PTI-125 for Mild-to-moderate Alzheimer's Disease Patients

Study Overview
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Brief Summary
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This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate Alzheimer's disease patients.

Detailed Description
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This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate AD patients, 50-85 years of age. A total of twelve (12) patients will be enrolled into the study. Patients will receive 100 mg b.i.d. of PTI-125. The objectives of this study are to investigate the safety, pharmacokinetics and effect on biomarkers of PTI-125 following 28-day repeat-dose oral administration.

Official Title
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A Phase 2a, Open-label, Multiple Dose, Safety, Pharmacokinetic and Biomarker Study of PTl-125 in Mild-to-moderate Alzheimer's Disease Patients

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: PTI-125, 100 mg tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages >= 50 and <= 85 years Informed consent form (ICF) signed by the subject or legally acceptable representative. Clinical diagnosis of dementia due to possible or probable Alzheimer's disease Mini-Mental State Examination score >= 16 and <= 24 at screening 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-hour) 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 and with continuous dosing for at least 3 months. If receiving donepezil, receiving any dose lower than 23 mg once daily. The patient is a non-smoker for at least 12 months. The patient or legal representative must agree to comply with the drawing of blood samples and with a lumbar puncture and the drawing of cerebrospinal fluid samples. The patient has a ratio of total tau/Abeta42 in cerebrospinal fluid >= 0.30. Patient has a caregiver or legal representative responsible for administering the drug and recording the time. Exclusion Criteria: Exposure to an experimental drug, experimental biologic or experimental medical device within the longer of 5 half-lives or 3 months before screening Residence in a skilled nursing facility 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 or requiring insulin Renal insufficiency (serum creatinine >2.0 mg/dL) 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) >2 times the upper limit of normal or total bilirubin greater than the upper limit of normal. 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 corrected QT 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 Alzheimer's disease (eg, Huntington's disease, Creutzfeld-Jacob disease, Down's syndrome, Frontotemporal Dementia, Parkinson's disease) Wernicke's encephalopathy Active acute or chronic Central Nervous System infection Donepezil 23 mg or greater quaque die currently or within 3 months prior to enrollment in the study Discontinued AChEI < 30 days prior to enrollment in the study 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 enrollment in the study 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 enrollment in the study 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 enrollment in the study Peripherally acting drugs with effects on cholinergic transmission 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 Positive serum hepatitis B surface antigen (HBsAg) or positive hepatitis C virus (HCV) antibody test at screening Positive HIV test at screening Loss of a significant volume of blood (> 450 mL) within 4 weeks prior to the study Metformin or cimetidine.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Simufilam (PTI-125)<br>Simufilam (PTI-125) 100 mg oral tablets administered twice daily (BID) | Drug: PTI-125, 100 mg tablets<br>* PTI-125, 100 mg tablets taken twice a day for 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) | Blood draws will be done to evaluate levels of PTI-125 in the plasma using non-compartmental methods in WinNonlin. | Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose | 
| Time to Maximum Plasma Concentration (Tmax) | Levels of PTI-125 will be assessed to determine how long it takes to reach the Cmax | Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose | 
| Last Quantifiable Plasma Concentration (Clast) | Levels of PTI-125 will be assessed to determine the last time point where PTI-125 can be detected. | Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose | 
| Time to Last Quantifiable Plasma Concentration (Tlast) | Levels of PTI-125 will be assessed to determine the elapsed time to where PTI-125 can last be detected in the plasma. | Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose | 
| Area Under the Curve (AUClast) | AUC for PTI-125 plasma concentration from time zero to the last quantifiable plasma concentration. | Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose | 
| Plasma Half-life (T1/2) | Assessment of the half-life in plasma of PTI-125 | Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SavaDx (Biomarker) | Blood samples will be tested for the complementary diagnostic/biomarker for Alzheimer's disease. | Study Day 1 and Day 28 | 
| CSF Biomarkers | A cerebrospinal fluid sample collection will be performed for Aβ42, tau, YKL40 and other potential CSF biomarkers | Change from Baseline to Day 28 |