Safety and Tolerability Study With VY-HTT01, in Adults With Early Manifesting Huntington's Disease

A Phase 1B, Open-label, Randomized, Controlled, Multicenter, Dose Escalation Study of the Safety, Tolerability, and Biological Effects of VY-HTT01 Administered Via Intraparenchymal Infusion of the Putamen and Thalamus in Adults With Huntington's Disease

This is the first clinical study of VY-HTT01, a gene therapy for early-stage Huntington's Disease (HD) patients. The primary goal of this trial is to evaluate the safety and tolerability of VY-HTT01. This study is a first in human study, Phase 1b, open-label, randomized, multicenter, dose escalation study with a delayed treatment control arm.

Study Overview

• Status: Withdrawn
• Conditions: Huntington Disease
• Intervention / Treatment: Genetic: Intraparenchymal rAAV1 - (mi)RNA HTT

Detailed Description

This dose escalation trial will evaluate the safety and tolerability of 4 single dose levels of VY-HTT01. The maximum duration that a subject randomized to treatment may be involved in the study is up to 15 months. Delayed treatment subjects will be followed for a minimum of 6 months as a control before moving up into the treatment arm in the next cohort. The maximum duration that a delayed treatment subject may be involved in the study is up to 24 months. Subjects who participate in this study will be asked to enroll in a long-term observation study.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Must be at least 18 years old.
• Have CAGn repeat >39.
• Have diagnostic confidence score of 4 based on motor, cognitive, or behavioral symptoms.
• Have a TFC score of 13 to 11.
• Have stable dosing of neurological and psychiatric medications.
• Capable of giving informed consent.
• Able to comply with all procedures and study visits.

Exclusion Criteria:

• Have any significant structural or degenerative neurologic disease other than HD.
• Have any chronic disability, significant systemic illness and/or, unstable medical condition, or clinical findings noted.
• Have primary or secondary immune-compromise due to infections or medical conditions or chronic therapies.
• Have contraindications to lumbar puncture or increased risks of bleeding upon surgery.
• Started or changed dose of a concomitant CNS medication within 30 days.
• Had prior neurosurgical procedures that could complicate the study procedures.
• Have used any investigational therapies within 30 days prior to Screening, oligonucleotide therapies within 9 months prior to Baseline, or any prior gene therapy.
• Male or female with reproductive capacity and is unwilling to use highly effective contraception for 12 months after surgery.
• Have contraindications to MRI such as claustrophobia, embedded metal in the body, or known allergy or intolerance to contrast agents.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 Unilateral low dose; 3.0 x 10^9 (vg/mL) rAAV1-miHHT	Genetic: Intraparenchymal rAAV1 - (mi)RNA HTT; Single dose MRI guided intraparenchymal infusion of rAAV1 - (mi)RNA HTT.; Other Names: VY-HTT01
Experimental: Cohort 2 Bilateral low dose; 3.0 x 10^9 (vg/mL) rAAV1-miHHT	Genetic: Intraparenchymal rAAV1 - (mi)RNA HTT; Single dose MRI guided intraparenchymal infusion of rAAV1 - (mi)RNA HTT.; Other Names: VY-HTT01
Experimental: Cohort 3 Bilateral mid dose; 1.7 x 10^10 (vg/mL) rAAV1-miHHT	Genetic: Intraparenchymal rAAV1 - (mi)RNA HTT; Single dose MRI guided intraparenchymal infusion of rAAV1 - (mi)RNA HTT.; Other Names: VY-HTT01
Experimental: Cohort 4 Bilateral high dose; 9.9 x 10^10 (vg/mL) rAAV1-miHHT	Genetic: Intraparenchymal rAAV1 - (mi)RNA HTT; Single dose MRI guided intraparenchymal infusion of rAAV1 - (mi)RNA HTT.; Other Names: VY-HTT01

