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

• ClinicalTrials.gov Identifier: NCT04388254
• Recruitment Status: Active, not recruiting
• First Posted: May 14, 2020
• Last Update Posted: February 16, 2023
• Sponsor: Cassava Sciences, Inc.
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Cassava Sciences, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Alzheimer Disease	Drug: Simufilam 100 mg oral tablet; Drug: Placebo	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Matching placebo for the 6-month randomized period (Month 12 to Month 18)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 24, 2020
• Estimated Primary Completion Date: December 15, 2023
• Estimated Study Completion Date: December 15, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Simufilam 100 mg oral tablets throughout; 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; Simufilam 100 mg oral tablet for b.i.d. administration; Other Names: PTI-125; Sumifilam
Placebo Comparator: Simufilam 100 mg oral tablets / Placebo / Simufilam 100 mg oral tablets; 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; Simufilam 100 mg oral tablet for b.i.d. administration; Other Names: PTI-125; Sumifilam; Drug: Placebo; Matching placebo oral tablets

Outcome Measures

Primary Outcome Measures :

1. Safety and Tolerability [ Time Frame: Day 1 to Month 24 ]
   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)
2. 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 [ Time Frame: Screening to Month 6 ]
   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
3. Change from baseline in ADAS-Cog-11 during open-label period 1 [ Time Frame: Day 1 to Month 12 ]
   Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item: Change from baseline in cognition during open-label period 1
4. Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-11) [ Time Frame: Month 12 to Month 18 ]
   Change in cognition vs. placebo during randomized withdrawal period

Secondary Outcome Measures :

1. Neuropsychiatric Inventory (NPI) [ Time Frame: Day 1 to Month 12 ]
   Change from baseline in behavioral symptoms during open-label period 1
2. Neuropsychiatric Inventory (NPI) [ Time Frame: Month 12 to Month 18 ]
   Change in neuropsychiatric symptoms vs. placebo during randomized withdrawal period
3. 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 [ Time Frame: Screening to Month 12 ]
   Change from baseline in cerebrospinal fluid biomarkers of AD pathology, neurodegeneration and neuroinflammation during open-label period 1 in a subset of 25 subjects
4. Change from baseline in plasma P-tau181 during open-label period 1 [ Time Frame: Day 1 to Month 12 ]
   Change from baseline in plasma concentrations (pg/mL) of phospho-tau181 during open-label period 1
5. Change in plasma P-tau181 during randomized withdrawal period [ Time Frame: Month 12 to Mont 18 ]
   Change in plasma concentrations (pg/mL) of phospho-tau181 vs. placebo during randomized withdrawal period
6. Change from baseline in plasma SavaDx during open-label period 1 [ Time Frame: Day 1 to Month 12 ]
   Change from baseline in a proprietary plasma biomarker during open-label period 1
7. Change in plasma SavaDx during randomized withdrawal period [ Time Frame: Month 12 to Month 18 ]
   Change in a proprietary plasma biomarker during the randomized withdrawal.

Eligibility Criteria

• Ages Eligible for Study: 50 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

INCLUSION CRITERIA:

1. Informed consent form (ICF) signed by the subject or legally acceptable representative.
2. Patient has a caregiver or legal representative responsible for administering the drug and recording the time.
3. Ages ≥ 50 and ≤ 85 years
4. 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.
5. If female, postmenopausal for at least 1 year
6. Patient living at home, senior residential setting, or an institutional setting without the need for continuous (i.e. 24-h) nursing care
7. General health status acceptable for participation in the study
8. Fluency (oral and written) in English or Spanish
9. 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.
10. The patient is a non-smoker for at least 3 years.
11. The patient or legal representative must agree to comply with the drawing of blood samples for the PK assessments, laboratory assessments and SavaDx.
12. 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:

