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

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

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Simufilam 100 mg oral tablet; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 220
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Z 1G3
      • Ottawa Memory Clinic
    • Toronto, Ontario, Canada, M3B 2S7
      • Toronto Memory Program
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85296
      • Cognitive Clinical Trials
    • Surprise, Arizona, United States, 85374
      • Cognitive Clinical Trials
  • California
    • Imperial, California, United States, 92251
      • Sun Valley Research Center, Inc.
  • Florida
    • Delray Beach, Florida, United States, 33445
      • Brain Matters Research
    • Fort Myers, Florida, United States, 33912
      • Neuropsychiatric Research Center of Southwest Florida
    • Miami, Florida, United States, 33125
      • Optimus U
    • Miami Lakes, Florida, United States, 33016
      • Adaptive Clinical Research, Inc
    • Palmetto Bay, Florida, United States, 33157
      • IMIC, Inc.
  • Nebraska
    • Bellevue, Nebraska, United States, 68005
      • Cognitive Clinical Trials
    • Omaha, Nebraska, United States, 68130
      • Cognitive Clinical Trials
  • New Jersey
    • Toms River, New Jersey, United States, 08755
      • Advanced Memory Research Institute
  • Ohio
    • North Canton, Ohio, United States, 44720
      • Neuro-Behavioral Clinical Research
  • Texas
    • Austin, Texas, United States, 78757
      • Senior Adults Specialty Research
    • Houston, Texas, United States, 77058
      • Centex Studies, Inc.
    • McAllen, Texas, United States, 78504
      • Centex Studies

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in ADAS-Cog-11	Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item: Change from baseline in cognition over the course of 24 months Possible range in score: 0-70; Subscales are summed; Higher values represent a more cognitively impaired participant Decrease in mean value represents improvement in cognition from one timepoint to the next.	Day 1 to Month 24
Change From Baseline in ADAS-Cog-11 (Month 12 to Month 24)	Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item: Change from baseline in cognition Starting at month 12 through month 24; Possible range in score: 0-70; Higher values represent a more cognitively impaired participant; Decrease in mean value represents improvement in cognition from one timepoint to the next.	Month 12 to Month 24
Safety and Tolerability (Open Label Abnormal Vital Signs)	The most frequently reported Treatment Emergent Adverse Events indicative of abnormal vital signs (hypertension/worsening of hypertension and blood pressure increase) of simufilam (PTI-125) during the open label portion of the study: Open-label period 1 (Day 1 to Month 12) and open-label period 2 (Month 18 to Month 24)	Day 1 to Month 12 and month 18 to month 24
Safety and Tolerability (Randomize Withdraw Abnormal Vital Signs)	The most frequently reported Treatment Emergent Adverse Event indicative of abnormal vital signs (hypotension) of simufilam (PTI-125) or placebo during the randomized withdraw portion of the study : Month 12 to Month 18	Month 12 to month 18
Safety and Tolerability (Open Label Electrocardiogram Results)	The number of subjects that had Treatment Emergent Adverse Events indicative of abnormal Electrocardiogram results while on simufilam (PTI-125) during the open label portion of the study: Open-label period 1 (Day 1 to Month 12) and open-label period 2 (Month 18 to Month 24)	Day 1 to Month 12 and month 18 to month 24
Safety and Tolerability (Randomize Withdraw Electrocardiogram Results)	The number of subjects that had Treatment Emergent Adverse Events indicative of abnormal Electrocardiogram results while on simufilam (PTI-125) or placebo during the randomized withdraw portion of the study: Month 12 to Month 18	Month 12 to Month 18
Safety and Tolerability (Open Label Abnormal Physical Examination)	The most frequently reported Treatment Emergent Adverse Events indicative of abnormal physical examination (weight increase or weight decrease) while administered simufilam (PTI-125) during the open label portion of the study: Open-label period 1 (Day 1 to Month 12) and open-label period 2 (Month 18 to Month 24)	Day 1 to Month 12 and month 18 to month 24
Safety and Tolerability (Randomize Withdraw Abnormal Physical Examination Findings)	The number of subjects that had Treatment Emergent Adverse Events of indicative of abnormal physical examination while on simufilam (PTI-125) or placebo during the randomized withdraw portion of the study: Month 12 to Month 18	Month 12 to Month 18
Safety and Tolerability (Open Label Abnormal Clinical Laboratory Results)	Treatment Emergent Adverse Events when three or more subjects reported abnormal clinical laboratory results while on simufilam (PTI-125) during the open label portion of the study: Open-label period 1 (Day 1 to Month 12) and open-label period 2 (Month 18 to Month 24)	Day 1 to Month 12 and month 18 to month 24
Safety and Tolerability (Randomize Withdraw Abnormal Clinical Laboratory Results)	Treatment Emergent Adverse Events when two or more subjects reported abnormal clinical laboratory results while on simufilam (PTI-125) or placebo during the randomized withdraw portion of the study: Month 12 to Month 18	Month 12 to Month 18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Month 12 in Cerebral Spinal Fluid for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Mean Concentration (pg/mL)	Change from baseline to month 12 in Cerebral Spinal Fluid for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory)	Day 1 to Month 12
Change From Baseline to Month 12 in Cerebral Spinal Fluid for Tau Protein Mean Concentration (pg/mL)	Change from baseline to month 12 in Cerebral Spinal Fluid for Tau Protein Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory)	Day 1 to Month 12
Change From Baseline to Month 12 in Cerebral Spinal Fluid for Neurogranin Mean Concentration (pg/mL)	Change from baseline to month 12 in Cerebral Spinal Fluid for Neurogranin Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory)	Day 1 to Month 12
Change From Baseline to Month 12 in Cerebral Spinal Fluid for Neurofilament Light Chain Protein Mean Concentration (pg/mL)	Change from baseline to month 12 in Cerebral Spinal Fluid for Neurofilament Light Chain Protein Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory)	Day 1 to Month 12
Change From Baseline to Month 12 in Cerebral Spinal Fluid for Glial Fibrillary Acidic Protein Mean Concentration (pg/mL)	Change from baseline to month 12 in Cerebral Spinal Fluid for Glial Fibrillary Acidic Protein Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory)	Day 1 to Month 12

Collaborators and Investigators

• Sponsor: Cassava Sciences, Inc.
• Collaborators: National Institute on Aging (NIA)
• Investigators: Study Chair: Lindsay Burns, PhD, Cassava Sciences

Publications and helpful links

General Publications

• 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, 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, 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. doi: 10.1523/JNEUROSCI.2154-21.2021. J Neurosci. 2022 Jan 19;42(3):529. doi: 10.1523/JNEUROSCI.2306-21.2021.

Helpful Links

• Cassava Sciences company website

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2020
• Primary Completion (Actual): November 9, 2023
• Study Completion (Actual): November 9, 2023

Study Registration Dates

• First Submitted: May 11, 2020
• First Submitted That Met QC Criteria: May 11, 2020
• First Posted (Actual): May 14, 2020

Study Record Updates

• Last Update Posted (Actual): April 22, 2025
• Last Update Submitted That Met QC Criteria: April 21, 2025
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease
• Other Study ID Numbers: PTI-125-04; R44AG065152 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No