Researchers find faster way to deliver Alzheimer's drug by opening the blood-brain barrier
USA: Findings from a proof-of-concept trial revealed lower cerebral amyloid-beta levels in Alzheimer's disease with Aducanumab (Aduhelm) infusions combined with focused ultrasound.
In the study, published in The New England Journal of Medicine, the investigational treatment involved creating an opening in the blood-brain barrier with MRI-guided focused ultrasound to boost drug delivery.
In each of the three participants who received aducanumab infusions, amyloid reduction was higher in brain regions targeted with focused ultrasound than in regions not exposed to focused ultrasound.
In patients with Alzheimer’s disease, anti-amyloid antibodies have been used to reduce cerebral amyloid-beta (Aβ) load. Ali Rezai, MD, of West Virginia University in Morgantown, and colleagues applied focused ultrasound with each of six monthly aducanumab infusions to temporarily open the blood–brain barrier to enhance amyloid removal in selected brain regions in three participants over 6 months.
"The reduction in Aβ level was numerically greater in regions treated with focused ultrasound than in the homologous regions in the contralateral hemisphere that were not treated with focused ultrasound, as measured by fluorine-18 florbetaben positron-emission tomography," the researchers wrote.
Cognitive tests and safety evaluations were conducted for 30 to 180 days after treatment.
The three participants in the trial were a 77-year-old man (participant 1), a 59-year-old man (participant 2), and a 64-year-old woman (participant 3). All received an Alzheimer's disease diagnosis within the year before enrollment. None had previously received aducanumab therapy and none carried an APOE4 allele.
For 6 months, participants received monthly IV aducanumab, escalated up to 6 mg/kg rather than the on-label dose. Opening the blood-brain barrier with focused ultrasound initiated 2 hours after each infusion. The blood-brain barrier closed within 24 to 48 hours after the procedure.
Focused ultrasound was applied to areas with high beta-amyloid in the frontal or temporal lobe or the hippocampus. In the contralateral hemisphere, homologous brain regions that were not exposed to focused ultrasound served as controls.
Participants 1 and 2 had no cognitive, neurologic, or behavioural changes at their last follow-up visit. On day 30 of follow-up, there was a decline in Participant 3's cognitive test scores, but she showed no neurologic change or change in activity of daily living scores.
The researchers led to the following findings:
- From baseline to the 26-week assessment, PET scans showed that focused ultrasound combined with aducanumab led to a drop in amyloid levels from 224.2 to 115.2 centiloids in Participant 1, from 185.6 to 104.6 centiloids in Participant 2, and from 251.5 to 84.9 centiloids in participant 3.
- Contralateral brain regions that did not have focused ultrasound showed little change in amyloid levels from baseline to 26 weeks.
- An average 32% reduction in SUVR [standardized uptake value ratio] was observed for the three participants combined after 26 weeks in the regions that had received treatment to open the blood-brain barrier and six combination treatments.
- Headaches were the most common adverse events and were mild except for one moderate headache.
- One participant had two severe adverse events during the focused ultrasound treatment due to discomfort with head and neck positioning; this resolved immediately after the procedure. No amyloid-related imaging abnormalities were seen.
- Low-intensity focused ultrasound has reversibly opened the blood-brain barrier in people with Alzheimer's disease or other neurologic disorders, including brain tumours, Parkinson's disease, and amyotrophic lateral sclerosis.
The findings were consistent with those of mouse studies that demonstrated increased penetration of aducanumab when combined with focused ultrasound to open the blood-brain barrier.
However, the authors acknowledged that the trial did not quantify monoclonal antibody penetration, and therefore enhanced delivery of the monoclonal antibody was not directly shown.
"Our study involved small tissue volumes in one side of the brain of only three patients," the researchers wrote. "Larger trials are needed and expanding treatment to both sides of the brain is crucial to determine efficacy."
Reference:
Rezai AR, et al "Ultrasound blood–brain barrier opening and aducanumab in Alzheimer's disease" N Engl J Med 2024; DOI: 10.1056/NEJMoa2308719.
Disclaimer: This site is primarily intended for healthcare professionals. Any content/information on this website does not replace the advice of medical and/or health professionals and should not be construed as medical/diagnostic advice/endorsement/treatment or prescription. Use of this site is subject to our terms of use, privacy policy, advertisement policy. © 2024 Minerva Medical Treatment Pvt Ltd