Simufilam 50 mg or 100 mg for Mild-to-Moderate Alzheimer's Disease (REFOCUS-ALZ)

A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, 76-week Study Evaluating the Safety and Efficacy of Two Doses of Simufilam in Subjects With Mild-to-Moderate Alzheimer's Disease

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.

Study Overview

• Status: Terminated
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Placebo; Drug: Simufilam

Detailed Description

The primary objective of this study is to investigate the safety and efficacy of simufilam (PTI-125) in enhancing cognition and slowing cognitive and functional decline following 76-week, repeat-dose oral administration in participants with mild-to-moderate AD. Secondary objectives are to assess neuropsychiatric symptoms and to replicate the cerebrospinal fluid (CSF) biomarker effects observed in the two Phase 2 studies (PTI-125-03 and PTI-125-02) after 76 weeks of simufilam treatment. A third objective is to investigate the effect of simufilam treatment on plasma biomarkers as well as anatomical correlates of disease progression (brain volume [hippocampus, ventricles and whole brain]; and amyloid and tau deposition in the brain). A limited number of research sites will be invited to participate in sub-studies to assess the impact of simufilam on anatomical and biomarker endpoints, including: change from Baseline in CSF biomarkers (30 subjects/group); brain volume via magnetic resonance imaging (MRI) (50 subjects/group); and amyloid and tau positron emission tomography (PET) (40 and 50 subjects/group, respectively). Participants in both PET sub-studies will be required to have an MRI during the Screening Period and provide plasma for a biomarker sub-study. Participants in the tau PET sub-study will also provide additional plasma for a pharmacokinetic (PK) exposure response analysis. Changes from baseline for these imaging and fluid biomarkers represent additional secondary endpoints. The 90 subjects (30 per group) in the CSF sub-study will undergo lumbar puncture during the Screening Period and again at the Week 76 End-of-Treatment Visit to collect CSF biomarkers.

Safety will be evaluated by adverse event monitoring, vital signs, clinical labs, and the Columbia Suicide Severity Rating Scale at every visit. Subjects will undergo MRI during screening to ensure entry criteria are met (unless recent MRI confirms entry criteria); however, 150 subjects (50 subjects per treatment group) will also undergo repeat MRI assessments at Weeks 40 and 76 to assess both long-term safety and drug impact on brain volume as noted above. Resting electrocardiograms will be conducted at Baseline (Study Day 1) and Weeks 4, 40 and 76. A complete physical and neurological examination will be performed at screening, and brief examinations will be performed at all other visits. Weight will be measured during the Screening Period, at Baseline (Study Day 1) and at all other visits.

An independent Data Safety Monitoring Board (DSMB) will meet periodically to review subject safety assessments and determine if dosing may continue. A charter will be developed with specific guidance for the DSMB.

