To Evaluate Safety, Tolerability and Pharmacological Effects of PU AD in Subjects With Mild AD Dementia

Exclusion Criteria

• •1. Meets National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS/AIREN) criteria for vascular dementia
• •2. Has current serious or unstable illnesses including cardiovascular, hepatic, renal, gastroenterological, respiratory, endocrinologic, neurologic (other than AD), psychiatric, immunologic, or hematologic disease and other conditions that, in the investigator's opinion, could interfere with the analyses of safety and pharmacologic effect in this study; or has a life expectancy of \< 2 years
• •3. Has had a history within the last 5 years of a serious infectious disease affecting the brain or head trauma resulting in protracted loss of consciousness
• •4. Has a history within the last 5 years of a primary or recurrent malignant disease with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal prostate specific antigen post treatment
• •5. Has a known history of human immunodeficiency virus (HIV), clinically significant multiple or severe drug allergies, or severe post treatment hypersensitivity reactions
• •6. Has a "yes" answer to Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation item 4 or 5, or any suicidal behavior assessment within 6 months of Screening, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening
• •7. Has received acetylcholinesterase inhibitor (AChEIs), memantine, and/or other AD therapy for less than 4 months or has less than 2 months of stable therapy on these treatments
• •8. Has not been stable on medications that affect the Central nervous system (CNS), for at least 4 weeks (including antidepressants, hypnotics, antipsychotics, etc.) except occasional use of benzodiazepine (definition of occasional use - not more than twice in a week or three times in a month during the past 3 months).
• •9. Has a history of chronic alcohol or drug abuse/dependence within the past 5 years
• •10. Any medical or neurological/neurodegenerative condition (other than AD) that, in the opinion of the investigator, might be a contributing cause to the subject's cognitive impairment (e.g., current history of substance abuse, uncontrolled vitamin B12 deficiency or abnormal thyroid function, stroke or other cerebrovascular condition, Parkinson's disease, Lewy body dementia, or frontotemporal dementia)
• •11. Transient ischemic attack or stroke or any unexplained loss of consciousness within 1 year prior to Screening Visit
• •12. History of bleeding disorder or predisposing conditions, blood clotting, or clinically significant abnormal results on coagulation profile at Screening, as determined by the investigator
• •13. History of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class III or IV), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year prior to Screening Visit
• •14. Clinically significant 12 lead Electrocardiogram (ECG) abnormalities, as determined by the investigator
• •15. Indication of impaired liver function as shown by an abnormal liver function profile at Screening (e.g., repeated values of Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≥ 2 × the upper limit of normal \[ULN\]) and/or indication of impaired renal function at Screening (e.g., repeated values of creatinine and blood urea nitrogen \[BUN\] ≥ 1.5 × Upper limit of normal (ULN) or estimated glomerular filtration rate \< 45 mL/minute/1.73 m2 and corroborating medical history and physical examination)
• •16. Contraindications to having a brain Magnetic resonance imaging (MRI) (e.g., MRI incompatible pacemaker; MRI incompatible aneurysm clips, artificial heart valves, or other metal foreign body; claustrophobia that cannot be medically managed); if the MRI compatibility of implanted devices is unknown, the subject must be excluded from the study
• •17. Contraindication to having a PET brain scan (e.g., inability to lie flat or still for the duration of the scan) or intolerance to previous PET scans (i.e., previous hypersensitivity reactions to any PET ligand or imaging agent, failure to participate in and comply with previous PET scans)
• •18. Contraindication to having an FDG PET scan, including uncontrollable glucose levels, inability to fast for the prescribed number of hours prior to the FDG PET scan, inability to withhold all insulin and oral diabetic medication after midnight prior to the PET scan
• •19. Inability to refrain from using sleep medication for the 24 hours prior to each FDG PET scan or to refrain from use of antipsychotics, sedatives, or other strong acting neuropsychiatric medication on the day of each PET scan prior to the scan
• •20. Current or recent participation (within 12 months before screening) in any procedures involving radioactive agents such that radiation exposure of the, in the judgement of the investigator (upon review of medical history), subject in any given year would exceed the whole-body limits of annual and total dose commitment of 5 rems set forth in the US Code of Federal Regulations (CFR) Title 21 section 361.1.
• •21. Any contraindications to lumbar puncture (LP), e.g., increased bleeding risk (platelet count \<100,000/μL, coagulopathies, anticoagulant drugs), lumbar spine deformity that might interfere with the procedure evidence on MRI contraindicating LP, risk for cerebral herniation, space occupying lesion with mass effect, abnormal intracranial pressure due to increased CSF pressure, Arnold Chiari malformation, local infections at the puncture site and patient fear of LP; abnormalities in the screening CSF profile that are considered by the Investigator to be clinically significant are exclusionary
• •22. Any major surgery within 12 weeks of Screening Visit or during the Screening Period
• •23. Has active ocular condition that in the opinion of the investigator may alter visual acuity during the course of the study.
• •24. Use of any drugs that are strong inhibitors of Cytochrome (CYP)450 (2D6 or 2C19) within 7 days or 5 half lives of the inhibitor (whichever is longer), prior to administration of the first dose of Investigational medicinal product (IMP) and/or plan to use throughout the study
• •25. Participation within the 12 months prior to Screening Visit in a study of any agent(s) with a purported disease modifying effect in AD (e.g., anti beta amyloid, β secretase inhibitors, γ secretase inhibitors), unless documentation of receipt of placebo is available
• •26. Has taken other investigational drugs or participated in any clinical study within 30 days or 5 half lives (if known) of the investigational drug, whichever is longer, prior to first dose of IMP in this study or is currently participating in another clinical study
• •27. Other unspecified reasons that, in the opinion of the investigator or Samus, and/or its delegated medical monitor, make the subject unsuitable for the study
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