First Alzheimer's Trial with Focused Ultrasound Begins

Newswise — Charlottesville, VA - May 2, 2017 - Researchers at Sunnybrook Health Sciences Centre in Toronto have begun the world’s first clinical trial evaluating the feasibility and safety of opening the blood-brain barrier (BBB) in patients with Alzheimer’s disease (AD) utilizing focused ultrasound.

For this trial, six Alzheimer’s patients, ages 50-85, will undergo two non-invasive focused ultrasound procedures. For the first stage, Insightec’s Exablate Neuro low-frequency platform will apply focused ultrasound in a small area of the right frontal lobe, and images will evaluate if the BBB was temporarily opened. In the second stage, approximately one month later, a similar procedure to the same patient will target a larger area of the right frontal lobe, and additional images will again evaluate if the BBB is reopened. No drugs will be administered in the study.

“Our trial investigates, for the first time, the use of focused ultrasound to open the BBB in patients with early-to-moderate AD, to determine both its safety and technical feasibility,” says Nir Lipsman, MD, co-principal investigator of the Sunnybrook study. “Results from our study will help us plan future clinical trials to establish what role focused ultrasound may play, whether alone or in conjunction with medical treatments, in the management of Alzheimer’s.”

Adds Sandra Black, MD, Senior Scientist and co-principal investigator at Sunnybrook, “It is possible that focused ultrasound may provide an important method for more effectively delivering antibodies to the brain and may therefore one day be a treatment for Alzheimer’s – we just don’t yet know. It is important to note that at this point we are assessing only the feasibility and safety of opening the blood-brain barrier in these patients.”

Alzheimer’s is the most common neurodegenerative condition, and it is estimated that by 2050, more than 13 million Americans will be diagnosed with AD, costing the US economy more than one trillion dollars. The accumulation of extracellular beta amyloid and intracellular neurofibrillary tangles (“plaques and tangles”) are believed responsible for cell death and tissue loss in Alzheimer’s patients. Medical treatments to date have been only modestly effective at slowing cognitive decline and can only treat the symptoms.

Funded by the Focused Ultrasound Foundation, this study lays the groundwork for using focused ultrasound to enable medications to reach the brain that are typically too large to penetrate the BBB. “An important challenge for Alzheimer’s disease therapeutics is the blood-brain barrier, which significantly limits the passage of potentially effective therapies into the brain,” says Foundation Chairman Neal Kassell, MD. “This effort is a small but critical step in what could potentially be a game-changing treatment by enhancing drug delivery to the areas of the brain where they are needed, and in much higher concentrations than can be achieved through intravenous or oral administration.”

“This is a significant milestone in the development of our MR-guided focused ultrasound technology,” adds Eyal Zadicario, General Manager at Insightec Israel, whose Exablate Neuro system is being used in the study. “Exablate Neuro was designed as a platform to support a wide range of transcranial applications and expand innovation in the neuroscience field. In the current study, Exablate Neuro is used in a new approach – to tackle neurodegenerative diseases by opening the BBB. This is just a first step, and we will continue to push the technology to make significant impact where it matters most – to patients.”

Sunnybrook Health Sciences Centre was recently named a Foundation Center of Excellence, the only Canadian site with this designation.

For more information on the clinical trial, which is open to Canadian residents only, contact or call 416-480-6100, ext. 3773.

