A Study to Evaluate the Safety and Effect of AVB-101, a Gene Therapy Product, in Subjects With a Genetic Sub-type of Frontotemporal Dementia (FTD-GRN)

Study Overview
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Brief Summary
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The goal of this clinical study is to learn about an investigational gene therapy product called AVB-101, which is designed to treat a disease called Frontotemporal Dementia with Progranulin Mutations (FTD-GRN). FTD-GRN is an early-onset form of dementia, a progressive brain disorder that affects behavior, language and movement. These symptoms result from below normal levels of a protein called progranulin (PGRN) in the brain, which leads to the death of nerve cells (neurons), affecting the brain's ability to function. The main questions that the study aims to answer are: Is a one-time treatment with AVB-101 safe for patients with FTD-GRN? Does a one-time treatment with AVB-101 restore PGRN levels to at least normal levels? Could AVB-101 work as a treatment to slow down or stop progression of FTD-GRN? In this study there is no placebo (a dummy pill or treatment used for comparison purposes), so all participants will receive a one-time treatment of AVB-101 delivered directly to the brain, with follow-up assessments for 5 years.

Official Title
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A Phase 1/2 Open-Label, Ascending Dose, Multicenter Study to Evaluate the Safety and Preliminary Efficacy of AVB-101 Administered by Bilateral Intrathalamic Infusion in Subjects With Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)

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

Intervention / Treatment
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* Procedure: Intrathalamic AAV.PGRN administration
* Genetic: Intrathalamic AVB-101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 30 to 75 years of age Carriers of a pathogenic GRN mutation FTD as evidenced by CDR + NACC FTLD global score of 0.5, 1.0, or 2.0 Presence of 1 or more of the criteria for diagnosis of possible bvFTD or PPA A protocol defined minimum thalamic volume on each side on Screening MRI Able and willing to comply with all procedures and the study visit schedule Able and willing to give written informed consent prior to study participation, and agree to designate a legal representative to act on their wishes to continue participation should they lose capacity to consent at some point during the study An identified, informed study partner who is able and willing to support the participant in the study and to provide assessments of the participant during the study Exclusion Criteria: Severe dementia, defined as CDR + NACC FTLD global score of 3.0, or other symptoms that preclude the ability to comply with study procedures and/or pose unacceptable safety risk to the subject Any concurrent disease that may cause cognitive impairment unrelated to mutations in the GRN gene, such as other causes of dementia, neurosyphilis, hydrocephalus, stroke, small vessel ischemic disease, uncontrolled hypothyroidism, or vitamin B12 deficiency Clinically significant abnormality on MRI at Screening considered to be a contraindication to Intrathalamic infusion Surgically significant pattern of brain atrophy on MRI at Screening that interferes with planned neurosurgical trajectory Previous treatment with any gene or cell therapy Previous treatment with any investigational medicinal product (IMP) within 60 days or 5 half-lives (whichever is longer) prior to study drug treatment Concomitant disease, any clinically significant laboratory abnormality, or treatment which, in the opinion of the Investigator, may pose an unacceptable safety risk to the participant or interfere with study conduct or the participant's ability to comply with study procedures including neurosurgical administration under anesthesia

