Aducanumab + Exablate BBB Disruption for Alzheimer's Disease

Overseen By Kiley Everson, RN

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Ali Rezai

Must be taking: Monoclonal antibodies

Disqualifiers: Cardiac disease, Liver disease, Depression, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: Variable, based on standard of care

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine whether combining a monoclonal antibody treatment, Aducanumab, with a procedure that temporarily opens the blood-brain barrier using the Exablate Model 4000 Type 2 system is safe for treating mild Alzheimer's disease or mild cognitive impairment. The blood-brain barrier usually protects the brain, but opening it might enhance the treatment's effectiveness. Individuals with mild memory problems due to Alzheimer's who can attend regular doctor visits may be suitable candidates. As an Early Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants the opportunity to be among the first to receive this innovative approach.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What prior data suggests that this device and treatment combination is safe for Alzheimer's patients?

Research shows that Aducanumab, a treatment for Alzheimer's, is being tested with the Exablate Model 4000 Type 2 device. This device uses focused ultrasound to temporarily open the blood-brain barrier, a protective layer around the brain.

Studies have found that using this device to open the blood-brain barrier is generally safe and well-tolerated by Alzheimer's patients. In one study, patients who underwent this procedure multiple times did not experience any serious side effects.

Aducanumab alone is already used to treat Alzheimer's. While it can have side effects, it is generally safe for regular use. Researchers are now observing how patients handle both Aducanumab and the Exablate device together.

This research is in the early stages, focusing mainly on ensuring participant safety. So far, results suggest that the combination treatment is promising in terms of safety, but ongoing studies will provide more detailed information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the Aducanumab + Exablate BBB Disruption treatment for Alzheimer's disease because it combines a new way to deliver medication with a promising drug. Unlike traditional treatments that only focus on slowing symptom progression, this approach uses focused ultrasound (FUS) to temporarily open the blood-brain barrier. This allows Aducanumab, an antibody that targets amyloid plaques in the brain, to more effectively reach its target. By enhancing drug delivery, this method has the potential to improve outcomes for patients with Alzheimer's disease.

What evidence suggests that Aducanumab combined with Exablate Model 4000 Type 2 might be an effective treatment for Alzheimer's disease?

Research has shown that Aducanumab can slow the progression of symptoms in individuals with mild Alzheimer's disease or mild memory problems. It targets and reduces amyloid plaques in the brain, which are believed to contribute to the disease. In this trial, participants will receive an intravenous infusion of Aducanumab or Lecanemab, followed by the use of the Exablate device to temporarily open the blood-brain barrier. Studies have found that using the Exablate device for this purpose is safe and feasible. This technique helps treatments like Aducanumab reach the brain more effectively. Combining these methods may enhance the treatment's success for Alzheimer's disease. ^{2 4 5 6 7}

Who Is on the Research Team?

Ali Rezai

Principal Investigator

WVU Rockerfeller Neuroscience Institute

Are You a Good Fit for This Trial?

This trial is for people with mild Alzheimer's or cognitive impairment who can communicate during the procedure, have certain scores on mental and depression scales, a specific type of PET scan result, and a reliable caregiver. It excludes those with significant heart disease, liver issues, bleeding disorders, severe depression risk of suicide, untreated sleep apnea, epilepsy, impaired kidney function or are in another clinical trial.

Inclusion Criteria

Short form Geriatric Depression Scale (GDS) score of <= 7

Amyloid PET scan consistent with the presence of β-amyloid (A+)

Able and willing to give informed consent

Exclusion Criteria

A severity score of 2 or more on any of the 'Delusions', 'Hallucinations' or 'Agitation/Aggression' subscales of the Neuropsychiatry Inventory (NPI-Q)

Significant depression (GDS > 7) and/or potential risk of suicide (C-SSRS > 2)

Known sensitivity/allergy to gadolinium (gadobutrol), DEFINITY or its components, or 18F-florbetaben

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intravenous infusion of Aducanumab or Lecanemab every 2-4 weeks followed by blood-brain barrier opening using the Exablate Model 4000 Type 2 device

Variable, based on standard of care

Every 2-4 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including neurological and cognitive/behavioral examinations and MRI assessments

Up to 5 years post last treatment

What Are the Treatments Tested in This Trial?

Interventions

• Aducanumab
• Exablate Model 4000 Type 2

Trial Overview The study tests the safety of combining Aduhelm (Aducanumab) infusions with Exablate Model 4000 Type 2 device to open the blood-brain barrier in patients. The goal is to see if this combination is safe and feasible for treating mild Alzheimer's disease or cognitive impairment.

How Is the Trial Designed?

Group I: Infusion plus Exablate BBBO Treatment Experimental Treatment 3 Interventions

Intravenous infusion of Aducanumab or Lecanemab every 2-4 weeks (per standard of care) followed by blood brain barrier opening by FUS.

Aducanumab is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Aduhelm for:

• Alzheimer's disease

Approved in European Union as Aducanumab for:

• Not approved due to insufficient evidence of efficacy

Approved in Canada as Aducanumab for:

• Not approved due to insufficient evidence of efficacy

Approved in Japan as Aducanumab for:

• Not approved due to insufficient evidence of efficacy

Who Is Running the Clinical Trial?

Ali Rezai

Lead Sponsor

Trials

6

Recruited

90+

InSightec

Industry Sponsor

Trials

92

Recruited

3,800+

Dr. Maurice R. Ferré

InSightec

Chief Executive Officer

MD

Dr. Arjun Desai

InSightec

Chief Medical Officer

MD

Published Research Related to This Trial

Aducanumab is a monoclonal antibody that targets aggregated amyloid β (Aβ) in Alzheimer's disease, showing an objective reduction in Aβ levels but conflicting results regarding its clinical efficacy in improving symptoms.

