A Study to Evaluate AB-1001 Striatal Administration in Adults With Early Manifest Huntington's Disease

An Open-Label Phase I/II Dose Finding Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of Striatal Administration of AB-1001 in Adult Subjects With Early Manifest Huntington's Disease (HD)

A Phase I/II Dose-Finding Study to Evaluate Striatal Administration of AB-1001 (previously BV-101) in Adults with Early Manifest Huntington's Disease

Study Overview

• Status: Active, not recruiting
• Conditions: Huntington Disease
• Intervention / Treatment: Genetic: AB-1001 Gene Therapy

Detailed Description

This is a Phase I/II, first-in-human, open-label study to evaluate the safety, tolerability, and preliminary efficacy signals in subjects with early manifest HD following treatment with one-time intracerebral bilateral injections of AB-1001 within the striatum (caudate and putamen).

This study consists of 2 parts: Dose-Finding Part and Expansion Part; each part consists of 3 phases: Screening Phase (8 weeks, with extension to 12 weeks to accommodate scheduling if needed), Treatment and Initial Follow-Up Phase (52 weeks) and Long-Term Follow-Up Phase (4 years). In the Dose-Finding Part, 2 dose titers will be tested in 3-6 subjects in each cohort. Once a dose is selected based on Dose-Limiting Toxicities, an additional 6 subjects will be enrolled into the Dose Expansion Part.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Ile-de-France
    • Paris, Ile-de-France, France, 75013
      • Institut du Cerveau (ICM), Hôpital La Pitié Salpêtrière APHP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or Female subjects between ages 18 and 65 years (both inclusive) at time of consenting, able to provide Informed Consent and able to understand and comply with all study procedures.
• Documented genetic confirmation of pathological CAG expansion in the huntingtin gene ≥40.
• Early manifest HD as defined by a UHDRS total functional capacity (TFC) score of 9 to 13 and a diagnostic classification level (DCL) of 4, or a DCL of 3 if present with cognitive impairment and clear evidence of disease progression.
• Striatal MRI volumes per hemisphere: Putamen ≥ 2.3 cm3 (per side); Caudate ≥ 1.7 cm3 (per side) on Screening MRI.
• All HD concomitant medications stable for at least 30 days prior to screening at the investigator's discretion.

Key Exclusion Criteria:

• Prior or ongoing medical condition, physical findings, ECG findings, or laboratory abnormality that, in the investigator's opinion, would impact subject's safety and compliance with the study procedures.
• Metastatic neoplasms within the five years prior to screening.
• Presence of clinically relevant immunologic, hematologic, hepatic, cardiac, or renal disease at the time of screening as per investigator's clinical judgment.
• Current untreated and unstable depressive disorder or a serious mood disorder requiring hospitalization.
• History of prior suicide attempt or imminent risk of self-harm based on investigator's judgment or with a "yes" answer on item 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS).
• Patients with history of confirmed stroke, known intracranial neoplasms, vascular malformations, or intracranial hemorrhage.
• Subjects not deemed suitable for the surgical procedure as per the Neurosurgeon's judgment.
• Any history of gene therapy, cell transplantation or any other experimental brain surgery.
• Any RNA or DNA targeted HD specific investigational agents such as antisense oligonucleotides within 6 months prior to screening.
• Subjects unable to tolerate or unwilling to undergo multiple lumbar punctures.
• Participation in any clinical trial of an approved or non-approved investigational drug or intervention within 12 weeks or 5 half-lives whichever is longer prior to treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Low-dose of AB-1001	Genetic: AB-1001 Gene Therapy; One-time intracerebral bilateral injections of AB-1001 (AAVrh10.CAG.hCYP46A1), an adeno-associated viral vector serotype Rh10 containing the human cholesterol 24-hydroxylase gene; Other Names: AAVrh10.CAG.hCYP46A1 (previously BV-101)
Experimental: Cohort 2; High-dose of AB-1001	Genetic: AB-1001 Gene Therapy; One-time intracerebral bilateral injections of AB-1001 (AAVrh10.CAG.hCYP46A1), an adeno-associated viral vector serotype Rh10 containing the human cholesterol 24-hydroxylase gene; Other Names: AAVrh10.CAG.hCYP46A1 (previously BV-101)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Dose-Limiting Toxicities (DLTs), Treatment-Emergent Adverse Events (TEAEs), and Serious Adverse Events (SAEs)	The incidence of DLTs, TEAEs, and SAEs will be measured according to protocol specifications.	Through Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anatomical and volumetric measures of brain regions impacted by HD as assessed by MRI	The magnitude and variability of change from baseline in anatomical and volumetric measures of brain regions impacted by HD as assessed by MRI will be measured	At Week 52
Composite Unified Huntington Disease Rating Scale (cUHDRS)	The change from baseline in the cUHDRS will be measured (a higher score indicates better functioning)	At Week 52
Mutant Huntingtin protein (mHTT)	The change from baseline in mHTT in blood and cerebrospinal fluid (CSF) will be measured	At Week 52
Neurofilament light chain (NfL)	The change from baseline in blood and CSF NfL will be measured	At Week 52
24OH cholesterol	The change from baseline in blood and CSF 24OH cholesterol will be measured	At Week 52
Magnetic resonance spectroscopy (MRS) metabolic profile	Change from baseline in MRS metabolic profile	At Week 52
Positron emission tomography (PET) fluoro-deoxyglucose (FDG) striatal profile	Change from baseline in PET FDG striatal profile	At Week 52

Collaborators and Investigators

• Sponsor: Brainvectis, a subsidiary of Asklepios BioPharmaceutical, Inc. (AskBio)

Study record dates

Study Major Dates

• Study Start (Actual): October 12, 2022
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: September 13, 2022
• First Submitted That Met QC Criteria: September 13, 2022
• First Posted (Actual): September 15, 2022

Study Record Updates

• Last Update Posted (Actual): July 10, 2023
• Last Update Submitted That Met QC Criteria: July 6, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Gene Therapy; Nervous System Diseases; Movement Disorders; Central Nervous System Diseases; Genetic Diseases, Inborn; Neurodegenerative Diseases; Huntington's Disease; Cognition Disorders; Viral Vector; Brain Diseases; AAV (adeno-associated virus); Neurocognitive Disorders; Early Manifest Huntington's Disease; Cholesterol 24-Hydroxylase; CYP46A1; AB-1001
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Dyskinesias; Heredodegenerative Disorders, Nervous System; Dementia; Cognition Disorders; Chorea; Huntington Disease
• Other Study ID Numbers: ASK-HD-01-CS-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No