The FDA has cleared the way for researchers to initiate a clinical study that will utilize MR-guided focused ultrasound to noninvasively open the blood-brain barrier (BBB) for enhancing the treatment of Alzheimer’s disease.

The multicenter, single-arm phase 2a trial follows a smaller one conducted by researchers in Toronto to evaluate the efficiency and safety of INSIGHTEC’s Exablate Neuro low-frequency ultrasound for temporarily opening the BBB of five AD patients repeatedly, to enable better delivery of drugs for Alzheimer’s and other neurodegenerative diseases. The phase 2a trial will evaluate the approach in a larger set of patients.

“The most common way through the blood-brain barrier is to inject hypertonic mannitol in the arteries going to the brain,” Dr. Neal Kassell, chairman of the Focused Ultrasound Foundation, told HCB News. “It opens the blood-brain barrier in the territory in which the arteries are feeding the brain. It’s sort of an indiscriminate approach and invasive and incredibly awkward to do. Focused ultrasound can be done in a very highly targeted manner and can be done to open the blood-brain barrier temporarily and reversibly; and it can be done repetitively.”

More than 6.4 million people in North America and 44 million worldwide are afflicted by dementia, with Alzheimer’s being the most common form.
While efficient at protecting the brain from toxins and infectious agents, the BBB blocks the entry of drugs treating diseases such as AD, with many unable to breach it due to their large sizes.

Utilizing low frequency ultrasound waves, Canadian researchers at Sunnybrook Health Sciences Centre in the phase one trial were able to noninvasively open the BBB in a small area of the frontal lobe in patients between 50 and 85 in the beginning stages of AD. They previously applied this approach in 2015 to evaluate the delivery of chemotherapy to brain tumors.

The trial was conducted to evaluate safety and feasibility in the repeated opening of the BBB with focused ultrasound, taking part in two stages. The first involved opening a small area of the brain to temporarily open the BBB, followed approximately one month later by the second, which involved opening a larger area. No drugs were administered in this study.

Published in Nature Communications, the trial is the first clinical, peer-reviewed report to evaluate feasibility and safety in opening the BBB in AD patients. The findings were presented last month at the Alzheimer’s Association International Conference (AAIC) in Chicago.

“Opening the blood-brain barrier in a so-called temporary and safe way is really important not just for Alzheimer’s disease but for administering drugs for treating Parkinson’s disease, brain tumors and other serious conditions,” said Kassell. “It’s a very exciting area, this focused ultrasound opening up the blood-brain barrier.”

The phase one trial, he adds, is just the “first small step” with the next being the phase 2a trial, and eventually another involving the administration of drugs into the brain.

The phase 2a trial is expected to begin this fall.

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