The most significant safety concern associated with aducanumab treatment is the occurrence of amyloid-related imaging abnormalities, which raises questions about its overall risk-benefit profile despite its recent accelerated approval by the FDA for mild Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aducanumab for the treatment of Alzheimer's disease. Tagliapietra, M.[2022]

Aducanumab, the first FDA-approved therapy for Alzheimer's disease, has been shown to reduce clinical decline in patients with mild cognitive impairment and mild dementia, based on data from the phase 3 EMERGE trial.

Long-term modeling predicts that aducanumab treatment can lead to significant benefits, including an increase of 0.65 quality-adjusted life-years (QALYs) per patient and a delay in the progression to more severe stages of Alzheimer's, providing both clinical and socioeconomic advantages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predicted Lifetime Health Outcomes for Aducanumab in Patients with Early Alzheimer's Disease. Herring, WL., Gould, IG., Fillit, H., et al.[2022]

Aducanumab has been shown to be safe and well-tolerated in a Class I clinical trial with doses up to 30 mg/kg, while three Class II studies indicated it can reduce amyloid deposition in the brain compared to placebo.

However, the efficacy of aducanumab in improving clinical outcomes was uncertain, as it either had no significant effect or only slightly reduced worsening of dementia symptoms, and it was associated with a higher risk of adverse effects, such as amyloid-related imaging abnormalities in about 40% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aducanumab Use in Symptomatic Alzheimer Disease Evidence in Focus: A Report of the AAN Guidelines Subcommittee. Day, GS., Scarmeas, N., Dubinsky, R., et al.[2023]

Aducanumab, a monoclonal antibody targeting amyloid β, was approved by the FDA in June 2021 for treating Alzheimer's disease in patients with mild cognitive impairment or mild dementia, based on clinical trials conducted in this specific population.

The long-term safety and tolerability of aducanumab are currently being assessed in a multinational phase 3b clinical study, as there is no data on its effectiveness or safety for patients at different stages of Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aducanumab: First Approval. Dhillon, S.[2021]

In the phase 3 studies EMERGE and ENGAGE, high-dose aducanumab showed significant treatment effects in EMERGE but not in ENGAGE, with post-hoc analyses revealing that differences were influenced by a small number of rapidly progressing patients and lower exposure to the target dose in ENGAGE.

The results were consistent in later enrolled patients who received the target dose of 10 mg/kg, indicating that proper dosing and patient selection are crucial for the efficacy of aducanumab in treating early Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating Partially Discordant Results in Phase 3 Studies of Aducanumab. Mallinckrodt, C., Tian, Y., Aisen, PS., et al.[2023]

Aducanumab, a monoclonal antibody recently approved for treating mild cognitive impairment and mild Alzheimer's disease, was found to be hypothetically suitable for 57% of patients with positive cerebrospinal fluid biomarkers in a study of 70 patients.

The study emphasizes the importance of developing resources to administer Aducanumab and similar anti-amyloid therapies, especially as they may soon be licensed in the European Union.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential eligibility for Aducanumab therapy in an Irish specialist cognitive service-Utilising cerebrospinal fluid biomarkers and appropriate use criteria. Togher, Z., Dolphin, H., Russell, C., et al.[2022]

Aducanumab, a monoclonal antibody targeting amyloid beta, was generally well tolerated at doses up to 30 mg/kg in patients with mild-to-moderate Alzheimer's disease, with no severe adverse events reported.

At the highest dose of 60 mg/kg, some patients experienced serious adverse events related to amyloid-related imaging abnormalities, but these resolved within 8 to 15 weeks, indicating a need for careful monitoring at higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer's disease. Ferrero, J., Williams, L., Stella, H., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05469009?cond=Alzheimer%20Disease&term=focused%20ultrasound&aggFilters=status:not%20rec&rank=3

Safety and Feasibility of Exablate Blood-Brain Barrier ... The primary objectives of this study is to evaluate the safety and feasibility of BBBO (blood-brain barrier opening) using the Exablate Model 4000 Type 2 in the ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8570037/

Extensive frontal focused ultrasound mediated blood–brain ... The major findings were: (1) repeated extensive BBB opening was safe and feasible with no serious side effects; (2) extensive BBB opening ...

3. thejns.org thejns.org/view/journals/j-neurosurg/142/5/article-p1263.xml

Repetitive and extensive focused ultrasound–mediated ... This study confirmed the safety and efficacy of more frequent and extensive bilateral frontal BBB opening over multiple sessions in patients with AD.

4. withpower.com withpower.com/trial/early-phase-1-alzheimer-disease-6-2022-01b0d

Aducanumab + Exablate BBB Disruption for Alzheimer's ... Aducanumab has been shown to reduce clinical decline in patients with mild cognitive impairment and mild Alzheimer's disease by targeting and reducing brain ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11288696/

Advancements and Challenges in Antiamyloid Therapy for ... Aducanumab Device: Exablate Model 4000 Type 2. Lecanemab, Treatment intervention-related adverse events, total number of adverse events following each ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05469009

NCT05469009 | Safety and Feasibility of Exablate Blood- ... The primary objectives of this study is to evaluate the safety and feasibility of BBBO (blood-brain barrier opening) using the Exablate Model 4000 Type 2 in the ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12275862/

Safety, Efficacy and Clinical Applications of Focused ... We review the safety, efficacy, and potential biological effects of FUS-mediated BBB opening in AD patients. Key words: Alzheimer's disease, ...