Simufilam (PTI-125), 100 mg, for Mild-to-moderate Alzheimer's Disease Patients

Study Overview
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Brief Summary
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A two-year safety study of simufilam (PTI-125) 100 mg oral tablets twice daily for participants of the previous simufilam studies as wells as additional new mild-to-moderate Alzheimer's disease subjects for a total of 200 participants. All participants will receive simufilam 100 mg tablets twice daily for one year, followed by a 6-month randomized, double-blind period where subjects will either continue on active treatment or be switched to placebo. The study concludes with an additional 6-month open-label treatment period. Clinic visits are every month or month and a half in the first year, and every 3 months in the second year with an additional visit at Month 13. Cognition and neuropsychiatric symptoms are evaluated.

Detailed Description
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The objectives of this study are to build the safety database for simufilam (PTI-125) and to investigate its effects on biomarkers, cognition and neuropsychiatric symptoms during 12-month twice-daily administration in mild-to-moderate AD patients. Additional objectives are to assess differences in cognition and neuropsychiatric symptoms between active and placebo arms in the 6-month randomized period. All subjects will undergo lumbar puncture at screening for baseline testing of cerebrospinal fluid (CSF) total tau and Abeta42, and the first 50 subjects will also provide a CSF sample at Month 6 or Month 12 for evaluation of change from baseline in CSF biomarkers. CSF will not be required of subjects with prior CSF, PET or MRI evidence of Alzheimer's disease. Plasma biomarkers will be evaluated in all subjects. Safety will be assessed by blood tests, electrocardiograms, adverse event monitoring and, at Months 12 and 24, full physical examinations.

Official Title
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A 12-Month, Open-Label Safety Study of Simufilam Followed by a 6-Month Randomized Withdrawal and 6 Additional Months Open-Label in Mild-to-moderate Alzheimer's Disease Patients

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Simufilam 100 mg oral tablet
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Informed consent form (ICF) signed by the subject or legally acceptable representative. Patient has a caregiver or legal representative responsible for administering the drug and recording the time. Ages ≥ 50 and ≤ 85 years Clinical diagnosis of dementia due to possible or probable AD consistent with criteria established by a workgroup of the National Institute on Aging and the Alzheimer's Disease Association. If female, postmenopausal for at least 1 year Patient living at home, senior residential setting, or an institutional setting without the need for continuous (i.e. 24-h) nursing care General health status acceptable for participation in the study Fluency (oral and written) in English or Spanish If receiving memantine, rivastigmine, galantamine or an AChEI, receiving a stable dose for at least 3 months (90 days) before screening. If receiving donepezil, receiving any dose lower than 23 mg once daily. Multiple medications are allowed. The patient is a non-smoker for at least 3 years. The patient or legal representative must agree to comply with the drawing of blood samples for the PK assessments, laboratory assessments and SavaDx. MMSE-2 score ≥ 16 and ≤ 26 at screening, OR if > 26, must have evidence of AD pathology such as a prior CSF total tau/Aβ42 ratio ≥ 0.28, an amyloid positive PET scan or hippocampal volume loss consistent with AD. EXCLUSION CRITERIA: Anything that in the opinion of the Investigator would preclude participation in a 2-year study. BMI < 18.5 Positive urine drug screen. Positive HIV, HCV or HbsAg screen. Suicidality on C-SSRS Exposure to an experimental drug other than simufilam, experimental biologic or experimental medical device within 3 months before screening A medical condition that would interfere with a lumbar puncture Residence in a skilled nursing facility and requiring 24 h care. Clinically significant laboratory test results Clinically significant untreated hypothyroidism (if treated, thyroid-stimulating hormone level and thyroid supplementation dose must be stable for at least 6 months before screening) Insufficiently controlled diabetes mellitus, including requiring insulin or metformin >1000 mg/day. Renal insufficiency (serum creatinine > ULN and clinically significant in the opinion of PI and/or Sponsor OR eGFR <60 ml/min/m2 as estimated by either the MDRD or CKD-EPI equation) Malignant tumor within 3 years before screening (except squamous and basal cell carcinoma or cervical carcinoma in situ or localized prostate cancer or localized stage 1 bladder cancer) History of ischemic colitis or ischemic enterocolitis Unstable medical condition that is clinically significant in the judgment of the investigator Alanine transaminase (ALT) or aspartate transaminase (AST) > ULN or total bilirubin > ULN and clinically significant in the opinion of PI and/or Sponsor. History of myocardial infarction or unstable angina within 6 months before screening History of more than 1 myocardial infarction within 5 years before screening Clinically significant cardiac arrhythmia (including atrial fibrillation), cardiomyopathy, or cardiac conduction defect (patients with a pacemaker are acceptable) Symptomatic hypotension, or uncontrolled hypertension Clinically significant abnormality on screening electrocardiogram (ECG), including but not necessarily limited to a confirmed QTc (Fridericia correction method) value ≥ 450 msec for males or ≥ 470 msec for females. Stroke within 18 months before screening, or history of a stroke concomitant with onset of dementia History of brain tumor or other clinically significant space-occupying lesion on CT or MRI Head trauma with clinically significant loss of consciousness within 12 months before screening or concurrent with the onset of dementia Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or resuscitation Specific degenerative CNS disease diagnosis other than AD (e.g., Huntington's disease, Creutzfeld-Jacob disease, Down's syndrome, Frontotemporal Dementia, Parkinson's disease) Wernicke's encephalopathy Active acute or chronic CNS infection Donepezil 23 mg or greater QD currently or within 3 months prior to randomization Discontinued AChEI < 30 days prior to randomization Antipsychotics; low doses are allowed only if given for sleep disturbances, agitation and/or aggression, and only if the subject has received a stable dose for at least 3 months before randomization Tricyclic antidepressants and monoamine oxidase inhibitors; all other antidepressants are allowed only if the subject has received a stable dose for at least 3 months before randomization Anxiolytics or sedative-hypnotics, including barbiturates (unless given in low doses for benign tremor); low doses of benzodiazepines and zolpidem are allowed only if given for insomnia/sleep disturbance, and only if the subject has received a stable dose for at least 3 months before randomization Immunosuppressants, including systemic corticosteroids, if taken in clinically immunosuppressive doses (Steroid use for allergy or other inflammation is permitted.) Antiepileptic medications if taken for control of seizures Chronic intake of opioid-containing analgesics Sedating H1 antihistamines Nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or similar therapeutic agent within 30 days before screening Clinically significant illness within 30 days of enrollment History of significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, or metabolic disease Loss of a significant volume of blood (> 450 mL) within 4 weeks prior to the study COVID-19 infection within 3 months