Trial is Multi-Year, Multi-Team Collaboration
This effort exemplifies the Foundation’s role in helping to expedite the translation of preclinical to clinical research; facilitating collaboration among industry and academic physicians to accelerate the development of FUS technology; and funding important research. The timeline below outlines the process – and the key stakeholders who have contributed to the study:

• 2001: Drs. Kullervo Hynynen, Nathan McDannold, Ferenc Jolesz, and colleagues first describe a controlled, temporary, and reproducible manner of opening the BBB using FUS in conjunction with microbubble contrast agents. Since then, further research has improved the phenomenon’s efficiency, efficacy, and safety. (When the FUS vibrates the microbubbles, the movement physically loosens the BBB’s tight junctions and allows molecules to move from the vasculature into the targeted region of the brain.)
• 2014: Dr. Hynynen, Sunnybrook Research Institute, discovers that BBB opening using FUS and microbubbles, with or without drugs, reduces amyloid plaques and improves cognition in mice with Alzheimer’s disease.
• February 2015: During a visit from Dr. Hynynen to the Foundation, FUSF articulates an interest in supporting a clinical trial subject to a pre-clinical or laboratory study confirming his observations in mice.
• March 2015: A Queensland, Australia, study independently demonstrates that BBB opening alone could reduce the number and volume of amyloid plaques and improve memory in mice. This validates earlier Alzheimer’s research exploring a similar strategy of combining focused ultrasound and microbubbles. The Queensland study provides confirmation to enable FUSF to proceed with the clinical trial.
• Summer 2015: Neuroradiologist and FUSF Chief Medical Officer Suzanne LeBlang is engaged to oversee a steering committee of FUS/BBB/AD experts to develop a protocol for the current trial. Drs. Nir Lipsman and Sandra Black are identified as co-principal investigators for the study. See below for list of AD Steering Committee members.
• September 2015: Alzheimer’s disease workshop organized by the Foundation is held in Bethesda, MD, to develop an AD clinical trial roadmap and the draft protocol for the current trial is discussed. The event is attended by scientists, engineers, neurologists, neurosurgeons, representatives from the FDA, and FUSF members.
• October 2015-October 2016: Steering Committee convenes monthly to develop the first in human trial for FUS and AD.
• November 2015: The BBB is non-invasively opened for the first time, with FUS, testing for more effective delivery of chemotherapy into a patient’s malignant brain tumor. The team is led by Todd Mainprize, MD, and Kullervo Hynynen, PhD, at Sunnybrook Health Sciences Centre in Toronto.
• January 2017: Health Canada’s REB (Research Ethics Board) approves the AD study. Insightec plays a critical role in the protocol submission and coordination with Health Canada.
• March 2017: Trial begins.

Below are the AD Steering Committee members who have been critical to the development, launch and ongoing support of this study. Says Suzanne LeBlang, MD, “These members worked carefully and conscientiously to develop the first in human clinical trial with FUS for AD. The preclinical researchers, manufacturers, and clinicians including neurologists, neurosurgeons, and neuroradiologists engaged in thoughtful and provocative discussions about inclusion and exclusion criteria, targeting location, and protocol design. It was so exciting to feel the enthusiasm of the group and watch the protocol evolve.”

• Nir Lipsman, MD (Committee Chairman), Neurosurgery Resident, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (neurosurgeon, study co-principal investigator)
• Sandra Black, MA, MD, Senior Scientist, Sunnybrook Health Sciences Centre, Toronto, Ontario Canada (neurologist, study co-principal investigator)
• Paul Fishman, MD, PhD, Professor of Neurology, University of Maryland, Baltimore, Maryland
• Kullervo Hynynen, MEc, PhD, Professor, Department of Medical Biophysics and Biomaterials and Biomedical Engineering, University of Toronto, Ontario, Canada
• Andres Lozano, MD, PhD, Professor of Surgery (Neurosurgery), Ron Tasker Chair of Stereotactic and Functional Neurosurgery, University of Toronto, Ontario, Canada
• Todd Mainprize, MD, Assistant Professor, Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada
• Lon Schneider, MD, Professor of Psychiatry, Neurology, and Gerontology, University of Southern California, Los Angeles, California
• James C. Torner, PhD, Professor and Chairman, Department of Epidemiology, University of Iowa, Iowa City, Iowa
• Eyal Zadicario, BSc, MSc, Director of Neurological Programs, Insightec, Tirat Carmel, Israel
• Suzanne LeBlang, MD, FUSF Chief Medical Officer, Neuroradiologist and Medical Director, MR Guided Focused Ultrasound, University MRI & Diagnostic Imaging Centers, Boca Raton, Florida