• Study Type: Interventional
• Enrollment (Actual): 1125
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 2Z9
      • OCT Research ULC DBA Okanagan Clinical Trials
    • Vancouver, British Columbia, Canada, V6T 1Z3
      • Djavad Mowafaghian Centre for Brain Health
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1C 2Z3
      • Centre Hospitalier Universitaire Dr-Georges-L.-Dumont (CHUDGLD)
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3S 1N2
      • True North Clinical Research - Halifax
    • New Minas, Nova Scotia, Canada, B4N 3R7
      • True North Clinical Research - New Minas
  • Ontario
    • London, Ontario, Canada, N6C 0A7
      • St. Joseph's Health Care London
    • Ottawa, Ontario, Canada, K1Z 1G3
      • Ottawa Memory Clinic
    • Ottawa, Ontario, Canada, K1Z 1G3
      • Recherches Neuro-Hippocampe Inc.
    • Peterborough, Ontario, Canada, K9H2P4
      • Kawartha Centre - Redefining Healthy Aging
    • Toronto, Ontario, Canada, M3B 2S7
      • Toronto Memory Program
    • Toronto, Ontario, Canada
      • The Centre for Memory and Aging
• Puerto Rico
  • Bayamón, Puerto Rico, 00961
    • Santa Cruz Behavioral PSC
  • San Juan, Puerto Rico, 00918
    • INSPIRA Clinical Research
  • San Juan, Puerto Rico, 00926
    • Barbara Diaz Hernandez MD Research, Inc.
  • San Juan, Puerto Rico
    • Instituto De Neurologia Dra. Ivonne Fraga
• South Korea
  • Dong-gu
    • Gwangju, Dong-gu, South Korea, 61469
      • Chonnam National University Hospital
  • Gyeonggi-do
    • Guri-si, Gyeonggi-do, South Korea, 11923
      • Hanyang University Guri Hospital
    • Seongnam-si, Gyeonggi-do, South Korea, 13620
      • Seoul National University Bundang Hospital
  • Incheon
    • Namdong-gu, Incheon, South Korea, 21565
      • Gachon University Gil Hospital
  • Jung-go
    • Incheon, Jung-go, South Korea, 22332
      • Inha University Medical Center
  • North Gyeongsang Province
    • Daegu, North Gyeongsang Province, South Korea, 61469
      • Kyungpook National University Chilgok Hospital
  • Seoul
    • Seongbuk-gu, Seoul, South Korea, 02841
      • Korea University Anam Hospital
    • Seongdong-gu, Seoul, South Korea, 04763
      • Hanyang University Hospital
  • Songpa-gu
    • Seoul, Songpa-gu, South Korea, 05505
      • Asan Medical Center
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner Alzheimer's Institute
    • Phoenix, Arizona, United States, 85032
      • Arizona Neuroscience Research, LLC
    • Scottsdale, Arizona, United States, 85258
      • Clinical Endpoints
    • Sun City, Arizona, United States, 85351
      • Banner Sun Health Research Institute
    • Tucson, Arizona, United States, 85718
      • Banner Alzheimer's Institute - Tucson
  • California
    • Carlsbad, California, United States, 92011
      • North County Neurology Associates
    • Fresno, California, United States, 93710
      • Neuro-Pain Medical Center
    • Fullerton, California, United States, 92835
      • Neurology Center of North Orange County
    • Long Beach, California, United States, 90804
      • Healthy Brain Clinic
    • Los Angeles, California, United States, 90027
      • California Research Insitute
    • Newport Beach, California, United States, 92663
      • Shankle Clinic and Hoag Memorial Hospital Presbyterian
    • San Diego, California, United States, 92103
      • Pacific Research Network, LLC
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Nuvance Health Medical Practice CT, Inc. - Associated Neurologists, PC
    • Stamford, Connecticut, United States, 06905
      • KI Health Partners, LLC
  • Florida
    • Atlantis, Florida, United States, 33462
      • JEM Research Institute
    • Boca Raton, Florida, United States, 33486
      • Parkinson's Disease and Movement Disorders Center of Boca Raton
    • Brandon, Florida, United States, 33511
      • Clinical Research Of Brandon, LLC
    • Deerfield Beach, Florida, United States, 33442
      • Quantum Laboratories
    • Delray Beach, Florida, United States, 33445
      • Brain Matters Research Inc
    • Hialeah, Florida, United States, 33012
      • Indago Research and Health Center, Inc.
    • Jupiter, Florida, United States, 33458
      • Alphab Global Research
    • Maitland, Florida, United States, 32751
      • K2 Medical Research
    • Miami, Florida, United States, 33176
      • Brainstorm Research
    • Miami, Florida, United States, 33137
      • Mind Institute at Miami Jewish Health
    • Okeechobee, Florida, United States, 34972
      • Health Synergy Clinical Research
    • Orlando, Florida, United States, 32801
      • Clinical Neuroscience Solutions, Inc. dba CNS Healthcare
    • Sarasota, Florida, United States, 34239
      • Intercoastal Medical Group - Sarasota
    • Stuart, Florida, United States, 34997
      • Alzheimer's Research & Treatment Center
    • Stuart, Florida, United States, 34997
      • Brain Matters Research Inc
    • Tampa, Florida, United States, 33613
      • USF Health - Byrd Alzheimer's Center and Research Institute
    • Wellington, Florida, United States, 33414
      • Alzheimer's Research & Treatment Center
    • Winter Park, Florida, United States, 32789
      • Conquest Research
  • Georgia
    • Columbus, Georgia, United States, 31909
      • Columbus Memory Center, PC
    • Decatur, Georgia, United States, 30030
      • Accel Research Sites - Neurostudies
  • Illinois
    • Chicago, Illinois, United States, 60640
      • Great Lakes Clinical Trials
    • Park Ridge, Illinois, United States, 60068
      • Advocate Aurora Health
  • Kentucky
    • Lexington, Kentucky, United States, 40504
      • University of Kentucky Sanders-Brown Center on Aging
  • Massachusetts
    • Foxborough, Massachusetts, United States, 02035
      • Neurology Center of New England
    • Methuen, Massachusetts, United States, 01844
      • ActivMed Practices & Research, LLC
    • Newton, Massachusetts, United States, 02459
      • Boston Center for Memory
    • Plymouth, Massachusetts, United States, 02360
      • Office of Donald S. Marks, M.D., P.C.
    • Waltham, Massachusetts, United States, 02451
      • MedVadis Research
  • New Jersey
    • Middletown, New Jersey, United States, 07748
      • Patient First MD
    • Princeton, New Jersey, United States, 08540
      • Global Medical Institutes, LLC
    • Springfield, New Jersey, United States, 07081
      • The Cognitive and Research Center of New Jersey (CRCNJ)
    • Toms River, New Jersey, United States, 08755
      • Advanced Memory Research Institute of NJ
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Albany, New York, United States, 12208
      • Neurological Associates of Albany
    • Brooklyn, New York, United States, 11229
      • Integrative Clinical Trials
    • Brooklyn, New York, United States, 11235
      • SPRI Clinical Trials Brooklyn
    • East Syracuse, New York, United States, 13057
      • Velocity Clinical Research, Formerly Clarity Clinical Research
    • Staten Island, New York, United States, 10312
      • Richmond Behavioral Associates
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
      • Accellacare Research of Winston-Salem
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
    • Dayton, Ohio, United States, 45459
      • Neurology Diagnostics
    • North Canton, Ohio, United States, 44720
      • Neuro-Behavioral Clinical Research (NBCR)
  • Oregon
    • Portland, Oregon, United States, 97225
      • Center for Cognitive Health - Portland
  • Pennsylvania
    • Jenkintown, Pennsylvania, United States, 19046
      • The Clinical Trial Center
    • Plymouth Meeting, Pennsylvania, United States, 19462
      • Keystone Clinical Studies, LLC
  • Tennessee
    • Franklin, Tennessee, United States, 37067
      • KCA Neurology, PLLC
  • Texas
    • Dallas, Texas, United States, 75243
      • Neurology Consultants of Dallas, PA
    • Irving, Texas, United States, 75062
      • Cedar Health Research
  • Vermont
    • Bennington, Vermont, United States, 05201
      • The Memory Clinic - Bennington
  • Washington
    • Bellevue, Washington, United States, 98007
      • Northwest Clinical Research Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 87 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. 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.
2. Evidence for AD pathophysiology, confirmed prior to or during screening.
3. MMSE score ≥ 16 and ≤ 27 at screening.
4. Clinical Dementia Rating - Global Score must be 0.5, 1 or 2.
5. 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.
6. The subject has not been a cigarette smoker or chewed tobacco for at least 3 years.
7. Availability of a study partner.
8. 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.
9. 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.

