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

Phase 1

Recruiting

• Conditions: Frontotemporal Dementia; FTD; FTD-GRN; Dementia Frontotemporal; C9orf72
• Interventions: Drug: PBFT02

• Registration Number: NCT04747431
• Lead Sponsor: Passage Bio, Inc.

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 granulin precursor (GRN) or chromosome 9 open reading frame 72 (C9ORF72) genes

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 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.

Study Timeline

• Study First Submitted: 2021-02-02
• Study First Submitted QC: 2021-02-05
• Study First Posted: 2021-02-10
• Study Start: 2021-09-14
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-21
• Last Update Posted: 2025-01-24
• Primary Completion: 2028-08
• Study Completion: 2031-08

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

1. Documented to be a pathogenic carrier of GRN or C9orf72 mutation
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" (FTD- GRN Cohorts 1-3) or C9orf72 HRE length ≤ 30 (FTD-C9orf72 Cohorts 4-5).

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 (FTD-GRN Cohorts 1-3) or homozygous C9orf72 mutation carrier (FTD-C9orf72 Cohorts 4-5).

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, tracheostomy, or reliance on non-invasive ventilation for >2 hours during waking hours

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 ICM 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 or C9orf72 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 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

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 > 100,000 per uL
    • INR < 1.5
    • aPTT < 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

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

33. ALSFRS-R < 35 at screening.

34. ALSFRS-R score declining at a rate > 0.4 unit/month from diagnosis to the screening assessment.

35. SVC < 75% of predicted normal adjusted for sex, age, and height (from the sitting position).

36. Bulbar-onset ALS.

37. Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period.

38. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 1	PBFT02	Drug: PBFT02 Dose 1; Single dose of PBFT02, via intra cisterna magna \*GC/g: gene copy per gram of estimated brain weight
Cohort 2, 3, 4 and 5	PBFT02	Drug: PBFT02 Dose 1 or 2; Single dose of PBFT02, via intra cisterna magna \*GC/g: gene copy per gram of estimated brain weight

Primary Outcome Measures

Name	Time	Method
Number of Participants with Treatment-Related AEs and SAEs	Up to 5 years (multiple visits)	Assess the number of treatment-related adverse events (AEs) and serious adverse events (SAEs)
Change in Nerve Conduction Velocity and Amplitude from Baseline on Nerve Conduction Studies	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 Cellular and Humoral Response Against the Vector and Transgene in Serum	From baseline to 5 years (multiple visits)	Assess ELISpot and antibody titers against AAV1 and against human progranulin

Secondary Outcome Measures

Name	Time	Method
Change in Brain anatomy as assessed by MRI	From baseline to 5 years (multiple visits)	Assess the effect of treatment with PBFT02 on Brain volume, white matter integrity, and cortical thickness as assessed by MRI
Change from baseline in CSF and plasma PGRN levels	From baseline to 5 years (multiple visits)	Assess effect of treatment with PBFT02 on CSF and plasma PGRN levels following administration of a single ICM dose.
Change from baseline in plasma and CSF neurofilament light chain (NfL) levels	From baseline to 5 years (multiple visits)	Assess the effect of treatment with PBFT02 on PGRN level in CSF and plasma
Change in Ocular Biomarkers of Disease Progression	From baseline to 5 years (multiple visits)	Assess changes in retinal thickness and retinal lipofuscin deposits assessed by optical coherence tomography as markers of disease progression
Change in FTLD disease progression	From baseline to 5 years (multiple visits)	Assess changes in the Clinical Dementia Rating Scale for Frontotemporal Lobar Degeneration plus National Alzheimer's Coordinating Center FTLD Behavior \& Language Domains (CDR® plus NACC FTLD SB)
Change in ALS disease progression in participants with FTD C9orf72	From baseline to 5 years (multiple visits)	Assess changes in ALS disease progression using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), percent predicted slow vital capacity (SVC) and in muscle strength as measured by handheld dynamometry (HHD)

Trial Locations

Locations (7)

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

University of Texas at Houston; 🇺🇸 Houston, Texas, United States

Hospital das Clinicas da Universidade Federal de Minas Gerais (UFMG); 🇧🇷 Minas Gerais, Brazil

Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP); 🇧🇷 São Paulo, Brazil

Montreal Neurological Institute-Hospital; 🇨🇦 Montréal, Quebec, Canada

University of Toronto, Toronto Western Hospital; 🇨🇦 Toronto, Ontario, Canada

Centro Hospitalar e Universitário de Coimbra; 🇵🇹 Coimbra, Portugal