About the BBB and Drug Delivery
The blood-brain barrier is a protective layer of tightly joined cells that lines the blood vessels of the brain and keeps harmful substances, such as toxins and infectious agents, from entering the surrounding brain tissue. Unfortunately, this barrier also prevents certain drugs and potentially our own immune cells from reaching their targets within the brain in adequate concentrations. Currently, there are limited options to circumvent the BBB for drug delivery. Drugs can be directly injected into the brain, with the risk of hemorrhage, infection, or damage to normal brain tissue from the needle or catheter. The pharmacological agent mannitol has been used to disrupt and open the BBB when injected into the peripheral veins, but this approach is uncontrolled and non-selective. In November 2015, researchers at Sunnybrook opened the BBB in a focal area of the brain using focused ultrasound for the first time in a patient with a malignant brain tumor. The small gaps between the tightly joined cells lining the blood vessels were enlarged using focused ultrasound and microbubbles.

About Alzheimer’s and Focused Ultrasound
With focused ultrasound, FUS-induced oscillations of microbubbles generate pressure on the lining of the blood vessels so that the small gaps between cells enlarge, allowing cells and/or drugs to be released from the blood stream and enter the targeted area of the brain. Several published preclinical studies show promise of focused ultrasound for treating AD, including an Australian study demonstrating that BBB opening alone could reduce the number and volume of amyloid plaques and improve memory in mice. This validates earlier Alzheimer’s preclinical research from Canada exploring a similar strategy of combining focused ultrasound and microbubbles to open the BBB. It is postulated that opening the BBB may stimulate the brain’s inflammatory response against beta amyloid, the protein that is abnormally deposited in the brain in AD patients, and allow for our own body to clear the amyloid. Prior studies also showed that focused ultrasound helped to deliver a low dose of anti-beta amyloid antibody across the BBB, which reduced amyloid burden. A recent follow up study from Australia also shows that opening the BBB with focused ultrasound along with peripheral injection of a Tau antibody results in enhanced therapeutic effects with increased delivery of the antibody into the neurons and a reduction in anxiety.

About Sunnybrook
Sunnybrook Health Sciences Centre is inventing the future of health care for the 1.2 million patients the hospital cares for each year through the dedication of its more than 10,000 staff and volunteers. An internationally recognized leader in research and education and a full affiliation with the University of Toronto distinguishes Sunnybrook as one of Canada’s premier academic health sciences centres. Sunnybrook specializes in caring for high-risk pregnancies, critically-ill newborns and adults, offering specialized rehabilitation and treating and preventing cancer, cardiovascular disease, neurological and psychiatric disorders, orthopaedic and arthritic conditions and traumatic injuries. The Hospital also has a unique and national leading program for the care of Canada’s war veterans. For more information please visit us at www.sunnybrook.ca.

About INSIGHTEC
INSIGHTEC is the world leader and innovator of non-invasive MR-guided Focused Ultrasound (MRgFUS).The company is dedicated to improving patient lives by collaborating with physicians, medical institutions, academic researchers and regulatory bodies around the world. More information can be found here.

About the Focused Ultrasound Foundation
The Focused Ultrasound Foundation was created to improve the lives of millions of people worldwide by accelerating the development of focused ultrasound, an early-stage, noninvasive, therapeutic technology with the potential to transform the treatment of many serious medical disorders. The Foundation works to clear the path to global adoption by coordinating and funding research, fostering collaboration, and building awareness among patients and professionals. It is dedicated to ensuring that focused ultrasound finds its place as a mainstream therapy for a range of conditions within years, not decades. Since its establishment in 2006, the Foundation has become the largest non-governmental source of funding for focused ultrasound research. More information can be found at www.fusfoundation.org.