A Study of PBFT02 in Patients With Frontotemporal Dementia and Progranulin Mutations (FTD-GRN) (upliFT-D)

• ClinicalTrials.gov Identifier: NCT04747431
• Recruitment Status: Recruiting
• First Posted: February 10, 2021
• Last Update Posted: April 27, 2022
• Sponsor: Passage Bio, Inc.
• Information provided by (Responsible Party): Passage Bio, Inc.

Study Description

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 progranulin gene (FTD-GRN).

Condition or disease	Intervention/treatment	Phase
Frontotemporal Dementia	Drug: PBFT02	Phase 1; Phase 2

Detailed Description:

PBFT02 is an adeno-associated viral vector serotype 1 carrying GRN, the gene encoding for human progranulin, formulated as a solution for injection into the cisterna magna. This is a global interventional, multicenter, open-label, single-arm, dose-escalation study of PBFT02 delivered as a one-time dose administered into the cisterna magna to patients with FTD-GRN. Subjects aged ≥ 35 and ≤ 75 years with early symptomatic FTD-GRN may be enrolled into the study.

Two dose levels of PBFT02 will be studied in patients with FTD-GRN. The study will sequentially enroll 2 cohorts. An optional third dose level cohort may be enrolled based on the results of the first two cohorts.

This is a 5-year study, with a 2-year main study, followed by a 3-year safety extension.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 6 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Open-label, multi-center, dose escalation
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b Open-Label, Multicenter, Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacodynamic Effects of a Single Dose of PBFT02 Delivered Into the Cisterna Magna of Adult Subjects With Frontotemporal Dementia and Mutations in the Progranulin Gene
• Actual Study Start Date: September 14, 2021
• Estimated Primary Completion Date: August 2024
• Estimated Study Completion Date: August 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; Drug: PBFT02 Dose 1: 3.3 x 10^10 GC/g* Single dose of PBFT02, via intra cisterna magna *GC/g: gene copy per gram of estimated brain weight	Drug: PBFT02; PBFT02
Experimental: Cohort 2; Drug: PBFT02 Dose 2: 1.1 x 10^11 GC/g* Single dose of PBFT02, via intra cisterna magna *GC/g: gene copy per gram of estimated brain weight	Drug: PBFT02; PBFT02
Experimental: Optional Cohort 3; Drug: PBFT02 Dose 3: 2.2 x 10^11 GC/g* Single dose of PBFT02, via intra cisterna magna *GC/g: gene copy per gram of estimated brain weight	Drug: PBFT02; PBFT02

Outcome Measures

Primary Outcome Measures :

1. Number of Participants with Treatment-Related AEs and SAEs as Characterized by CTCAEv5.0 [ Time Frame: Up to 5 years (multiple visits) ]
   Assess the number of treatment-related adverse events (AEs) and serious adverse events (SAEs) as characterized by CTCAEv5.0
2. Change in Nerve Conduction Velocity from Baseline on Nerve Conduction Studies [ Time Frame: From baseline to 5 years (multiple visits) ]
   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.
3. Change in Nerve Conduction Amplitude from Baseline on Nerve Conduction Studies [ Time Frame: From baseline to 5 years (multiple visits) ]
   Assess changes in nerve conduction amplitude in the distal segments of the sural, radial, and median sensory nerves and peroneal motor nerve as measured on conventional nerve conduction studies.
4. Assess Humoral Response Against the Vector and Transgene in Serum [ Time Frame: Up to 5 years (multiple visits) ]
   Assess serum antibody titers against AAV1 and against progranulin following ICM administration of PBFT02
5. Assess Humoral Response Against the Vector and Transgene in CSF [ Time Frame: Up to 5 years (multiple visits) ]
   Assess antibody titers in the cerebrospinal fluid against AAV1 and against progranulin following ICM administration of PBFT02

Secondary Outcome Measures :

1. Change from baseline in FTD clinical domains as assessed by the Clinical Dementia Rating National Alzheimer's Coordinating Center frontotemporal lobar degeneration domains (CDR Plus NACC FTLD) [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess changes in cognitive, behavioral and language domains using the CDR Plus NACC FTLD
2. Change from baseline in neurocognitive and other assessments [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess changes using the Multilingual Naming Test (MINT).
3. Change from baseline in neurocognitive and other assessments [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess changes using the Number Span Test
4. Change from baseline in neurocognitive and other assessments [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess changes using Verbal Fluency
5. Change from baseline in neurocognitive and other assessments [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess changes using Semantic Fluency
6. Change from baseline in neurocognitive and other assessments [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess changes using the Trail Making Test A and B
7. Change from baseline in neurocognitive and other assessments [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess changes using California Verbal Learning Test (CVLT)
8. Change from baseline in neurocognitive and other assessments [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess changes using the Benson Complex Figure Copy (immediate and delayed recall)
9. Change from baseline in neurocognitive and other assessments [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess changes using the Montreal Cognitive Assessment (MoCA)
10. Change from baseline in neurocognitive and other assessments [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess changes using the Frontotemporal Dementia Rating Scale (FRS)
11. Change from baseline in neurocognitive and other assessments [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess changes using the Cambridge Behavioral Inventory - Revised (CBI-R)
12. Change from baseline in neurocognitive and other assessments [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess changes using the Clinical Global Impression of Severity and Change (CGI-S, CGI-C)
13. Change in Biomarkers of Progranulin Levels in Plasma [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in progranulin levels in plasma when compared with baseline
14. Change in Biomarkers of Progranulin Levels in CSF [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in progranulin levels in CSF when compared with baseline
15. Change in Concentration of Biomarkers of Disease Progression in Plasma [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess changes in neurofilament light chain (NfL) concentration and glial fibrillary acidic protein (GFAP) as markers for neurodegeneration and disease progression in plasma
16. Change in Concentration of Biomarker of Disease Progression in CSF [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in neurofilament light chain concentration (NfL) as a marker for neurodegeneration and disease progression in CSF
17. Change in Ocular Biomarkers of Disease Progression [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess changes in retinal thickness and retinal lipofuscin assessed by optical coherence tomography as markers of disease progression
18. Change in Brain Anatomy as Assessed by MRI [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in brain volume by MRI imaging
19. Change in Brain Anatomy as Assessed by MRI [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in cortical thickness by MRI imaging
20. Change in Brain Anatomy as Assessed by MRI [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in white matter integrity by MRI imaging
21. Change in Activities of Daily Living Scales [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in activities of daily living as measured by the Schwab and England Activities of Daily Living Scale
22. Change in Activities of Daily Living Scales [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in activities of daily living as measured by the Functional Activities Questionnaire
23. Change in Survival [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in vital status

Eligibility Criteria

• Ages Eligible for Study: 35 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