1. Anything that in the opinion of the Investigator would preclude participation in a 2-year study.
2. BMI < 18.5
3. Positive urine drug screen.
4. Positive HIV, HCV or HbsAg screen.
5. Suicidality on C-SSRS
6. Exposure to an experimental drug other than simufilam, experimental biologic or experimental medical device within 3 months before screening
7. A medical condition that would interfere with a lumbar puncture
8. Residence in a skilled nursing facility and requiring 24 h care.
9. Clinically significant laboratory test results
10. Clinically significant untreated hypothyroidism (if treated, thyroid-stimulating hormone level and thyroid supplementation dose must be stable for at least 6 months before screening)
11. Insufficiently controlled diabetes mellitus, including requiring insulin or metformin >1000 mg/day.
12. 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)
13. 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)
14. History of ischemic colitis or ischemic enterocolitis
15. Unstable medical condition that is clinically significant in the judgment of the investigator
16. Alanine transaminase (ALT) or aspartate transaminase (AST) > ULN or total bilirubin > ULN and clinically significant in the opinion of PI and/or Sponsor.
17. History of myocardial infarction or unstable angina within 6 months before screening
18. History of more than 1 myocardial infarction within 5 years before screening
19. Clinically significant cardiac arrhythmia (including atrial fibrillation), cardiomyopathy, or cardiac conduction defect (patients with a pacemaker are acceptable)
20. Symptomatic hypotension, or uncontrolled hypertension
21. 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.
22. Stroke within 18 months before screening, or history of a stroke concomitant with onset of dementia
23. History of brain tumor or other clinically significant space-occupying lesion on CT or MRI
24. Head trauma with clinically significant loss of consciousness within 12 months before screening or concurrent with the onset of dementia
25. Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or resuscitation
26. Specific degenerative CNS disease diagnosis other than AD (e.g., Huntington's disease, Creutzfeld-Jacob disease, Down's syndrome, Frontotemporal Dementia, Parkinson's disease)
27. Wernicke's encephalopathy
28. Active acute or chronic CNS infection
29. Donepezil 23 mg or greater QD currently or within 3 months prior to randomization
30. Discontinued AChEI < 30 days prior to randomization
31. 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
32. 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
33. 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
34. Immunosuppressants, including systemic corticosteroids, if taken in clinically immunosuppressive doses (Steroid use for allergy or other inflammation is permitted.)
35. Antiepileptic medications if taken for control of seizures
36. Chronic intake of opioid-containing analgesics
37. Sedating H1 antihistamines
38. Nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or similar therapeutic agent within 30 days before screening
39. Clinically significant illness within 30 days of enrollment
40. History of significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, or metabolic disease
41. Loss of a significant volume of blood (> 450 mL) within 4 weeks prior to the study
42. COVID-19 infection within 3 months

Contacts and Locations

Locations

United States, Arizona

Cognitive Clinical Trials

Gilbert, Arizona, United States, 85296

Cognitive Clinical Trials

Surprise, Arizona, United States, 85374

United States, California

Sun Valley Research Center, Inc.

Imperial, California, United States, 92251

United States, Florida

Brain Matters Research

Delray Beach, Florida, United States, 33445

Neuropsychiatric Research Center of Southwest Florida

Fort Myers, Florida, United States, 33912

Adaptive Clinical Research, Inc

Miami Lakes, Florida, United States, 33016

Optimus U

Miami, Florida, United States, 33125

IMIC, Inc.

Palmetto Bay, Florida, United States, 33157

United States, Nebraska

Cognitive Clinical Trials

Bellevue, Nebraska, United States, 68005

Cognitive Clinical Trials

Omaha, Nebraska, United States, 68130

United States, New Jersey

Advanced Memory Research Institute

Toms River, New Jersey, United States, 08755

United States, Ohio

Neuro-Behavioral Clinical Research

North Canton, Ohio, United States, 44720

United States, Texas

Senior Adults Specialty Research

Austin, Texas, United States, 78757

Centex Studies, Inc.

Houston, Texas, United States, 77058

Centex Studies

McAllen, Texas, United States, 78504

Canada, Ontario

Ottawa Memory Clinic

Ottawa, Ontario, Canada, K1Z 1G3

Toronto Memory Program

Toronto, Ontario, Canada, M3B 2S7

Sponsors and Collaborators

Cassava Sciences, Inc.

National Institute on Aging (NIA)

Investigators

• Study Chair: Lindsay Burns, PhD; Cassava Sciences

More Information

Additional Information:

Cassava Sciences company website 

Publications:

Wang HY, Pei Z, Lee KC, Lopez-Brignoni E, Nikolov B, Crowley CA, Marsman MR, Barbier R, Friedmann N, Burns LH. PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients. J Prev Alzheimers Dis. 2020;7(4):256-264. doi: 10.14283/jpad.2020.6.

Wang HY, Lee KC, Pei Z, Khan A, Bakshi K, Burns LH. PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. Neurobiol Aging. 2017 Jul;55:99-114. doi: 10.1016/j.neurobiolaging.2017.03.016. Epub 2017 Mar 31.

Wang HY, Bakshi K, Frankfurt M, Stucky A, Goberdhan M, Shah SM, Burns LH. Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A. J Neurosci. 2012 Jul 18;32(29):9773-84. doi: 10.1523/JNEUROSCI.0354-12.2012. Erratum In: J Neurosci. 2021 Dec 15;41(50):10405. J Neurosci. 2022 Jan 19;42(3):529.

• Responsible Party: Cassava Sciences, Inc.
• ClinicalTrials.gov Identifier: NCT04388254
• Other Study ID Numbers: PTI-125-04; R44AG065152 ( U.S. NIH Grant/Contract )
• First Posted: May 14, 2020
• Last Update Posted: February 16, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders