Phase 1/2 Multicenter Study Evaluating Safety and Efficacy of AVB-101 via Bilateral Intrathalamic Infusion in Frontotemporal Dementia with Progranulin Mutations

Trial ID: 2023-509444-10-00
Protocol: AVB-PGRN-001
Sponsor: Aviadobio Limited

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Diseases & Conditions

Frontotemporal dementia

Objectives

The primary objective of this study is to evaluate the **safety** and tolerability of a one-time, intrathalamic administration of AVB-101 in subjects with **Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)**. This is clinically relevant as it aims to determine the potential risks and adverse effects associated with the treatment, which is crucial for ensuring patient safety and guiding future therapeutic applications.

Secondary objectives include:

Evaluating the preliminary clinical and biomarker measures of efficacy of a one-time, bilateral, intrathalamic administration of AVB-101 in subjects with FTD-GRN. This will provide initial insights into the therapeutic potential and biological impact of the treatment on the disease pathology.

Participants

The clinical trial involves a total of **9 participants** diagnosed with **Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)**. The study population includes both male and female subjects, aged between **30 to 75 years**. Participants are required to be carriers of a pathogenic granulin mutation, confirmed by a sponsor-approved genetic test. The trial population was selected based on specific inclusion criteria, including the presence of frontotemporal dementia as evidenced by a Clinical Dementia Rating and a National Alzheimer's Coordinating Center frontotemporal lobar degeneration global score. Participants must have an identified study partner to support their participation and provide assessments. The study includes individuals who are able and willing to comply with all procedures and the study visit schedule. Women of childbearing potential must have a negative pregnancy test and agree to use effective birth control methods. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study population is considered vulnerable, and participants must provide written informed consent or have a legal representative do so if they lack the capacity to consent.

Plans and Procedures

The clinical trial is designed as 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)**. The primary objective is to assess the safety and tolerability of a one-time, intrathalamic administration of AVB-101. The trial will span an initial 26-week period followed by a total follow-up duration of 5 years. Participants will be involved in a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age range (30 to 75 years), confirmed genetic mutation, and the presence of frontotemporal dementia. The study will include regular follow-up visits to monitor safety endpoints, including the incidence of adverse events, changes in vital signs, and neurological assessments. The end-of-study visit will conclude the participant's involvement, unless early termination is warranted due to safety concerns or withdrawal of consent. The expected length of participant involvement is up to 5 years, with conditions for early termination including significant adverse events or non-compliance with study procedures. The trial will not include a control group, as it is an open-label study, and all participants will receive the investigational product. The study aims to provide valuable insights into the potential therapeutic effects of AVB-101 in a rare and challenging condition. The trial's design ensures rigorous monitoring and data collection to support the evaluation of both safety and preliminary efficacy outcomes.

Treatment

The clinical trial involves the administration of **AVB-101**, an experimental medication designed for the treatment of **Frontotemporal Dementia with Progranulin Mutations (FTD-GRN)**. AVB-101 is a **recombinant AAV-9 vector** that expresses the human progranulin protein. The pharmaceutical form of AVB-101 is a **solution for injection/infusion**. The administration route is **intracerebral**, specifically via bilateral intrathalamic infusion. This is a one-time administration, and the study is structured as an open-label, ascending dose, multicentre trial. The primary objective is to evaluate the safety and tolerability of AVB-101 in the specified patient population.

AVB-101 is not a paediatric formulation and has been designated as an orphan drug, indicating its use in a rare condition. The active substance, also named AVB-101, is classified as a structurally diverse substance. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance will be monitored through standard clinical trial procedures, ensuring adherence to the dosing schedule and administration protocol. The trial does not specify a maximum daily dose, total dose, or treatment period, as the administration is a single event.

