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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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FTD, Frontotemporal Dementia, FTD-GRN, Dementia Frontotemporal

Intervention / Treatment
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* Drug: PBFT02


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented to be a pathogenic GRN mutation carrier 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 Exclusion Criteria: Classification of the GRN mutation as not pathogenic, likely benign variant, benign variant, or pathogenic nature unclear 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 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 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 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) Immunocompromised status Peripheral axonal sensory neuropathy Receipt of a vaccine within 14 days of dosing 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 Malignant neoplasia (except localized skin cancer) or a documented history of hereditary cancer syndrome 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 Current or recent history of clinically significant suicidal ideation within the past 6 months 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 Women who are breastfeeding 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 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 Any acute illness requiring hospitalization within 30 days of enrollment 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 Use of anticoagulants in the 2 weeks prior to screening, or anticipated use of anticoagulants during the study. Antiplatelet therapies may be acceptable Hypersensitivity or contraindications to corticosteroid use Known or suspected intolerance or hypersensitivity to PBFT02 or any of its ingredients or to closely related compounds

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Open-label, multi-center, dose escalation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>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<br>* PBFT02<br>|
| Experimental: Cohort 2<br>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<br>* PBFT02<br>|
| Experimental: Optional Cohort 3<br>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<br>* PBFT02<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 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 Nerve Conduction Amplitude from Baseline on Nerve Conduction Studies | 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. | From baseline to 5 years (multiple visits) | 
| Assess Humoral Response Against the Vector and Transgene in Serum | Assess serum antibody titers against AAV1 and against progranulin following ICM administration of PBFT02 | Up to 5 years (multiple visits) | 
| Assess Humoral Response Against the Vector and Transgene in CSF | Assess antibody titers in the cerebrospinal fluid against AAV1 and against progranulin following ICM administration of PBFT02 | Up to 5 years (multiple visits) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Assess changes in cognitive, behavioral and language domains using the CDR Plus NACC FTLD | From baseline to 2 years (multiple visits) | 
| Change from baseline in neurocognitive and other assessments | Assess changes using the Multilingual Naming Test (MINT). | From baseline to 2 years (multiple visits) | 
| Change from baseline in neurocognitive and other assessments | Assess changes using the Number Span Test | From baseline to 2 years (multiple visits) | 
| Change from baseline in neurocognitive and other assessments | Assess changes using Verbal Fluency | From baseline to 2 years (multiple visits) | 
| Change from baseline in neurocognitive and other assessments | Assess changes using Semantic Fluency | From baseline to 2 years (multiple visits) | 
| Change from baseline in neurocognitive and other assessments | Assess changes using the Trail Making Test A and B | From baseline to 2 years (multiple visits) | 
| Change from baseline in neurocognitive and other assessments | Assess changes using California Verbal Learning Test (CVLT) | From baseline to 2 years (multiple visits) | 
| Change from baseline in neurocognitive and other assessments | Assess changes using the Benson Complex Figure Copy (immediate and delayed recall) | From baseline to 2 years (multiple visits) | 
| Change from baseline in neurocognitive and other assessments | Assess changes using the Montreal Cognitive Assessment (MoCA) | From baseline to 2 years (multiple visits) | 
| Change from baseline in neurocognitive and other assessments | Assess changes using the Frontotemporal Dementia Rating Scale (FRS) | From baseline to 2 years (multiple visits) | 
| Change from baseline in neurocognitive and other assessments | Assess changes using the Cambridge Behavioral Inventory - Revised (CBI-R) | From baseline to 2 years (multiple visits) | 
| Change from baseline in neurocognitive and other assessments | Assess changes using the Clinical Global Impression of Severity and Change (CGI-S, CGI-C) | From baseline to 2 years (multiple visits) | 
| Change in Biomarkers of Progranulin Levels in Plasma | Assess change in progranulin levels in plasma when compared with baseline | From baseline to 2 years (multiple visits) | 
| Change in Biomarkers of Progranulin Levels in CSF | Assess change in progranulin levels in CSF when compared with baseline | From baseline to 2 years (multiple visits) | 
| Change in Concentration of Biomarkers of Disease Progression in Plasma | Assess changes in neurofilament light chain (NfL) concentration and glial fibrillary acidic protein (GFAP) as markers for neurodegeneration and disease progression in plasma | From baseline to 2 years (multiple visits) | 
| Change in Concentration of Biomarker of Disease Progression in CSF | Assess change in neurofilament light chain concentration (NfL) as a marker for neurodegeneration and disease progression in CSF | From baseline to 2 years (multiple visits) | 
| Change in Ocular Biomarkers of Disease Progression | Assess changes in retinal thickness and retinal lipofuscin assessed by optical coherence tomography as markers of disease progression | From baseline to 2 years (multiple visits) | 
| Change in Brain Anatomy as Assessed by MRI | Assess change in brain volume by MRI imaging | From baseline to 2 years (multiple visits) | 
| Change in Brain Anatomy as Assessed by MRI | Assess change in cortical thickness by MRI imaging | From baseline to 2 years (multiple visits) | 
| Change in Brain Anatomy as Assessed by MRI | Assess change in white matter integrity by MRI imaging | From baseline to 2 years (multiple visits) | 
| Change in Activities of Daily Living Scales | Assess change in activities of daily living as measured by the Schwab and England Activities of Daily Living Scale | From baseline to 2 years (multiple visits) | 
| Change in Activities of Daily Living Scales | Assess change in activities of daily living as measured by the Functional Activities Questionnaire | From baseline to 2 years (multiple visits) | 
| Change in Survival | Assess change in vital status | From baseline to 2 years (multiple visits) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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frontotemporal dementia, Progranulin Mutations, FTD-GRN, Gene Therapy, Dementia Gene Therapy, AAV1, Fronto-temporal Dementia