Assessment of Foralumab Safety and Modulation of Microglial Activation in Alzheimer's Disease

Assessment of Foralumab Safety and Modulation of Microglial Activation Evaluated by PET Imaging in Patients With Early Symptomatic Alzheimer's Disease

This phase 2a study will research the safety and tolerability of Foralumab, a human anti-CD3 antibody. An antibody is a molecule secreted by the immune system. These molecules are created to identify a specific pathogen. Previous data on experimental mice has suggested that Foralumab increases the immune system activity in the brain to reduce the inflammation of microglia, the brain's main immune cells. This combination of increased immune reactivity and less microglia inflammation may improve the immune response throughout the brain. Alzheimer's disease and other forms of dementia are characteristically known for the build-up of certain proteins in the brain. This trial will evaluate whether nasal Foralumab can improve cognition in participants with mild cognitive impairment due to early Alzheimer's or dementia.

The trial will ask participants to administer Foralumab nasally three times a week for eight weeks. The administration will occur intermittently, with breaks between each dosing cycle. Participants will also receive brain scans (Amyloid PET and MRI), undergo cognitive testing, blood draws, and physical, neurological, and nasal exams. Volunteers are expected to remain in the trial for six months.

Preliminary data has shown that Foralumab, a human anti-CD3 antibody, may improve cognition in APP/PS1and 3xTg mouse models of AD. Nasal Foralumab has been given to healthy volunteers with progressive multiple sclerosis (MS). When given nasally for five consecutive days, doeses up to 250 µg are well-tolerated.

This is a randomized, double-blind, placebo-controlled study assessing two dose levels of nasal foralumab (50 µg/dosing day and 100 µg/dosing day) or placebo, given in three-week "treatment cycles". A treatment cycle is defined as Investigational Product (IP) dosing on Monday, Wednesday, and Friday for two consecutive weeks, followed by a one-week pause in dosing or a "rest week." All treatment cycles follow the identical dosing regimen. Randomization will be 3:1 Active to Placebo.

Two cohorts of eight (8) subjects each will be enrolled in this study, and enrollment in these cohorts will be staggered. Both cohorts, Cohort A and Cohort B, will consist of six (6) subjects who will complete three months (4 cycles) of active treatment and two (2) subjects who receive Placebo treatment. Enrollment into Cohort B may begin once all subjects in Cohort A complete 2 cycles of treatment.

Subjects will be screened and enrolled at the Center for Alzheimer Research and Treatment (CART). Initial treatment visits will occur in the Center for Clinical Investigation (CCI) with follow-up visits occurring in CART. Both centers are in the Building for Transformative Medicine, Brigham and Women's Hospital (BWH) at 60 Fenwood Road, Boston, MA 02115.

Subjects will undergo screening procedures, including laboratory studies (hematology, clinical chemistry, CRP, EBV serology, HIV testing, Hepatitis B and Hepatitis C), vital signs, cognitive testing, and a complete physical exam by the physician investigator or a mid-level practitioner, and a detailed neurologic examination performed by a neurologist. Each subject must have normal laboratory tests, or results must be in a clinically acceptable range in the opinion of the Investigator. An additional screening visit will consist of an amyloid PET scan (if subjects do not already have those results prior to screening). Prior to each treatment cycle and at the end of treatment, an ENT physician will conduct a nasal exam and safety blood labs will be collected. At baseline and end of treatment, each subject will have blood samples collected for immunological study and undergo an MRI and a microglial PET scan. Blood samples for immunologic studies will be collected at baseline and after 3 months of treatment. A lumbar puncture will be performed at the screening visit and after 3 months of treatment to assess for changes in amyloid and tau.

Inclusion Criteria:

1. The Sponsor will rely on NIA-AA Alzheimer's Disease Diagnostic Guidelines for Early Symptomatic Alzheimer's Disease (AD) with a 20-30 MMSE score, Clinical Dementia Rating (CDR) global score of 0.5 or 1, and impaired memory performance below an education adjusted cut-off score on the Logical Memory II subscale delayed paragraph recall (LM-IIa) of the Wechsler Memory Scale- Revised (WMS-R) (127) (≥16 years: ≤8; 8-15 years: ≤4; 0-7 years: ≤2).
2. Age between 60 and 85 years (inclusive).
3. Good general health with no disease likely to interfere with the study assessments.
4. On a stable medication regimen for eight weeks prior to the study and is anticipated to remain stable during the study.
5. Subject is not pregnant, lactating, or of childbearing potential (i.e., women must be two years post-menopausal or surgically sterile). If a woman is of childbearing potential, her partner must use barrier contraception throughout the study.
6. Amyloid-positive PET scan (performed only if the subject meets all other inclusion criteria). An amyloid-positive PET scan is classified by an SUVR composite score cutoff of 1.18 units. Prior evidence of amyloid positivity by PET or CSF will also be accepted for eligibility.
7. Ability to understand and provide informed consent.
8. Has availability of a study partner who has regular contact with the participant and knows him/her well.

Exclusion Criteria:

1. Any significant neurologic disease including Parkinson's disease, stroke, multiinfarct dementia, frontotemporal dementia, Lewy body dementia, normal pressure hydrocephalus, brain tumor, brain hemorrhage with persistent neurologic deficits, progressive supra-nuclear palsy, seizure disorder, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits or known structural brain abnormalities.
2. Clinically significant or unstable medical conditions, including uncontrolled hypertension, uncontrolled diabetes, or significant cardiac, pulmonary, renal, hepatic, endocrine, or other systemic diseases.
3. History of autoimmune disease.
4. Current treatment with immunomodulatory or immunosuppressive drugs or corticosteroid administration by any route of administration (including nasal corticosteroids) within the past month.
5. Major depressive disorder (within the past 1 year), or a history of bipolar disorder, or a history of schizophrenia.
6. History of alcohol or substance abuse or dependence within the past two years.
7. History of malignancy within the past 3 years.
8. Clinically significant abnormalities in screening laboratories (defined as greater than mild on the FDA's vaccine toxicity grading scale).
9. Participation in another clinical trial of an investigational drug concurrently or within the past 30 days.
10. Low affinity TSPO binders (for PET ligand [18F]PBR06) determined by having a Thr/Thr polymorphism in the TSPO gene at screening.
11. Sensitivity to florbetapir F18.
12. Active COVID-19 disease.
13. Amyloid-negative PET scan.
14. COVID-19 vaccine within the past ten days or any other vaccine within the past seven days (at dosing)