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

Overview

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).

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: August 2024

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 stage 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 will be a 2-year study with a 3-year safety extension.

Interventions

  • Drug: PBFT02
    • PBFT02

Arms, Groups and Cohorts

  • 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
  • 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
  • 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

Clinical Trial Outcome Measures

Primary Measures

  • 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
  • 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.
  • 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.
  • Change in Total Neuropathy Score-Nurse from Baseline
    • Time Frame: From baseline to 5 years (multiple visits)
    • Assess changes in Total Neuropathy Score-Nurse scores including sensory, motor, autonomic, pin, and vibration sensibility from 0-20.
  • Change in Neurological Examination from Baseline
    • Time Frame: From baseline to 5 years (multiple visits)
    • Assess change in neurological examination as measured by Strength, Sensation, Coordination, Reflexes, Tone, Gait, Cranial Nerves, Motor, Sensory, and Deep Tendon Reflexes
  • Number of Participants with Clinically Significant Laboratory Abnormalities as Measured Using Hematology, Chemistry and Coagulation Tests
    • Time Frame: Up to 5 years (multiple visits)
    • Assess the number of participants with clinically significant laboratory changes including hematology, serum chemistry, and coagulation tests
  • 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
  • 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 Measures

  • 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
  • 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).
  • Change from baseline in neurocognitive and other assessments
    • Time Frame: From baseline to 2 years (multiple visits)
    • Assess changes using the Number Span Test
  • Change from baseline in neurocognitive and other assessments
    • Time Frame: From baseline to 2 years (multiple visits)
    • Assess changes using Verbal Fluency
  • Change from baseline in neurocognitive and other assessments
    • Time Frame: From baseline to 2 years (multiple visits)
    • Assess changes using Semantic Fluency
  • 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
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Change in Survival Compared with Natural History Data
    • Time Frame: From baseline to 2 years (multiple visits)
    • Assess change compared with natural history data in survival

Participating in This Clinical Trial

Inclusion Criteria

1. Documented to be a GRN mutation carrier 2. Clinical diagnosis of frontotemporal dementia 3. Plasma NfL level > 50 pg/mL 4. Have a reliable informant / caregiver (and back-up informant / caregiver) who personally speaks with or sees the subject at least weekly 5. CDR plus NACC FTLD global score of 0.5 or 1.0 6. Should be living in the community (ie, not in a nursing home); assisted living may be permitted at the discretion of the investigator Exclusion Criteria:

1. Biomarker evidence of Alzheimer's disease (AD). 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. Evidence through history or laboratory testing of unregulated hypothyroidism (thyroid stimulating hormone [TSH] > 150% of normal) 10. Serum creatinine > 2 mg/dL 11. Total bilirubin above the upper limit of normal 12. Elevated hepatic enzymes (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 2 × upper limit of normal [ULN]) 13. Respiratory failure that requires supplemental oxygen 14. Inability to provide full consent or the lack of a legally authorized caregiver with adequate contact who can provide consent 15. Any contraindication to MRI or lumbar puncture (LP) (eg, local infection, history of thrombocytopenia, coagulopathy) 16. Any contraindication to the ICM administration procedure 17. Medical conditions or laboratory or vital sign abnormalities that would increase risk of complications from intra-cisterna magna injection, anesthesia, LP, and/or MRI (Temperature > 38°C, oxygen saturation below 95% on room air or baseline oxygen requirement, heart rate or respiratory rate abnormal for age of the subject, abnormal blood pressure for age, evidence of infection) 18. Immunocompromised patients 19. Peripheral axonal sensory neuropathy 20. Receipt of a vaccine within 14 days of dosing 21. A positive test result for human immunodeficiency virus (HIV) or Hepatitis B or C; a Mycobacterium tuberculosis positive test within 1 year of or determined at screening 22. Malignant neoplasia (except localized skin cancer) or a documented history of hereditary cancer syndrome 23. 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 24. Current or recent history of clinically significant suicidal ideation within the past 6 months 25. 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 26. Women who are breastfeeding 27. For men of childbearing potential, 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 28. 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 29. Any acute illness requiring hospitalization within 30 days of enrollment 30. Subjects who do not meet the protocol-specified coagulation test criteria 31. Use of anticoagulants in the 2 weeks prior to screening, or anticipated use of anticoagulants during the study is exclusionary. Antiplatelet therapies may be acceptable 32. Subjects with hypersensitivity or contraindications to corticosteroid use 33. Subjects with known or suspected intolerance or hypersensitivity to PBFT02 or any of its ingredients or to closely related compounds

Gender Eligibility: All

Minimum Age: 35 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Passage Bio, Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Gary Romano, MD, PhD, Study Director, Passage Bio, Inc.
  • Overall Contact(s)
    • Patient/Family Inquiries, 267-866-0133, patientservices@passagebio.com

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