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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Huntington Disease

Intervention / Treatment
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* Genetic: Intraparenchymal rAAV1 - (mi)RNA HTT


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 |