Efficacy and Safety of MMFS in Early AD

This is a phase 2 study in patients with probable Early Alzheimer's disease (AD). Early AD includes Stage 3 AD patients (MCI due to AD) and Stage 4 AD patients (mild AD). The study is a randomized, double-blind, placebo controlled, parallel group design, in which participants (up to 6 per arm; 12 total) will receive oral placebo or MMFS twice daily for 24 weeks. Randomized patients and their informants (required) will complete 3 assessments total: at baseline (prior to taking any study tablets), week 12, and week 24 visits. At each of the three visits, participants will complete cognitive and behavioral measures and clinical interviews, a blood sample will be collected for safety and biomarkers related to Alzheimer's disease, and the informant will complete an interview concerning the patient's cognition, mood, and function. A range of safety and tolerability assessments will also be performed (including vital signs, laboratory tests, and ECGs). Participants will be contacted by phone between clinical assessments for monitoring.

Inclusion criteria

Patients meeting all of the following inclusion criteria should be considered for admission to the study:

• MMSE ≥ 19
• ≥ 55 and ≤ 85 years old at Screening
• Meet criteria for at least one of the following Stages of Early Alzheimer's Disease as defined below:

Stage 3 AD (MCI due to AD)

• CDR Global score = 0.5, with

• 0.5 on memory box score; and
• 0.5 on at least one of the following functional measures: community affairs, home & hobbies, or personal care
• MMSE ≥ 24

Stage 4 AD (Mild AD):

• CDR Global score = 1, with

• 0.5 on memory box score; and
• 0.5 on at least one of the following functional measures: community affairs, home & hobbies, or personal care; OR
• CDR Global score = 0.5, with

• 0.5 on memory box score; and
• 0.5 on at least one of the following functional measures: community affairs, home & hobbies, or personal care; and MMSE 19-23
• ≥ 3 on at least one of the following Neuropsychiatric Inventory (NPI) behavioral areas: Agitation/Aggression, Depression/Dysphoria, Anxiety, Apathy/Indifference, Disinhibition, or Irritability/Lability, and total NPI score in these behavioral areas ≥ 6.
• Total Body weight (bw) must be ≥50 kg and ≤110 kg and lean body mass (LBM) must be ≤ 85 kg at screening
• Must be fluent in English
• Must have a friend/family member who frequently spends time with the subject (≥10 hours per week), and is willing to serve as an informant, and accompany the subject to, and participate in, all clinic visits
• Completion of at least 10 years of formal education (i.e., possess high school diploma, GED, or equivalent)
• Hearing and Vision ability sufficient to complete neurocognitive testing
• Be able and willing to collect urine (at home) for 12 hours the day prior to follow up visits (optional for Stage 4 patients).

Exclusion criteria

Patients meeting any of the following exclusion criteria will not be enrolled in the study:

Exclusions to rule out subjects with cognitive impairment likely due to something other than AD:

• Known negative biomarker for brain amyloid pathology as indicated by either amyloid PET or CSF assessment or both
• Stroke or Transient Ischemic Attack (TIA) or unexplained loss of consciousness in the past 1 year
• Clinically significant psychiatric illness in past 6 months requiring hospitalization
• Seizure in the past 3 years
• Within 1 year before the screening or between screening and baseline, any of the following: myocardial infarction; moderate or severe congestive heart failure, New York Heart Association class III or IV; hospitalization for, or symptom of, unstable angina; syncope due to orthostatic hypotension or unexplained syncope; known significant structural heart disease (e.g., significant valvular disease, hypertrophic cardiomyopathy), or hospitalization for arrhythmia; congenital QT prolongation
• Subject report of human immunodeficiency virus (HIV) infection
• History of evidence of acute or sub-acute micro or macrohemorrhage, greater than 4 microhemorrhages, cortical infarct, or greater than one 1 lunar infarct
• Alcohol or substance abuse in past 1 year
• Untreated and/or uncontrolled hypothyroidism
• Evidence of vascular dementia (Modified Hachinski Ischemia Scale score >5)
• History of clinically important carotid or vertebrobasilar stenosis or plaque
• Systemic chemotherapy in past 1 year
• Diagnosis of Multiple Sclerosis
• Unintentional rapid weight loss (>10% body weight within past 12 months)

Exclusions to rule out subjects with potential issues absorbing or metabolizing MMFS:

• Poor kidney function; corrected estimated glomerular filtration rate (eGFRcorr) < 40 mL/min/m2
• History of significant gastrointestinal disorder, such as chronic Diarrhea, irritable bowel syndrome, ulcerative colitis, Chron's disease, etc.

Exclusions to rule out subjects with sleeping problems not related to CNS disorder:

• Diagnosed with apnea/hypopnea but not using Continuous Positive Airway Pressure (CPAP) or Bilevel Positive Airway Pressure (BIPAP). If diagnosed with apnea/hypopnea, subject must maintain use of device throughout study
• Untreated nocturia that affects sleep

Exclusions to rule out subjects with conditions that could affect their safety:

• Females of child-bearing potential, as defined as menstruation within past 12 months or not surgically sterile.
• Systolic blood pressure > 150 mm Hg
• An affirmative response on the C-SSRS, indicating suicidal ideation with intent, with or without a plan or method, or suicidal behavior, in the past 6 months.

Exclusions to rule out subjects with conditions that could inhibit or confound the effects of MMFS or the ability of the subject to complete the study:

• Serious or unstable clinically important systemic illness or disease that, in the judgment of the investigator, is likely to affect cognitive assessment, deteriorate, or affect the participant's safety or ability to complete the study, including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, or hematologic disorders
• Currently living in an institutional facility such as a nursing home
• History or diagnosis of any of the following sleep conditions:

• Narcolepsy
• Cataplexy (familial or idiopathic)
• Circadian Rhythm Sleep Disorder
• Primary Hypersomnia
• Severe physical disability not associated with cognitive function that limits ability to complete neurocognitive testing (e.g., severe tremor, debilitating arthritis)
• Changes in medications or doses of medication in past 30 days prior to Screening

• All allowed concomitant medications, supplements, or other substances (with the exception of sleep, mood, cognitive and neuropsychiatric drugs) must be at stable doses for at least 30 days prior to screening and must be kept as stable as medically possible during the trial. Dosing change of ConMeds within 30 days of Screening may be allowed if in the opinion of the investigator, will not affect or influence study results.
• If a change in medication dosage occurs during the study, this will lead to discontinuation from study participation unless it relates to a medication that, in the view of the study investigator, does not affect participation in the trial.
• Allowed Sleep, Neuropsychiatric and Cognitive drugs must be stable for 90 days prior to Screening. Dosing change of Neuropsychiatric and Cognitive drugs within 90 days of Screening may be allowed if in the opinion of the investigator, will not affect or influence study results.
• Use of prohibited medications/substances.