Key Exclusion Criteria:

1. A neurologic condition other than AD that significantly contributes to the subject's dementia.
2. Any current primary psychiatric diagnosis other than AD if it is likely to confound cognitive assessment or ability to comply with study procedures.
3. 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).
4. Suicidal ideation during the past 3 months or suicidal behavior during the past 12 months.
5. Alcohol or substance use disorder within 2 years of screening.
6. MRI presence of cerebral vascular or other significant pathology.
7. History of transient ischemic attack or stroke within 12 months of screening.
8. Seizure within 12 months of screening.
9. Severe head trauma or head trauma considered likely to be contributing to the subject's cognitive impairment.
10. Sleep apnea that is considered likely to be contributing to the subject's cognitive impairment.
11. Insufficiently controlled diabetes mellitus or hypertension.
12. Body mass index < 18.5 or > 37.5.
13. History or diagnosis of clinically significant cardiac disease.
14. Currently or previously prescribed/administered aducanumab, lecanemab, or any anti-amyloid monoclonal antibody, more than 2 doses.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching placebo, supplied by Cassava as coated tablets, and taken twice daily (b.i.d.) for 76 weeks	Drug: Placebo; Matching placebo given b.i.d. for 76 weeks
Experimental: Simufilam 50 mg; Simufilam 50 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks	Drug: Simufilam; 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.; Other Names: PTI-125
Experimental: Simufilam 100 mg; Simufilam 100 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks	Drug: Simufilam; 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.; Other Names: PTI-125

