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

NCT04388254 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: PTI-125-04R44AG065152
• Study Type: interventional
• Target: 220
• Locations: 2 countries
• Sites: 17

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.

Conditions

Alzheimer Disease

Outcome Measures

Primary Outcomes (10)

• 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 Outcomes (5)

• Change From Baseline to Month 12 in Cerebral Spinal Fluid for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Mean Concentration (pg/mL)

  Day 1 to Month 12

• Change From Baseline to Month 12 in Cerebral Spinal Fluid for Tau Protein Mean Concentration (pg/mL)

  Day 1 to Month 12

• Change From Baseline to Month 12 in Cerebral Spinal Fluid for Neurogranin Mean Concentration (pg/mL)

  Day 1 to Month 12

• Change From Baseline to Month 12 in Cerebral Spinal Fluid for Neurofilament Light Chain Protein Mean Concentration (pg/mL)

  Day 1 to Month 12

• Change From Baseline to Month 12 in Cerebral Spinal Fluid for Glial Fibrillary Acidic Protein Mean Concentration (pg/mL)

  Day 1 to Month 12

Study Arms (2)

Simufilam 100 mg oral tablets throughout

EXPERIMENTAL

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 tablets / Placebo / Simufilam 100 mg oral tablets

PLACEBO COMPARATOR

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; Drug: Placebo

Interventions

Simufilam 100 mg oral tablet DRUG

Simufilam 100 mg oral tablet for b.i.d. administration

Also known as: PTI-125, Sumifilam

Simufilam 100 mg oral tablets / Placebo / Simufilam 100 mg oral tablets; Simufilam 100 mg oral tablets throughout

Placebo DRUG

Matching placebo oral tablets

Simufilam 100 mg oral tablets / Placebo / Simufilam 100 mg oral tablets

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Cassava Sciences, Inc.: lead
• National Institute on Aging (NIA): collaborator

Study Sites (17)

Cognitive Clinical Trials

Gilbert, Arizona, 85296, United States

Location

Cognitive Clinical Trials

Surprise, Arizona, 85374, United States

Location

Sun Valley Research Center, Inc.

Imperial, California, 92251, United States

Location

Brain Matters Research

Delray Beach, Florida, 33445, United States

Location

Neuropsychiatric Research Center of Southwest Florida

Fort Myers, Florida, 33912, United States

Location

Optimus U

Miami, Florida, 33125, United States

Location

Adaptive Clinical Research, Inc

Miami Lakes, Florida, 33016, United States

Location

IMIC, Inc.

Palmetto Bay, Florida, 33157, United States

Location

Cognitive Clinical Trials

Bellevue, Nebraska, 68005, United States

Location

Cognitive Clinical Trials

Omaha, Nebraska, 68130, United States

Location

Advanced Memory Research Institute

Toms River, New Jersey, 08755, United States

Location

Neuro-Behavioral Clinical Research

North Canton, Ohio, 44720, United States

Location

Senior Adults Specialty Research

Austin, Texas, 78757, United States

Location

Centex Studies, Inc.

Houston, Texas, 77058, United States

Location

Centex Studies

McAllen, Texas, 78504, United States

Location

Ottawa Memory Clinic

Ottawa, Ontario, K1Z 1G3, Canada

Location

Toronto Memory Program

Toronto, Ontario, M3B 2S7, Canada

Location

Related Publications (4)

• 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.

  PMID: 32920628 BACKGROUND

• 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.

  PMID: 28438486 BACKGROUND

• 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.

  PMID: 22815492 BACKGROUND

• Brodtmann A, Darby D, Oboudiyat C, Mahoney CJ, Le Heron C, Panegyres PK, Brew B. Assessing preparedness for Alzheimer disease-modifying therapies in Australasian health care systems. Med J Aust. 2023 Apr 3;218(6):247-249. doi: 10.5694/mja2.51880. Epub 2023 Mar 19. No abstract available.

  PMID: 36934371 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Simufilam; Tablets

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: Sr. Associate Director
• Organization: Cassava Sciences

bmurray@cassavasciences.com

5125013180

Study Officials

• Lindsay Burns, PhD

  Cassava Sciences

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Matching placebo for the 6-month randomized period (Month 12 to Month 18)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: May 11, 2020
• First Posted: May 14, 2020
• Study Start: March 24, 2020
• Primary Completion: November 9, 2023
• Study Completion: November 9, 2023
• Last Updated: April 22, 2025
• Results First Posted: April 22, 2025

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (15); CA (2)