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Approximately two hundred (200) patients will be enrolled into the study. All participants will receive open-label simufilam 100 mg b.i.d. for a year. At Month12, participants will be randomized (1:1) to continue taking simufilam 100 mg b.i.d. or to be switched to placebo for 6 months. At Month 18, all participants will enter a final 6-month treatment period of open-label simufilam 100 mg b.i.d.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Simufilam 100 mg oral tablets throughout<br>Simufilam 100 mg oral tablets administered twice daily (BID) for the full 24 months (including the randomized period Month 12 to Month 18) | Drug: Simufilam 100 mg oral tablet<br>* Simufilam 100 mg oral tablet for b.i.d. administration<br>* Other names: Sumifilam;|
| Placebo Comparator: Simufilam 100 mg oral tablets / Placebo / Simufilam 100 mg oral tablets<br>This placebo arm is only for Month 12 to Month 18. Day 1 to Month 12, as well as Month 18 to Month 24 are open-label treatment periods of simufilam 100 mg b.i.d. for all subjects. | Drug: Simufilam 100 mg oral tablet<br>* Simufilam 100 mg oral tablet for b.i.d. administration<br>* Other names: Sumifilam;Drug: Placebo<br>* Matching placebo oral tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | Safety and tolerability of simufilam (PTI-125) during the full study: Open-label period 1 (Day 1 to Month 12), the randomized withdrawal (Month 12 to Month 18), and open-label period 2 (Month 18 to Month 24) | Day 1 to Month 24 | 
| Change from baseline in CSF P-tau, Total Tau, Abeta42, neurofilament light chain, neurogranin, YKL-40, soluble TREM2 and HMGB1 during first 6 months of open-label period 1 | Change from baseline in cerebrospinal fluid biomarkers of AD pathology, neurodegeneration and neuroinflammation during first 6 months of open-label period 1 in a subset of 25 subjects | Screening to Month 6 | 
| Change from baseline in ADAS-Cog-11 during open-label period 1 | Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item: Change from baseline in cognition during open-label period 1 | Day 1 to Month 12 | 
| Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-11) | Change in cognition vs. placebo during randomized withdrawal period | Month 12 to Month 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuropsychiatric Inventory (NPI) | Change from baseline in behavioral symptoms during open-label period 1 | Day 1 to Month 12 | 
| Neuropsychiatric Inventory (NPI) | Change in neuropsychiatric symptoms vs. placebo during randomized withdrawal period | Month 12 to Month 18 | 
| Change from baseline in CSF P-tau, Total Tau, Abeta42, neurofilament light chain, neurogranin, YKL-40, soluble TREM2 and HMGB1 during open-label period 1 | Change from baseline in cerebrospinal fluid biomarkers of AD pathology, neurodegeneration and neuroinflammation during open-label period 1 in a subset of 25 subjects | Screening to Month 12 | 
| Change from baseline in plasma P-tau181 during open-label period 1 | Change from baseline in plasma concentrations (pg/mL) of phospho-tau181 during open-label period 1 | Day 1 to Month 12 | 
| Change in plasma P-tau181 during randomized withdrawal period | Change in plasma concentrations (pg/mL) of phospho-tau181 vs. placebo during randomized withdrawal period | Month 12 to Mont 18 | 
| Change from baseline in plasma SavaDx during open-label period 1 | Change from baseline in a proprietary plasma biomarker during open-label period 1 | Day 1 to Month 12 | 
| Change in plasma SavaDx during randomized withdrawal period | Change in a proprietary plasma biomarker during the randomized withdrawal. | Month 12 to Month 18 |