Efficacy

The efficacy of AVB-101 in the clinical trial will be assessed through several secondary endpoints over a 26-week initial and 5-year total follow-up period. These endpoints include the change from baseline in **PGRN protein levels** in cerebrospinal fluid (CSF) and blood. Additionally, changes from baseline in the Clinical Dementia Rating (CDR) combined with the National Alzheimer's Coordinating Center (NACC) Frontotemporal Lobar Degeneration Sum of Boxes (FTLD-SB) score will be evaluated. The trial will also assess changes in the Clinical Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Caregiver Global Impression of Change (CaGI-C).

Inclusion and Exclusion Criteria

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Inclusion Criteria

Are male or female, 30 to 75 years of age, inclusive, at Screening
Have an identified, informed study partner who is able and willing to support the subject’s participation in the study and to provide assessments of the subject during the study (separate, written informed consent to be obtained from the study partner for their participation, where required to do so by the relevant country’s competent authorities).
Are carriers of a pathogenic granulin (GRN) mutation (ie, heterozygous loss-of-function mutation causative of FTD) as confirmed by a Sponsor approved genetic test.
Have frontotemporal dementia (FTD) as evidenced by Clinical Dementia Rating (CDR) + National Alzheimer’s Coordinating Center (NACC) frontotemporal lobar degeneration (FTLD) global score of 0.5, 1.0, or 2.0
Have presence of 1 or more of the criteria for diagnosis of possible behavioral variant FTD or primary progressive aphasia
For women of childbearing potential, must have a negative serum pregnancy test at Screening, a negative urine dipstick, and not be breastfeeding within 2 weeks prior to treatment
Are willing to practice a highly effective birth control method as outlined in the Protocol if the subject or partner is of childbearing potential
Able and willing to comply with all procedures and the study visit schedule as outlined in the Protocol
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

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Exclusion Criteria

Have a classification of the mutation in the GRN gene as “not pathogenic,” “likely benign variant,” or “benign variant”
Have any contraindications to MRI as per local guidelines
Have any contraindications to gadolinium-based contrast agents per local guidelines
Have any contraindications to general anesthesia for a period of up to 10 hours and/or cardiopulmonary disorders that would result in higher American Society of Anesthesiology risk classification
Have any contraindications to lumbar puncture as per local guidelines
Have been hospitalized for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned procedure during the study
Are using anticoagulants at Screening, or will have an anticipated need during the period of treatment. Antiplatelet therapies are acceptable concomitant medications if they can be stopped at least 48 hours prior to treatment
Have a positive drug screen for drugs of abuse
Have a history of substance abuse disorder
Have the presence of an implanted deep brain stimulation device, ventriculoperitoneal or other cerebrospinal fluid (CSF) shunt, or other implanted device
Have 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
Have evidence of suicide risk, as assessed by the Columbia-Suicide Severity Rating Scale, defined as either a suicide attempt within 6 months prior to Screening or have a significant risk of suicide as judged by the Investigator
Have a known or suspected intolerance or hypersensitivity to the study drug or any of the stated ingredients.
Have 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
Have a clinically significant abnormality on magnetic resonance imaging (MRI) at Screening considered to be a contraindication to intrathalamic infusion
Have a surgically significant pattern of brain atrophy on MRI at Screening that in the determination of the neurosurgeon interferes with planned neurosurgical trajectory
Have had previous treatment with any gene or cell therapy
Have had previous treatment with any investigational medicinal product within 60 days or 5 half-lives (whichever is longer) prior to study drug treatment
Have had a concomitant disease, any clinically significant laboratory abnormality, or treatment which, in the opinion of the Investigator, may pose an unacceptable safety risk to the subject or interfere with study conduct or the subject's ability to comply with study procedures
Have a malignancy within 5 years of Screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Recruiting	01 Sept 2023	2
Italy	Recruiting	01 Sept 2023	2
The Netherlands	Not Yet Recruiting	01 Sept 2023	—
Poland	Recruiting	01 Sept 2023	8
Spain	Recruiting	01 Sept 2023	1
Sweden	Not Yet Recruiting	01 Sept 2023	1
Netherlands	—	—	2