Adeno-associated viral vector serotype 9 expressing codon-optimized human GRN gene for Frontotemporal dementia (FTD) with progranulin (GRN) mutations|Frontotemporal dementia

Inclusion criteria

• {"criterion_text":"- Men or women aged 30 to 85 years (inclusive), at the time of informed consent.\n- Patient has a reliable study partner/informant (e.g., family member, friend) willing and able to participate in the study as a source of information on the patient’s health status and cognitive and functional abilities (including providing input into the rating scales).\n- Patient is generally ambulatory and not dependent on a walker or wheelchair.\n- Patient is living in the community (i.e. not in a nursing home); some levels of assisted living may be permitted at the Investigator's discretion.\n- Pneumococcal pneumonia and shingles vaccines are required within 10 years of Screening (allowed to be performed during Screening but must be given at least 4 weeks prior to initiation of immunosuppressant regimen).\n- Body weight range of ≥40 kg (88 lb) to ≤110 kg (242 lb) and a body mass index (BMI) of 18 to 34 kg/m2.\n- Has symptomatic frontotemporal dementia (FTD), including mild behavioral, cognitive, motor or language impairment per Investigator’s assessment (behavioral-variant FTD, primary progressive aphasia-FTD, FTD with corticobasal syndrome, or a combination of syndromes are allowed for enrollment).\n- Score ≥0.5 and ≤15 on CDR plus NACC FTLD sum of boxes (Cohorts 1-4 only). Note: In Cohort 5 only patients with CDR plus NACC FTLD with sum of boxes ≥0.5 and ≤9 AND global score of 0.5 or 1 will be enrolled.\n- Stable use of background medications at least 8 weeks prior to LY3884963 dosing.\n- Carrier of a pathogenic progranulin gene (GRN) mutation confirmed by the central laboratory.\n- Negative screening test for Mycobacterium tuberculosis (MTB) or documented negative MTB test within 1 year prior to Screening.\n- Age- and gender-appropriate cancer screenings are up to date and completed per the Investigator's judgment and local standard of care prior to Screening.\n- Patient and/or patient’s legally authorized representative (LAR) (where applicable by local regulation) has the ability to understand the purpose and risks of the study, and provide written informed consent and authorization to use protected health information in accordance with national and local privacy regulations."}

Exclusion criteria

• {"criterion_text":"- Diagnosis of a significant central nervous system (CNS) disease other than FTD that may be a cause for the patient's FTD symptoms or may confound study objectives.\n- Use of blood thinners (e.g., warfarin, heparin, and novel oral anticoagulants) in the 2 weeks prior to Screening or the anticipated need to initiate blood thinners during the study. Antiplatelet therapies (prophylactic aspirin, clopidogrel) are acceptable if the patient is medically able to temporarily stop 48 hours to 7 days (depending on the antiplatelet medication used) prior to and at least 48 hours after ICM injection and LP. Note: the use of blood thinners as part of prophylaxis or treatment of an emergent VTE or another AE during the study does not exclude the patient, unless there is a baseline high risk of thromboembolic events, and use of blood thinners is highly anticipated in the opinion of the Investigator.\n- Contraindications or intolerance to imaging methods (MRI, MRA, and/or computed tomography [CT]), including claustrophobia and intolerance to contrast agents used for MRI, MRA, or CT (including, but not limited to, gadolinium contrast agents and iohexol).\n- Contraindications to general anesthesia or deep sedation.\n- Positive urine test for drugs of abuse (including opiates, amphetamines, cocaine, barbiturates, and phencyclidine) without prescription at Screening and on Day -1.\n- Brain or cervical spine magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) imaging indicating clinically significant abnormality considered to prevent intracisternal magna (ICM) injection.\n- Hypersensitivity or contraindications to corticosteroid, and/or sirolimus use (including, but not limited to, osteoporosis with vertebral fractures within 1 year prior to Screening, poorly controlled diabetes, uncontrolled hypertension, and uncontrolled hyperlipidemia or hypercholesterolemia per Investigator’s assessment).\n- Clinical evidence of peripheral symmetric sensory polyneuropathy (stable sensory mononeuropathies and radiculopathies are not exclusionary).\n- Concomitant disease or condition within 6 months of Screening that could interfere with, or treatment of which might interfere with, the conduct of the study or that would, in the opinion of the Investigator, pose an unacceptable safety risk to the patient or interfere with the patient's ability to comply with study procedures.\n- Clinically significant abnormalities in laboratory test results at Screening.\n- Participation within 3 months prior to Screening in another therapeutic investigational drug or device study with purported disease-modifying effects on FTD, unless it can be documented that the patient received placebo only.\n- Any type of prior gene or cell therapy.\n- Live vaccines in the 4 weeks prior to Screening. Note: Pneumococcal vaccine and/or shingles vaccine administration is allowed at least 4 weeks prior to initiation of immunosuppressant regimen."}