1. Classification of the GRN mutation as "not pathogenic," "likely benign variant," "benign variant," or "pathogenic nature unclear"
2. 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
3. Homozygous GRN mutation carrier
4. Rosen-modified Hachinski Ischemic Scale score > 7
5. Known presence of a structural brain lesion (eg, tumor, cortical infarct) that could reasonably explain symptoms in a symptomatic subject
6. Known presence of an AD-causing mutation in PSEN1, PSEN2 or APP based on genetic testing history (if performed)
7. 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
8. History of untreated vitamin B12 deficiency
9. Presence of untreated hypothyroidism (thyroid stimulating hormone [TSH] > ULN and free T4 < LLN)
10. eGFR ≤ 30 ml/min (as calculated using the CKD-EPI equation)
11. Alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 2 × ULN, or total bilirubin > ULN)
12. Respiratory failure that requires supplemental oxygen
13. Inability to provide full consent or the lack of a legally authorized caregiver with adequate contact who can provide consent
14. Any contraindication to MRI or lumbar puncture (LP) (eg, local infection, history of thrombocytopenia, coagulopathy)
15. Any contraindication to the ICM administration procedure
16. Medical conditions or laboratory or vital sign abnormalities that would increase risk of complications from intra-cisterna magna injection, anesthesia, LP, and/or MRI (e.g., fever, hypoxia, tachycardia, or evidence of active infection)
17. Immunocompromised status
18. Peripheral axonal sensory neuropathy
19. Receipt of a vaccine within 14 days of dosing
20. A positive test result for human immunodeficiency virus (HIV), human T cell leukemia virus (HTLV) type 1 or type 2, or Hepatitis B or C; a Mycobacterium tuberculosis positive test within 1 year of or determined at screening
21. Malignant neoplasia (except localized skin cancer) or a documented history of hereditary cancer syndrome
22. Any concurrent disease that, in the opinion of the investigator, may cause cognitive impairment unrelated to GRN mutations, including other causes of dementia, neurosyphilis, hydrocephalus, stroke, small vessel ischemic disease, uncontrolled hypothyroidism, or vitamin deficiency
23. Current or recent history of clinically significant suicidal ideation within the past 6 months
24. For females of childbearing potential, a positive serum pregnancy test at the screening visit, a positive serum result on Day 1 prior to administration of the investigational product, or unwillingness to have additional pregnancy tests during the study. Females of childbearing potential must use a highly effective method of birth control or engage in abstinence until 90 days postdose
25. Women who are breastfeeding
26. For sexually active men, unwillingness to use a medically accepted method of double-barrier contraception (such as a condom/diaphragm used with spermicide) or engage in abstinence from the date of screening until 90 days postdose
27. Any condition (eg, history of any disease, evidence of any current disease, any finding upon physical examination, or any laboratory abnormality) that, in the opinion of the investigator, would put the subject at undue risk or would interfere with evaluation of the investigational product or interpretation of subject safety or study results
28. Any acute illness requiring hospitalization within 30 days of enrollment

29. Failure to meet the protocol-specified coagulation test criteria:

    • Platelet count over 100,000 per uL
    • INR less than 1.5
    • aPTT less than 40 seconds
30. Use of anticoagulants in the 2 weeks prior to screening, or anticipated use of anticoagulants during the study. Antiplatelet therapies may be acceptable
31. Hypersensitivity or contraindications to corticosteroid use
32. Known or suspected intolerance or hypersensitivity to PBFT02 or any of its ingredients or to closely related compounds

Contacts and Locations

Contacts

Contact: Patient/Family Inquiries; 267-866-0113; patientservices@passagebio.com

Contact: Physician Inquiries; medinfo@passagebio.com

Locations

United States, California

University of California at San Francisco; Not yet recruiting

San Francisco, California, United States, 94143

United States, Pennsylvania

University of Pennsylvania; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Dahlia Kamel Dahlia.kamel@pennmedicine.upenn.edu

United States, Texas

University of Texas at Houston; Recruiting

Houston, Texas, United States, 77030

Contact: Omar Hasan 713-486-2647 omar.hasan@uth.tmc.edu

Brazil

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

Minas Gerais, Brazil

Contact: Sílvia Correa Cleto Villela silviacleto.correa@gmail.com

Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP); Not yet recruiting

São Paulo, Brazil

Canada

University of Toronto; Not yet recruiting

Toronto, Canada

Italy

Besta Institute; Not yet recruiting

Milan, Italy

Portugal

Centro Hospitalar e Universitário de Coimbra; Not yet recruiting

Coimbra, Portugal

United Kingdom

University of Cambridge; Not yet recruiting

Cambridge, United Kingdom

Sponsors and Collaborators

Passage Bio, Inc.

Investigators

• Study Director: Tiffini Voss, MD; Passage Bio, Inc.

More Information

• Responsible Party: Passage Bio, Inc.
• ClinicalTrials.gov Identifier: NCT04747431
• Other Study ID Numbers: PBFT02-001; 2020-004499-17 ( EudraCT Number )
• First Posted: February 10, 2021
• Last Update Posted: April 27, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Passage Bio, Inc.:

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

Additional relevant MeSH terms:

Dementia; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Neurodegenerative Diseases; Frontotemporal Lobar Degeneration; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases; Aphasia; Speech Disorders; Language Disorders; Communication Disorders; Neurobehavioral Manifestations; Neurologic Manifestations