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and type of AEs	Safety will be assessed by measuring the number and type of AE or SAEs.	Collected for duration of study, average of 1 year after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of VY-HTT01 in blood	Change in baseline of the levels of VY-HTT01 vector genome in blood over time.	Collected for duration of study, average of 1 year after treatment
Unified Huntington Disease Rating Scale (UHDRS)	UHDRS will assess changes from baseline in summary scores of motor function, cognitive function, behavioral function, and functional abilities. UHDRS uses a 5-point ordinal scale ranging from 0-4 with the highest score indicating a more severe (worse) outcome.	Collected for duration of study, average of 1 year after treatment
Clinical Global Impression (CGI) Measures	CGI-Global Improvement measure will assess changes from baseline in CGI-Severity of Illness score. Both CGI-Global Improvement and CGI- Severity measures are based on a 7-point scale, with the highest score indicating a more severe (worse) outcome.	Collected for duration of study, average of 1 year after treatment
Huntington's Disease Quality of Life (HD-QOL) Measure	HD-QOL measure will assess changes from baseline in the HD-QOL score using a 40-question scale to identify quality of life in HD. HD-QOL is based on a 7-point scale of frequency ranging from "never" to "all of the time" with "extreme problems" indicating a more severe (worse) outcome.	Collected for duration of study, average of 1 year after treatment
EuroQol 5 Dimension 5 Level (EQ-5D-5L) Measure	EQ-5D-5L measure will assess changes from baseline in the EQ-5D-5L score across 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D-5L is scored on a 5-level severity ranking that ranges from "no problems" through "extreme problems", with "extreme problems" indicating a more severe (worse) outcome.	Collected for duration of study, average of 1 year after treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Magnetic Resistance Imagining (MRI)	MRI assessments will include whole brain volume, white matter volume, gray matter volume, and ventricular volume, and volumes of the putamen and thalamus covered by VY-HTT01 infusions during surgery.	Collected for duration of study, average of 1 year after treatment
Levels of HTT protein in CSF	Change from baseline in levels of HTT protein in CSF (Cerebrospinal fluid) over time.	Collected for duration of study, average of 1 year after treatment
Levels of HTT protein in blood	Change from baseline in levels of HTT protein in blood over time.	Collected for duration of study, average of 1 year after treatment
Huntington's Disease Cognitive Assessment Battery (HD-CAB) Measure	HD-CAB measure will assess changes from baseline in the HD-CAB score for cognitive dysfunction in early manifest HD patients. HD-CAB consists of 6 tests; (1) Symbol Digit Modality Test (SDMT), (2) Paced Tapping, (3) One Touch Stockings of Cambridge, (4) Emotional Recognition, (5) Trial Making B and (6) Hopkins Learning Test. A multi-component score is derived by transforming the subject's score on each cognitive test to a z-score. The six z-scores are averaged to produce the HD-CAB score. A positive change from baseline indicates improvement in cognitive function; a negative change indicates worsening in cognitive function.	Collected for duration of study, average of 1 year after treatment
Level of Neurofilament Light chain (NfL) in CSF	Change from baseline in levels of NfL in CSF over time.	Collected for duration of study, average of 1 year after treatment
Level of Neurofilament Light chain (NfL) in blood	Change from baseline in levels of NfL in blood over time.	Collected for duration of study, average of 1 year after treatment

Collaborators and Investigators

• Sponsor: Voyager Therapeutics

Study record dates

Study Major Dates

• Study Start (Anticipated): July 30, 2021
• Primary Completion (Anticipated): December 30, 2024
• Study Completion (Anticipated): December 30, 2024

Study Registration Dates

• First Submitted: March 2, 2021
• First Submitted That Met QC Criteria: May 7, 2021
• First Posted (Actual): May 13, 2021

Study Record Updates

• Last Update Posted (Actual): August 16, 2021
• Last Update Submitted That Met QC Criteria: August 9, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• 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: VY-HTT01-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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