Primary endpoints

• {"endpoint_text":"- The following primary safety endpoints will be measured up to 5 years: • Incidence and severity of treatment-emergent adverse events and serious adverse events (see study protocol for details).","definition_or_measurement_approach":"Measured up to 5 years; incidence and severity recorded per study protocol and adverse event reporting procedures."}
• {"endpoint_text":"- • For patients who received Sirolimus: treatment-emergent hypercholesterolemia or hyperlipidemia; treatment-emergent proteinuria; treatment-emergent interstitial lung disease; and sirolimus trough levels.","definition_or_measurement_approach":"Safety laboratory assessments and sirolimus trough level measurements for patients with sirolimus exposure."}
• {"endpoint_text":"- • For patients who received Rituximab: treatment-emergent hypogammaglobulinemia; and lymphocyte immunophenotyping.","definition_or_measurement_approach":"Laboratory monitoring for immunoglobulin levels and lymphocyte immunophenotyping assays."}
• {"endpoint_text":"- • Incidence of procedure or treatment-emergent safety findings per brain and spine MRI.","definition_or_measurement_approach":"MRI assessments of brain and cervical spine to identify procedure- or treatment-related safety findings."}
• {"endpoint_text":"- • Change from baseline in immunogenicity of AAV9, PGRN, and NfL in blood and in CSF over time.","definition_or_measurement_approach":"Immunogenicity assays measuring anti-AAV9 and PGRN responses, and neurofilament light (NfL) quantification in blood and CSF over time."}
• {"endpoint_text":"- The following are the primary efficacy endpoints: • Change from baseline in PGRN levels in blood over time. • Change from baseline in PGRN levels in CSF over time.","definition_or_measurement_approach":"Quantification of progranulin (PGRN) levels in blood and CSF against baseline at scheduled timepoints."}

Secondary endpoints

• {"endpoint_text":"- • Change from baseline in CDR plus NACC FTLD over time. • Change from baseline in NfL levels in blood over time. • Change from baseline in NfL levels in CSF over time.","definition_or_measurement_approach":"Clinical Dementia Rating plus NACC FTLD assessments for clinical staging; NfL measured in blood and CSF over time."}

Methods

• Use of recruitment and informed consent materials (patient letters, IP brochures, caregiver inserts, IC flipcharts) provided in local languages for participating countries (documents labelled K1/K2 available for France and Belgium).
• Patient-facing materials including appointment cards, branded cards, quick visit guides, safety cards and visit guides to support recruitment and retention (available in French, English, Dutch depending on country).

France

Earliest CTIS Part Ii Submission Date

28-06-2024

Latest Decision Or Authorization Date

26-11-2025

Processing Time Days

516

Number Of Sites

3

Number Of Participants

8

Belgium

Earliest CTIS Part Ii Submission Date

28-06-2024

Latest Decision Or Authorization Date

12-05-2026

Processing Time Days

683

Number Of Sites

1

Number Of Participants

5

Primary sponsor

Full Name

Prevail Therapeutics Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

PPD Development LP

Responsibilities

sponsorDuties codes: 1,10,11,12,5,6,7; contact EUCTRInquiry.sm@ppd.com

Name

Pharmaceutical Product Development LLC

Responsibilities

sponsorDuties codes: 4; contact amber.hood@ppd.com

Name

QPS LLC

Responsibilities

sponsorDuties codes: 4; contact susan.zondlo@qps.com

Third parties

• {"country":"United States","full_name":"QPS LLC","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"sponsorDuties codes: 1,10,11,12,5,6,7","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"University College London","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Educational Institution"}
• {"country":"United States","full_name":"Unisphere Travel Ltd. Inc.","duties_or_roles":"Travel and accommodation Reimbursement (code 15)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Nextcea Inc.","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"WCG Clinical Inc.","duties_or_roles":"Clinical Scales licensing, site scale administrator qualification and operations support (code 15)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Veeva Systems Inc.","duties_or_roles":"eTMF (code 15)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Pharmaceutical Product Development LLC","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Centogene GmbH","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Quanterix Corp.","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"medical imaging analysis (code 15)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Pharmaceutical Product Development LLC (second address)","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Labcorp Early Development Laboratories Limited","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Industry"}