding in the brain, also noting that the use of antithrombotic or thrombolytic medications while on the therapy may increased the risk of bleeding in the brain.2

Click here for more coverage of CTAD 2023.

1. Resai AL, D’haese P, Haut M, et al. Accelerated b-amyloid plaque reduction in Alzheimer’s disease combining aducanumab infusion with focused ultrasound blood-brain barrier opening. Presented at: Clinical Trials on Alzheimer’s Disease conference; October 24-27, 2023; POSTER OC09
2. Drug Safety-related Labeling Changes: Aduhelm. FDA. Updated February 8, 2023. Accessed October 26, 2023.
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