Simufilam 50 mg or 100 mg for Mild-to-Moderate Alzheimer's Disease

NCT05026177 | Terminated Phase 3 Results DMC FDA Drug

• 1 other identifier: PTI-125-06
• Study Type: interventional
• Target: 1,125
• Locations: 4 countries
• Sites: 89

Brief Summary

A 76-week safety and efficacy study of simufilam (PTI-125) given twice daily to participants with mild-to-moderate Alzheimer's disease (AD) for 76 weeks. Approximately 1083 participants will be randomized (1:1:1) to receive either placebo, 50 mg tablets of simufilam, or 100 mg tablets of simufilam, twice daily, for 76 weeks. Clinic visits will occur 4 weeks after the baseline visit, and then every 12 weeks until the end of the study. The safety of simufilam, and its efficacy in enhancing cognition and slowing cognitive and functional decline will be evaluated.

Conditions

Alzheimer Disease

Outcome Measures

Primary Outcomes (2)

• Change From Baseline in the 12-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12)

  The change from baseline to Week 76 in the ADAS-Cog12, a psychometrician-administered battery comprised of several cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Scores range from 0 (best) to 80 (worst).

  Baseline (Study Day 1) to Week 76

• Change From Baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)

  The change from baseline to Week 76 in the ADCS-ADL, a 23-item study partner questionnaire that covers both basic activities of daily living (ADL) and more complex ADL or instrumental ADL for the subject. Scores range from 0 to 78, with a lower score indicating greater severity of functional loss.

  Baseline (Study Day 1) to Week 76

Secondary Outcomes (5)

• Change From Baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS)

  Baseline (Study Day 1) to Week 76

• Change From Baseline in the Neuropsychiatric Inventory (NPI)

  Baseline (Study Day 1) to Week 76

• Change From Baseline in the MMSE

  Baseline (Study Day 1) to Week 76

• Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB)

  Baseline (Study Day 1) to Week 76

• Change From Baseline in the Zarit Burden Interview (ZBI)

  Baseline (Study Day 1) to Week 76

Other Outcomes (6)

• Changes From Baseline in Brain Volume Via MRI

  Baseline (Study Day 1) to Week 76

• Changes From Baseline in Amyloid Positron Emission Tomography (PET)

  Baseline (Study Day 1) to Week 76

• Changes From Baseline in Tau Positron Emission Tomography (PET)

  Baseline (Study Day 1) to Week 76

Study Arms (3)

Placebo

PLACEBO COMPARATOR

Matching placebo, supplied by Cassava as coated tablets, and taken twice daily (b.i.d.) for 76 weeks

Drug: Placebo

Simufilam 50 mg

EXPERIMENTAL

Simufilam 50 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks

Drug: Simufilam

Simufilam 100 mg

EXPERIMENTAL

Simufilam 100 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks

Drug: Simufilam

Interventions

Simufilam DRUG

Simufilam is a novel drug candidate designed to treat and slow the progression of AD. Simufilam binds with femtomolar affinity to an altered conformation of filamin A that is present in the brain of patients with AD and critical to the toxicity of Aβ42. In this study, simufilam will be given b.i.d. for 76 weeks at a dose of 50 mg or 100 mg.

Also known as: PTI-125

Simufilam 100 mg; Simufilam 50 mg

Placebo DRUG

Matching placebo given b.i.d. for 76 weeks

Placebo

Eligibility Criteria

• Age: 50 Years - 87 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Meets National Institute on Aging and Alzheimer's Association Research Framework criteria for individuals in clinical Stage 4 or 5 of the Alzheimer's continuum.
• Evidence for AD pathophysiology, confirmed prior to or during screening.
• MMSE score ≥ 16 and ≤ 27 at screening.
• Clinical Dementia Rating - Global Score must be 0.5, 1 or 2.
• If receiving background AD medications, the dosing regimen must be stable for at least 12 weeks prior to randomization. Chronic medications for conditions other than AD (such as depression) must be prescribed at a stable dose for at least 4 weeks prior to screening.
• The subject has not been a cigarette smoker or chewed tobacco for at least 3 years.
• Availability of a study partner.
• Individuals who have participated in a clinical study with an investigational drug targeting the underlying AD process may be permitted to participate in this study.
• Completed a COVID-19 vaccine primary series ("fully vaccinated") at least 2 weeks prior to randomization or had an unambiguous COVID-19 infection diagnosed more than 3 months before the start of the Screening Period.

You may not qualify if:

• A neurologic condition other than AD that significantly contributes to the subject's dementia.
• Any current primary psychiatric diagnosis other than AD if it is likely to confound cognitive assessment or ability to comply with study procedures.
• Geriatric Depression Scale (15-item) score \> 8 (Note - a subject with a score \> 8 may continue in screening if, in the judgment of the Investigator, the elevated score is not attributed to a major depressive episode).
• Suicidal ideation during the past 3 months or suicidal behavior during the past 12 months.
• Alcohol or substance use disorder within 2 years of screening.
• MRI presence of cerebral vascular or other significant pathology.
• History of transient ischemic attack or stroke within 12 months of screening.
• Seizure within 12 months of screening.
• Severe head trauma or head trauma considered likely to be contributing to the subject's cognitive impairment.
• Sleep apnea that is considered likely to be contributing to the subject's cognitive impairment.
• Insufficiently controlled diabetes mellitus or hypertension.
• Body mass index \< 18.5 or \> 37.5.
• History or diagnosis of clinically significant cardiac disease.
• Currently or previously prescribed/administered aducanumab, lecanemab, or any anti-amyloid monoclonal antibody, more than 2 doses.

