Topline:

• A safety study published in The New England Journal of Medicine assessed the use of focused ultrasound (FUS) with anti-amyloid immunotherapy aducanumab (marketed as Aduhelm) in three patients with mild cognitive impairment and amyloid pathology. Each person was treated for six months with aducanumab delivered through FUS on just one side of their brain followed by treatment for six months aducanumab without FUS.
• FUS is being explored as a way to improve drug access to the brain. The blood-brain barrier (BBB) selectively keeps most molecules the size of typical drugs from crossing into the brain.  This class of drug has been associated with potentially serious side effects (ARIA – Amyloid Related Imaging Abnormalities) at the doses that achieve clinical benefit, especially in APOE4 carriers.  Since FUS physically makes holes in the BBB large enough for aducanumab to get through, a lower dose delivered with FUS might be as effective as the previously tested higher dose of aducanumab.
• There were no serious negative physical side effects associated with adding FUS to aducanumab in the three participants; the blood-brain barrier seemed to re-close soon after treatment. However, none of the three participants is an APOE4 carrier. One person experienced cognitive decline but the study cannot establish whether FUS was associated with that decline.
• Plaque reduction was approximately 30% greater at the location of FUS than at the corresponding location on the other side of each person’s brain. The study did not assess whether more drug was present in the brain at the site of FUS.
• Since FUS is a well-established technology for other diseases and has FDA approval for the treatment of Parkinson’s, there is public interest in this study (60 Minutes, NYT). However, although this is a promising indicator of baseline safety, the practicality and utility of FUS for Alzheimer’s disease is not yet clear.
  • Alzheimer’s pathology is spread wider in the brain than in Parkinson’s, so more extensive application of FUS throughout the brain might be required to achieve meaningful clinical benefits. When the BBB is physically opened, any material in the bloodstream at that location that can fit through the hole and enter the brain – including pathogens and debris – creates new risks that might not be captured in a research setting.
  • Since the study was limited to three patients, and none were a carrier of APOE4, this study does not tell us much about whether adding FUS will reduce the risk of ARIA. If ARIA results from the drug’s action within the brain, improving how well the drug enters the brain will not reduce ARIA.
  • Adding FUS to the anti-amyloid immunotherapy drug delivery protocol will add new costs and medical logistics to an already-expensive drug regime.
• We are gratified to see thoughtful science being pursued to investigate new and creative approaches to AD and look forward to further data and results about FUS.

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A recent report in the New England Journal of Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa2308719) of a three-patient safety test using focused ultrasound for improving delivery of an anti-amyloid immunotherapy garnered high-profile coverage in the popular press.* Dr. Ali Rezai of the West Virginia University Rockefeller Neuroscience Institute and his team used focused ultrasound (FUS) to open the blood-brain barrier in three people, all APOE4 non-carriers with mild cognitive impairment. During six monthly treatments, the anti-amyloid immunotherapy aducanumab (Aduhelm) was administered via IV infusion into the bloodstream, with the goal of making the Aduhelm doses more effective at reducing amyloid aggregates in the targeted area. Proponents of FUS believe that the dose of these drugs needed to achieve clinical benefit could be lower if FUS is added to the administration protocol to increase the amount of drug that actually reaches the interior of the brain.

The recent approval of anti-amyloid immunotherapies like Aduhelm for the treatment of individuals early in Alzheimer’s disease brings new hope to the patient community.  However, these drugs are expensive to produce and have the risk of significant and potentially dangerous side effects, termed ARIA. ARIA is associated with this class of drugs and increases with higher dosing levels and also in APOE4 carriers.

Aduhelm demonstrated in clinical studies to be very effective at removing amyloid from the brain.  During the study, the two hemispheres of each patient’s brain were evaluated to compare the levels of amyloid with FUS and without FUS. Following the initial 6 monthly treatments with FUS, the patients then received 6 months of treatments without FUS. PET scans showed an average additional 32% reduction in amyloid plaque in the areas treated with FUS as compared to those without the treatment. No incidents of ARIA were reported.  The three patients also received cognitive testing before and throughout the treatments. One of the three patients experienced cognitive decline 30 days into the second phase, but the study was not designed and did not have sufficient participants to support a determination of whether Aduhelm and FUS together were clinically superior to Aduhelm alone.

One of the most challenging aspects of treating diseases of the brain, including Alzheimer’s, is the blood-brain barrier (BBB), a multi-cell structure that strictly controls what materials can enter the brain from the bloodstream.  The BBB regulates access to the brain based on the size of materials and their chemical properties to ensure that the brain receives vital nutrients and signals while protecting against pathogens and debris.  Drugs that look promising in laboratory experiments, where they can be injected or applied directly to brain cells, often cannot get past the BBB in meaningful quantities in people, and thus fail to achieve benefits for patients.  In this test, FUS  was used as a way to bypass the BBB.

FUS has been used in a wide variety of medical indications as a treatment modality (in, for example, Parkinson’s disease), for imaging and, as in this instance, for drug delivery.  For drug delivery into the brain, FUS uses a two-step process to temporarily open a targeted area of the BBB. First, clinicians inject tiny bubbles of perfluorocarbon gas into a patient’s bloodstream and administer the drug targeted to the brain.  Perfluorocarbon gas is not toxic to humans and there are no direct health effects from exposure to it, although it is a potent and long-lasting “greenhouse” gas.  After the gas and drug spread through the circulatory system and the blood vessels feeding the brain, a clinician applies pulses of low frequency ultrasound that increase the size of the gas bubbles.  As their size increase, the gas bubbles pry open the connections among the cells of the BBB, creating a hole that allows any material that can fit through it to pass from the blood vessel in that area into the brain.  Proponents of FUS say their data indicates that the BBB then seals quickly and the perfluorocarbon gas bubbles are, eventually, harmlessly filtered out of the body by the kidneys and liver.

Improving delivery of drugs across the BBB is a high priority in AD research and FUS is one of a number of different efforts, each with its own strengths and concerns.  The ideal solution would protect the BBB’s integrity while allowing a drug to pass across the entire BBB so that the therapeutic can reach the amyloid that exists through the entirety of the brain’s interior. FUS limits the delivery of the drug to a very small area of the pathology. Using FUS to open the BBB, some investigators worry, may introduce dangerous pathogens and material the BBB would otherwise exclude, and the BBB degrades as we age causing additional concerns.  Seeking to solve the BBB access challenge, investigators at Roche are pursuing a new anti-amyloid immunotherapy packaged with a chemical shuttle that enables it to cross the BBB throughout the brain rather than at only one FUS-targeted site while leaving the BBB itself unaffected.  The risk/reward ratio for FUS will continue to be assessed as new data emerges.

CureAlz CEO Meg Smith commented, “Cure Alzheimer’s Fund has enabled cutting-edge Alzheimer’s research since our founding 20 years ago.  We celebrate when innovation and rigorous science come together to identify and test interventions that hold data-justified promise for our community and congratulate Dr. Rezai and his team.  We look forward to the vital additional research that will determine whether adding FUS to anti-amyloid immunotherapy will offer patients improved cognition, safety, and treatment accessibility, and to further exploration of other interventions designed to achieve these goals.”

*(1/14/24 60 Minutes; “An Ultrasound Experiment Tackles a Giant Problem in Brain Medicine,” https://www.nytimes.com/2024/01/10/health/blood-brain-barrier-alzheimers-ultrsound.html?unlocked_article_code=1.Pk0.GV_y.T9xX244Grgnl&smid=url-share).

January 2024