Ages Eligible for Study
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Minimum Age: 30 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (dose 1)<br>Initial dose, delivered as a one-time only, intrathalamic administration. | Procedure: Intrathalamic AAV.PGRN administration<br>* One-time MRI-guided stereotaxic infusion of AAV.PGRN into the brain<br>Genetic: Intrathalamic AVB-101<br>* AVB-101 is made from an adeno-associated virus, serotype 9 (AAV9). AAVs are small viruses that are naturally occurring and do not cause illness or infection on their own. AVB-101 has been modified to contain a copy of the correct (non-mutated) GRN gene, plus some other genetic material to enable the GRN gene to function inside neurons (cells within the brain). AVB-101 has also been modified so that it cannot divide and make new copies of itself (known as 'replication'), which means that it cannot cause disease or a large immune response in your body.<br>|
| Experimental: Cohort 2 (dose 2)<br>Escalated dose, delivered as a one-time only, intrathalamic administration. | Procedure: Intrathalamic AAV.PGRN administration<br>* One-time MRI-guided stereotaxic infusion of AAV.PGRN into the brain<br>Genetic: Intrathalamic AVB-101<br>* AVB-101 is made from an adeno-associated virus, serotype 9 (AAV9). AAVs are small viruses that are naturally occurring and do not cause illness or infection on their own. AVB-101 has been modified to contain a copy of the correct (non-mutated) GRN gene, plus some other genetic material to enable the GRN gene to function inside neurons (cells within the brain). AVB-101 has also been modified so that it cannot divide and make new copies of itself (known as 'replication'), which means that it cannot cause disease or a large immune response in your body.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and incidence of AEs and SAEs | Type and incidence of adverse events | Up to week 26 | 
| Change from baseline in the Mini-Mental State Examination (MMSE) | Mini-Mental State Examination (MMSE) is a global assessment of cognitive status. Score range 0-30; higher scores reflect better cognitive function. Change in MMSE score from baseline visit to post-treatment visit will be assessed. | Up to week 12 | 
| Time to achieve clearance of vector genomes | Measured in plasma and semen (males only) | Up to week 26 | 
| Incidence of treatment emergent suicidal ideation or behavior | The Columbia-Suicide Severity Rating Scale (C-SSRS) is an assessment tool that evaluates suicidal ideation and behavior. C-SSRS will be measured at each visit to assess for absence/presence of suicidal ideation and/or behavior. | 26 week initial, 5-year total follow-up period | 
| Incidence of treatment-emergent clinically significant abnormalities in clinical examination findings |  | 5-year total follow-up period | 
| Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values |  | 5-year total follow-up period | 
| Change from baseline in brain structure | Assessed by presence of any clinically significant MRI findings at post treatment visits including brain swelling or bleeding | 5-year total follow-up period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in PGRN protein levels in CSF and blood | Change over time in level of PGRN | 26-week initial and 5-year total follow-up period | 
| Change from baseline in NfL levels in CSF and blood | Change over time in level of NfL | 26-week initial and 5-year total follow-up period | 
| Change from baseline in CDR + NACC FTLD-SB score | The Clinical Dementia Staging Instrument (CDR) plus National Alzheimer's Coordinating Center Frontotemporal Degeneration domains (NACC FTLD) was developed as a way to improve characterization of cognitive and global function in patients with FTLD. The CDR+NACC FTLD score will capture patients' disease status. CDR+NACC FTLD Sum of Boxes (SB) score refers to the sum of the scores of each domain (sum of boxes) that ranges from 0 to 24. | 5-year total follow-up period | 
| Change from baseline in brain volumes | Calculation based upon 3DT1 MRI scans | 5-year total follow-up period | 
| Change from baseline in AAV9 immunogenicity in blood | Measured by level of antibodies and ELISPOT to AAV9 capsid | 5-year total follow-up period | 
| Change from baseline in AAV9 immunogenicity in CSF | Measured by level of antibodies to AAV9 capsid | 5-year total follow-up period | 
| Change from baseline in PGRN immunogenicity in CSF | Measured by level of antibodies to PGRN protein | 5-year total follow-up period | 
| Change from baseline in PGRN immunogenicity in blood | Measured by level of antibodies and ELISPOT to PGRN protein | 5-year total follow-up period | 
| Change in Caregiver Global Impression of Change (CaGI-C) | Global impression of change as assessed by the caregiver. The CaGI-C is a 7 point scale where 1= very much improved, 7= very much worse. | 5-year total follow-up period | 
| Change in Patient Global Impression of Change (PGI-C) | Global impression of change as assessed by the patient. The PGI-C is a 7 point scale where 1= very much improved, 7= very much worse. | 5-year total follow-up period | 
| Change in Clinical Global Impression of Change (CGI-C) | Global impression of change as assessed by the investigator (clinician). The CGI-C is a 7 point scale where 1= very much improved, 7= very much worse. | 5-year total follow-up period | 
| Change from baseline in GRN-specific Genetic Frontotemporal Initiative Cognitive (GENFI-Cog) composite score | Calculated from the neuropsychological test battery that assesses various cognitive domains: language, attention/processing speed, executive function, verbal and visuospatial memory and social cognition. Scores from the neuropsychological test battery are converted using standard statistical methods into the composite score. The GRN specific composite score is expected to be more sensitive to detect changes in cognition that are associated with FTD, and will be compared to the baseline score. Lower scores indicate worse performance. | 5-year total follow-up period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AAV, PGRN, Gene Therapy, Intrathalamic, Intraparenchymal, Progranulin, Behavioral Variant FTD, Primary Progressive Aphasia, Granulin, Dementia, Dementia Gene Therapy, AAV9