Sponsors & Collaborators

• Cassava Sciences, Inc.: lead
• Premier Research: collaborator

Study Sites (89)

Banner Alzheimer's Institute

Phoenix, Arizona, 85006, United States

Location

Arizona Neuroscience Research, LLC

Phoenix, Arizona, 85032, United States

Location

Clinical Endpoints

Scottsdale, Arizona, 85258, United States

Location

Banner Sun Health Research Institute

Sun City, Arizona, 85351, United States

Location

Banner Alzheimer's Institute - Tucson

Tucson, Arizona, 85718, United States

Location

North County Neurology Associates

Carlsbad, California, 92011, United States

Location

Neuro-Pain Medical Center

Fresno, California, 93710, United States

Location

Neurology Center of North Orange County

Fullerton, California, 92835, United States

Location

Healthy Brain Clinic

Long Beach, California, 90804, United States

Location

California Research Insitute

Los Angeles, California, 90027, United States

Location

Shankle Clinic and Hoag Memorial Hospital Presbyterian

Newport Beach, California, 92663, United States

Location

Pacific Research Network, LLC

San Diego, California, 92103, United States

Location

Nuvance Health Medical Practice CT, Inc. - Associated Neurologists, PC

Danbury, Connecticut, 06810, United States

Location

Ki Health Partners, LLC

Stamford, Connecticut, 06905, United States

Location

JEM Research Institute

Atlantis, Florida, 33462, United States

Location

Parkinson's Disease and Movement Disorders Center of Boca Raton

Boca Raton, Florida, 33486, United States

Location

Clinical Research of Brandon, LLC

Brandon, Florida, 33511, United States

Location

Quantum Laboratories

Deerfield Beach, Florida, 33442, United States

Location

Brain Matters Research Inc

Delray Beach, Florida, 33445, United States

Location

Indago Research and Health Center, Inc.

Hialeah, Florida, 33012, United States

Location

Alphab Global Research

Jupiter, Florida, 33458, United States

Location

K2 Medical Research

Maitland, Florida, 32751, United States

Location

Mind Institute at Miami Jewish Health

Miami, Florida, 33137, United States

Location

Brainstorm Research

Miami, Florida, 33176, United States

Location

Health Synergy Clinical Research

Okeechobee, Florida, 34972, United States

Location

Clinical Neuroscience Solutions, Inc. dba CNS Healthcare

Orlando, Florida, 32801, United States

Location

Intercoastal Medical Group - Sarasota

Sarasota, Florida, 34239, United States

Location

Alzheimer's Research & Treatment Center

Stuart, Florida, 34997, United States

Location

Brain Matters Research Inc

Stuart, Florida, 34997, United States

Location

USF Health - Byrd Alzheimer's Center and Research Institute

Tampa, Florida, 33613, United States

Location

Alzheimer's Research & Treatment Center

Wellington, Florida, 33414, United States

Location

Conquest Research

Winter Park, Florida, 32789, United States

Location

Columbus Memory Center, PC

Columbus, Georgia, 31909, United States

Location

Accel Research Sites - NeuroStudies

Decatur, Georgia, 30030, United States

Location

Great Lakes Clinical Trials

Chicago, Illinois, 60640, United States

Location

Advocate Aurora Health

Park Ridge, Illinois, 60068, United States

Location

University of Kentucky Sanders-Brown Center on Aging

Lexington, Kentucky, 40504, United States

Location

Neurology Center of New England

Foxborough, Massachusetts, 02035, United States

Location

ActivMed Practices & Research, LLC

Methuen, Massachusetts, 01844, United States

Location

Boston Center for Memory

Newton, Massachusetts, 02459, United States

Location

Office of Donald S. Marks, M.D., P.C.

Plymouth, Massachusetts, 02360, United States

Location

MedVadis Research

Waltham, Massachusetts, 02451, United States

Location

Patient First MD

Middletown, New Jersey, 07748, United States

Location

Global Medical Institutes, LLC

Princeton, New Jersey, 08540, United States

Location

The Cognitive and Research Center of New Jersey (CRCNJ)

Springfield, New Jersey, 07081, United States

Location

Advanced Memory Research Institute of NJ

Toms River, New Jersey, 08755, United States

Location

Albany Medical Center

Albany, New York, 12208, United States

Location

Neurological Associates of Albany

Albany, New York, 12208, United States

Location

Integrative Clinical Trials

Brooklyn, New York, 11229, United States

Location

SPRI Clinical Trials Brooklyn

Brooklyn, New York, 11235, United States

Location

Velocity Clinical Research, Formerly Clarity Clinical Research

East Syracuse, New York, 13057, United States

Location

Richmond Behavioral Associates

Staten Island, New York, 10312, United States

Location

Accellacare Research of Winston-Salem

Winston-Salem, North Carolina, 27103, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Neurology Diagnostics

