A Study of PBFT02 in Participants With FTD and Mutations in the Granulin Precursor (GRN) or C9ORF72 Genes

NCT04747431 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: PBFT02-0012020-004499-17
• Study Type: interventional
• Target: 30
• Locations: 5 countries
• Sites: 10

Brief Summary

PBFT02 is a gene therapy for frontotemporal dementia intended to deliver a functional copy of the GRN gene to the brain. This study will assess the safety, tolerability and efficacy of this treatment in patients with frontotemporal dementia and mutations in the granulin precursor (GRN) or chromosome 9 open reading frame 72 (C9ORF72) genes

Conditions

Frontotemporal Dementia; FTD; FTD-GRN; Dementia Frontotemporal; C9orf72

Keywords

frontotemporal dementia; Progranulin Mutations; FTD-GRN; Gene Therapy; Dementia Gene Therapy; AAV1; Fronto-temporal Dementia; C9orf72

Outcome Measures

Primary Outcomes (3)

• Number of Participants with Treatment-Related AEs and SAEs

  Assess the number of treatment-related adverse events (AEs) and serious adverse events (SAEs)

  Up to 5 years (multiple visits)

• Change in Nerve Conduction Velocity and Amplitude from Baseline on Nerve Conduction Studies

  Assess changes in nerve conduction velocity in the distal segments of the sural, radial, and median sensory nerves and peroneal motor nerve as measured on conventional nerve conduction studies.

  From baseline to 5 years (multiple visits)

• Change in Cellular and Humoral Response Against the Vector and Transgene in Serum

  Assess ELISpot and antibody titers against AAV1 and against human progranulin

  From baseline to 5 years (multiple visits)

Secondary Outcomes (6)

• Change from baseline in CSF and plasma PGRN levels

  From baseline to 5 years (multiple visits)

• Change from baseline in plasma and CSF neurofilament light chain (NfL) levels

  From baseline to 5 years (multiple visits)

• Change in Brain anatomy as assessed by MRI

  From baseline to 5 years (multiple visits)

• Change in FTLD disease progression

  From baseline to 5 years (multiple visits)

• Change in ALS disease progression in participants with FTD C9orf72

  From baseline to 5 years (multiple visits)

Study Arms (2)

Cohort 1

EXPERIMENTAL

Drug: PBFT02 Dose 1; Single dose of PBFT02, via intra cisterna magna \*GC/g: gene copy per gram of estimated brain weight

Drug: PBFT02

Cohort 2, 3, 4 and 5

EXPERIMENTAL

Drug: PBFT02 Dose 1 or 2; Single dose of PBFT02, via intra cisterna magna \*GC/g: gene copy per gram of estimated brain weight

Drug: PBFT02

Interventions

PBFT02 DRUG

PBFT02

Cohort 1; Cohort 2, 3, 4 and 5

Eligibility Criteria

• Age: 35 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Documented to be a pathogenic carrier of GRN or C9orf72 mutation
• Clinical diagnosis of frontotemporal dementia
• Have a reliable informant / caregiver (and back-up informant / caregiver) who personally speaks with or sees the subject at least weekly
• Living in the community (i.e., not in a nursing home); assisted living may be permitted at the discretion of the investigator

You may not qualify if:

• Classification of the GRN mutation as "not pathogenic," "likely benign variant," "benign variant," or "pathogenic nature unclear" (FTD- GRN Cohorts 1-3) or C9orf72 HRE length ≤ 30 (FTD-C9orf72 Cohorts 4-5).
• Previous treatment with any gene therapy. Any other therapies with the potential to alter PGRN levels must be washed out for at least 5 half-lives prior to entry into this study
• Homozygous GRN mutation carrier (FTD-GRN Cohorts 1-3) or homozygous C9orf72 mutation carrier (FTD-C9orf72 Cohorts 4-5).
• Rosen-modified Hachinski Ischemic Scale score \> 7
• Known presence of a structural brain lesion (eg, tumor, cortical infarct) that could reasonably explain symptoms in a symptomatic subject
• Known presence of an AD-causing mutation in PSEN1, PSEN2 or APP based on genetic testing history (if performed)
• Previous history of Korsakoff encephalopathy, severe alcohol or substance dependence (within 5 years of onset of dementia), except where onset of increased alcohol consumption occurs at the time of FTD disease onset
• History of untreated vitamin B12 deficiency
• Presence of untreated hypothyroidism (thyroid stimulating hormone \[TSH\] \> ULN and free T4 \< LLN)
• eGFR ≤ 30 ml/min (as calculated using the CKD-EPI equation)
• Alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] \> 2 × ULN, or total bilirubin \> ULN)
• Respiratory failure that requires supplemental oxygen, tracheostomy, or reliance on non-invasive ventilation for \>2 hours during waking hours
• Inability to provide full consent or the lack of a legally authorized caregiver with adequate contact who can provide consent
• Any contraindication to MRI or lumbar puncture (LP) (eg, local infection, history of thrombocytopenia, coagulopathy)
• Any contraindication to the ICM administration procedure

Sponsors & Collaborators

• Passage Bio, Inc.: lead

Study Sites (10)

Michigan Alzheimer's Disease Center

Ann Arbor, Michigan, 48105, United States

RECRUITING

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

RECRUITING

University of Texas at Houston

Houston, Texas, 77030, United States

RECRUITING

Eastern Health-Box Hill Hospital

Melbourne, Victoria, 3128, Australia

RECRUITING

Hospital das Clinicas da Universidade Federal de Minas Gerais (UFMG)

Minas Gerais, Brazil

RECRUITING

Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP)

São Paulo, Brazil

RECRUITING

University of Toronto, Toronto Western Hospital

Toronto, Ontario, M5T 2S8, Canada

RECRUITING

Montreal Neurological Institute-Hospital

Montreal, Quebec, H3A 2B4, Canada

RECRUITING

Centro Hospitalar e Universitário de Coimbra

Coimbra, Portugal

RECRUITING

MeSH Terms

Conditions

Frontotemporal Dementia; Pick Disease of the Brain; Frontotemporal Dementia With Motor Neuron Disease

Condition Hierarchy (Ancestors)

Frontotemporal Lobar Degeneration; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; TDP-43 Proteinopathies; Neurodegenerative Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Neurocognitive Disorders; Mental Disorders

Study Officials

• Tiffini Voss, MD, PhD

  Passage Bio, Inc.

  STUDY DIRECTOR

Central Study Contacts

Patient/Family Inquiries

CONTACT

267-866-0113; patientservices@passagebio.com

Physician Inquiries

CONTACT

medinfo@passagebio.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open-label, multi-center, dose escalation

Study Record Dates

• First Submitted: February 2, 2021
• First Posted: February 10, 2021
• Study Start: September 14, 2021
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2031
• Last Updated: December 31, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

BR (2); PT (1); AU (1); CA (2); US (4)