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS)	The change from baseline to Week 76 in the iADRS, where scores range from 0 to 146 with lower scores indicating worse performance.	Baseline (Study Day 1) to Week 76
Change From Baseline in the Neuropsychiatric Inventory (NPI)	The change from baseline to Week 76 in the NPI, a 12-item study partner interview, which records the frequency and severity of common neuropsychiatric symptoms in dementia for the subject, as well as the level of study partner distress due to the neuropsychiatric problems. Scores range from 0 to 144, with higher scores indicating more frequent and severe symptoms, and greater levels of partner distress.	Baseline (Study Day 1) to Week 76
Change From Baseline in the MMSE	The change from baseline to Week 76 in the MMSE, a set of standardized questions covering several target areas: orientation, registration, attention and calculation, short-term verbal recall, naming, repetition, 3-step command, reading, writing, and visuospatial cognitive assessment. Scores range from 0 to 30; lower scores indicate more severe impairment.	Baseline (Study Day 1) to Week 76
Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB)	The change from baseline to Week 76 in the CDR-SB, which characterizes 6 domains of cognitive and functional performance applicable to AD and related dementias: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Scores for each domain have a minimum of 0 and a maximum of 3, and the 6 domain scores are summed to give the CDR-SB, which has a minimum score of 0 and a maximum score of 18. Higher scores indicate more severe impairment.	Baseline (Study Day 1) to Week 76
Change From Baseline in the Zarit Burden Interview (ZBI)	The change from baseline to Week 76 in the ZBI, a 22-item study partner questionnaire designed to assess the stress or burden experienced by caregivers of people with dementia. Scores range from 0 to 88, with a higher score indicating greater stress or burden.	Baseline (Study Day 1) to Week 76

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes From Baseline in Brain Volume Via MRI	Changes from baseline in hippocampus, ventricles, and whole brain volume.	Baseline (Study Day 1) to Week 76
Changes From Baseline in Amyloid Positron Emission Tomography (PET)	Changes from baseline in amyloid deposition in the brain.	Baseline (Study Day 1) to Week 76
Changes From Baseline in Tau Positron Emission Tomography (PET)	Changes from baseline in tau deposition in the brain	Baseline (Study Day 1) to Week 76
Changes From Baseline in Plasma Biomarkers	Change from baseline in the following plasma biomarkers of AD pathology, neurodegeneration, and neuroinflammation: phospho-tau217 (P-tau217), total tau, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).	Baseline (Study Day 1) to Week 76
Changes From Baseline in CSF Biomarkers	Changes from baseline in CSF biomarkers of AD pathology, neurodegeneration, and neuroinflammation: P-tau217, total tau, GFAP, and NfL.	Baseline (Study Day 1) to Week 76
Change From Baseline in Plasma Biomarker SavaDx	Change from baseline in SavaDx, a novel plasma biomarker.	Baseline (Study Day 1) to Week 76

Collaborators and Investigators

• Sponsor: Cassava Sciences, Inc.
• Collaborators: Premier Research Group plc
• Investigators: Study Chair: James Kupiec, MD, Cassava Sciences

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2021
• Primary Completion (Actual): December 30, 2024
• Study Completion (Actual): December 30, 2024

Study Registration Dates

• First Submitted: August 9, 2021
• First Submitted That Met QC Criteria: August 25, 2021
• First Posted (Actual): August 30, 2021

Study Record Updates

• Last Update Posted (Actual): September 22, 2025
• Last Update Submitted That Met QC Criteria: September 17, 2025
• Last Verified: September 1, 2025

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; Simufilam
• Other Study ID Numbers: PTI-125-06

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