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

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 study of PBFT02 delivered as a one-time dose administered into the cisterna magna to participants with FTD-GRN or C9orf72. Participants aged ≥ 35 and ≤ 75 years with early symptomatic FTD-GRN or with symptomatic FTD-C9orf72 may be enrolled into the study.

PBFT02 will be studied in three cohorts of FTD-GRN participants and two cohorts of FTD-C9orf72 participants.

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

Inclusion criteria

• 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

Exclusion criteria

• 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
• Medical conditions or laboratory or vital sign abnormalities that would increase risk of complications from ICM 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 or C9orf72 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 women 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. Women 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 > 100,000 per uL
• INR < 1.5
• aPTT < 40 seconds
• Use of anticoagulants in the 2 weeks prior to screening
• Hypersensitivity or contraindications to corticosteroid use
• Known or suspected intolerance or hypersensitivity to PBFT02 or any of its ingredients or to closely related compounds
• Any condition expected to increase risk of thrombosis
• Hypersensitivity or contraindications to apixaban

Additional Criteria for FTD-C9orf72 (Cohorts 4-5) ONLY: Presence of concurrent ALS is permitted provided the following criteria are NOT met:

• ALSFRS-R < 35 at screening.
• SVC < 75% of predicted normal adjusted for sex, age, and height (from the sitting position).
• Bulbar-onset ALS.
• Current or anticipated need, in the opinion of the Investigator for a diaphragm pacing system (DPS) during the study period.
• If taking riluzole or edaravone, participant's dose has not been stable for ≥ 30 days prior to Day 1 and/or dose adjustments are anticipated before the Day 60 study visit.