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)

Official title

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)

Overview

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: 1. Is a one-time treatment with AVB-101 safe for patients with FTD-GRN? 2. Does a one-time treatment with AVB-101 restore PGRN levels to at least normal levels? 3. 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.

Interventions

• Procedure Intrathalamic AAV.PGRN administration
  One-time MRI-guided stereotaxic infusion of AAV.PGRN into the brain
• Genetic Intrathalamic AVB-101
  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 canno

Primary outcome measures

• Number and incidence of AEs and SAEs [Time frame: Up to week 26]
• Change from baseline in the Mini-Mental State Examination (MMSE) [Time frame: Up to week 12]
• Incidence of treatment emergent suicidal ideation or behavior [Time frame: 26 week initial, 5-year total follow-up period]
• Incidence of treatment-emergent clinically significant abnormalities in clinical examination findings [Time frame: 5-year total follow-up period]
• Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values [Time frame: 5-year total follow-up period]
• Change from baseline in brain structure [Time frame: 5-year total follow-up period]

Secondary outcome measures (12)

• Change from baseline in PGRN protein levels in CSF and blood [Time frame: 26-week initial and 5-year total follow-up period]
• Change from baseline in NfL levels in CSF and blood [Time frame: 26-week initial and 5-year total follow-up period]
• Change from baseline in CDR + NACC FTLD-SB score [Time frame: 5-year total follow-up period]
• Time to achieve clearance of vector genomes [Time frame: Up to week 26]
• Change from baseline in brain volumes [Time frame: 5-year total follow-up period]
• Change from baseline in AAV9 immunogenicity in blood [Time frame: 5-year total follow-up period]
• Change from baseline in AAV9 immunogenicity in CSF [Time frame: 5-year total follow-up period]
• Change from baseline in PGRN immunogenicity in CSF [Time frame: 5-year total follow-up period]
• Change from baseline in PGRN immunogenicity in blood [Time frame: 5-year total follow-up period]
• Change in Caregiver Global Impression of Change (CaGI-C) [Time frame: 5-year total follow-up period]
• Change in Patient Global Impression of Change (PGI-C) [Time frame: 5-year total follow-up period]
• Change in Clinical Global Impression of Change (CGI-C) [Time frame: 5-year total follow-up period]

Eligibility criteria

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
• 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 OR If, in the Investigator's opinion, the subject lacks capacity to consent, written informed consent of their legal representative must be obtained in accordance with local laws, regulations, and/or customs. In countries where local laws, regulations, and/or customs do not permit subjects who lack capacity to consent to participate in this study, these subjects will not be enrolled
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Poland · 6 centers

• NEURO-CARE Sp. z o.o. Sp. Komandytowa — Katowice
• Neurologia Slaska Centrum Medyczne — Katowice
• Uniwersyteckie Centrum Kliniczne, SUM w Katowicach — Katowice
• Euromedis Sp. z o.o. — Szczecin
• Centrum Medyczne NeuroProtect Sp z o.o. — Warsaw
• Mazowiecki Szpital Brodnowski Sp. z o. o. — Warsaw

United States · 3 centers

• The Ohio State University (OSU) Wexner Medical Center — Columbus
• Vanderbilt University Medical Centre — Nashville
• Houston Methodist Hospital — Houston

United Kingdom · 3 centers

• Cambridge University Hospitals NHS Foundation Trust — Cambridge
• University Hospital of Wales — Cardiff
• University College London Hospitals — London

Spain · 2 centers

• Hospital Clinic Barcelona — Barcelona
• Hospital Universitari i Politecnic La Fe — Valencia

Belgium · 1 center

• UZ Leuven — Leuven

Canada · 1 center

• Sunnybrook Health Sciences Centre — Toronto

Italy · 1 center

• Fondazione IRCCS Istituto Neurologico Carlo Besta — Milan

Netherlands · 1 center

• Amsterdam UMC — Amsterdam

Sweden · 1 center

• Skåne University Hospital — Lund

Identifiers

NCT: NCT06064890 · AVB-PGRN-001 · 2023-509444-10-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