PhI/II Dose-Finding Study to Evaluate BV-101 Striatal Administration in Adults With Early Manifest Huntington's Disease

Sponsor

Brainvectis, a subsidiary of Asklepios BioPharmaceutical, Inc. (AskBio) (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05541627

Collaborator

(none)

Enrollment

Location

Arms

86.5

Anticipated Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Huntington Disease	Genetic: BV-101 Gene Therapy	Phase 1/Phase 2

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 BV-101 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 Design

Study Type:

Interventional

Anticipated Enrollment :

18 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-Label Phase I/II Dose Finding Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of Striatal Administration of BV-101 in Adult Subjects With Early Manifest Huntington's Disease (HD)

Anticipated Study Start Date :

Oct 15, 2022

Anticipated Primary Completion Date :

Dec 31, 2025

Anticipated Study Completion Date :

Dec 31, 2029

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Cohort 1

Low-dose of BV-101

Genetic: BV-101 Gene Therapy

One-time intracerebral bilateral injections of BV-101 (AAVrh10.CAG.hCYP46A1), an adeno-associated viral vector serotype Rh10 containing the human cholesterol 24-hydroxylase gene

Other Names:

AAVrh10.CAG.hCYP46A1

Experimental: Cohort 2

High-dose of BV-101

Genetic: BV-101 Gene Therapy

One-time intracerebral bilateral injections of BV-101 (AAVrh10.CAG.hCYP46A1), an adeno-associated viral vector serotype Rh10 containing the human cholesterol 24-hydroxylase gene

Other Names:

AAVrh10.CAG.hCYP46A1

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.