Dayton, Ohio, 45459, United States

Location

Neuro-Behavioral Clinical Research (NBCR)

North Canton, Ohio, 44720, United States

Location

Center for Cognitive Health - Portland

Portland, Oregon, 97225, United States

Location

The Clinical Trial Center

Jenkintown, Pennsylvania, 19046, United States

Location

Keystone Clinical Studies, LLC

Plymouth Meeting, Pennsylvania, 19462, United States

Location

KCA Neurology, PLLC

Franklin, Tennessee, 37067, United States

Location

Neurology Consultants of Dallas, PA

Dallas, Texas, 75243, United States

Location

Cedar Health Research

Irving, Texas, 75062, United States

Location

The Memory Clinic - Bennington

Bennington, Vermont, 05201, United States

Location

Northwest Clinical Research Center

Bellevue, Washington, 98007, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

OCT Research ULC DBA Okanagan Clinical Trials

Kelowna, British Columbia, V1Y 2Z9, Canada

Location

Djavad Mowafaghian Centre for Brain Health

Vancouver, British Columbia, V6T 1Z3, Canada

Location

Centre Hospitalier Universitaire Dr-Georges-L.-Dumont (CHUDGLD)

Moncton, New Brunswick, E1C 2Z3, Canada

Location

True North Clinical Research - Halifax

Halifax, Nova Scotia, B3S 1N2, Canada

Location

True North Clinical Research - New Minas

New Minas, Nova Scotia, B4N 3R7, Canada

Location

St. Joseph's Health Care London

London, Ontario, N6C 0A7, Canada

Location

Ottawa Memory Clinic

Ottawa, Ontario, K1Z 1G3, Canada

Location

Recherches Neuro-Hippocampe Inc.

Ottawa, Ontario, K1Z 1G3, Canada

Location

Kawartha Centre - Redefining Healthy Aging

Peterborough, Ontario, K9H2P4, Canada

Location

Toronto Memory Program

Toronto, Ontario, M3B 2S7, Canada

Location

The Centre for Memory and Aging

Toronto, Ontario, Canada

Location

Santa Cruz Behavioral PSC

Bayamón, 00961, Puerto Rico

Location

Inspira Clinical Research

San Juan, 00918, Puerto Rico

Location

Barbara Diaz Hernandez Md Research, Inc.

San Juan, 00926, Puerto Rico

Location

Instituto De Neurologia Dra. Ivonne Fraga

San Juan, Puerto Rico

Location

Chonnam National University Hospital

Gwangju, Dong-gu, 61469, South Korea

Location

Hanyang University Guri Hospital

Guri-si, Gyeonggi-do, 11923, South Korea

Location

Seoul National University Bundang Hospital

Seongnam-si, Gyeonggi-do, 13620, South Korea

Location

Gachon University Gil Hospital

Namdong-gu, Incheon, 21565, South Korea

Location

Inha University Medical Center

Incheon, Jung-go, 22332, South Korea

Location

Kyungpook National University Chilgok Hospital

Daegu, North Gyeongsang Province, 61469, South Korea

Location

Korea University Anam Hospital

Seongbuk-gu, Seoul, 02841, South Korea

Location

HanYang University Hospital

Seongdong-gu, Seoul, 04763, South Korea

Location

Asan Medical Center

Seoul, Songpa-gu, 05505, South Korea

Location

Related Publications (1)

• Kupiec JW, Porsteinsson AP, Turner RS, Hendrix S, Mallinckrodt C, Khan A, Cohen I, Liss J, Clarnette R, Park KH, Hernandez AM, Burns LH. Phase 3 randomized clinical trials of simufilam in mild-to-moderate Alzheimer's disease. J Prev Alzheimers Dis. 2026 Jan 1:100469. doi: 10.1016/j.tjpad.2025.100469. Online ahead of print.

  PMID: 41500915 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Simufilam

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Study Director
• Organization: Cassava Sciences, Inc.

ClinicalTrials.gov@cassavasciences.com

737-910-1045

Study Officials

• James Kupiec, MD

  Cassava Sciences

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Randomized treatments will be assigned by subject numbers in a randomly generated numeric sequence. Randomization (1:1:1) will be stratified by low or high Mini-Mental State Exam (MMSE; 16-20 and 21-27). The randomization code will not be revealed to study subjects, Investigators, clinical staff, study monitors or the Sponsor until all subjects have completed therapy and the database has been finalized and locked.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 9, 2021
• First Posted: August 30, 2021
• Study Start: November 18, 2021
• Primary Completion: December 30, 2024
• Study Completion: December 30, 2024
• Last Updated: September 22, 2025
• Results First Posted: September 22, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

KR (9); PR (4); US (65); CA (11)