Safety and Efficacy of AMT-130 in European Adults With Early Manifest Huntington's Disease

Study Overview
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Brief Summary
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This is the second study of AMT-130 in patients with early manifest HD and is designed as part of an integrated two-study phase I/II program under a single data safety monitoring board (DSMB) with staggered enrollment based upon continued demonstration of safety of AMT-130 administration.

Detailed Description
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The aim of the European study is to build upon the safety demonstrated in the first human dose (FHD) randomized, double blind, sham-controlled sequential dose escalation study (CT-AMT-130-01; clinicaltrials.gov NCT04120493) being conducted in the US and expand the number of patients exposed to the two doses to provide sufficient sample size for comparisons of safety and efficacy. CT-AMT-130-02 is a Phase Ib/II open-label sequential ascending dose study that will be conducted in approximately 5 to 8 European HD centers; 3 to 4 of these centers will serve as surgical sites. Both studies will share a common set of clinical, safety, imaging, and biomarker evaluations over 5 years of follow-up. The DSMB will evaluate safety and other parameters to enable the staggered treatment of patients within each of the dosing cohorts

Official Title
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A Phase Ib/II Study to Explore Safety, Tolerability, and Efficacy Signals of Multiple Ascending Doses of Striatally-Administered rAAV5-miHTT Total Huntingtin Gene (HTT) Lowering Therapy (AMT 130) in Early Manifest Huntington's Disease

Conditions
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Huntington Disease

Intervention / Treatment
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* Genetic: intra-striatal rAAV5-miHTT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Early manifest HD as defined by a UHDRS total functional capacity (TFC) score of 9 to 13 and EITHER a diagnostic classification level (DCL) of 4 OR a DCL of 3 if the subject either meets the definition of multidimensional manifest HD (UHDRS question 80) or DSM5 HTT gene expansion testing with the presence of ≥40 CAG repeats. Striatal MRI volume requirements per hemisphere: Putamen ≥2.5 cm3 (per side); Caudate ≥2.0 cm3 (per side) All HD concomitant medications (addressing motor, behavioral, and cognitive symptoms) stable for 3 months prior to Screening. Able and willing to provide written informed consent Able and willing to comply with all procedures and study visits Exclusion Criteria: Evidence of suicide risk Receipt of an experimental agent within 60 days or five half-lives prior to Screening or anytime over the duration of this study. Participation in an investigational trial or investigational paradigm (such as exercise/physical activity, cognitive therapy, brain stimulation, etc.) within 60 days prior to Screening or anytime over the duration of this study. Presence of an implanted deep brain stimulation device, ventriculoperitoneal or other CSF shunt, or other implanted catheter Any history of gene therapy, RNA or DNA targeted HD specific investigational agents, such as antisense oligonucleotides (ASO), cell transplantation or any other experimental brain surgery. Any contraindication to lumbar puncture or 3.0 Tesla MRI as per local guidelines. Brain and spinal pathology that may interfere with the surgical delivery of AMT-130 or represents a significant neurologic comorbid disorder. 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. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study. Current or recurrent disease, infection, or other significant concurrent medical condition or medications that could confound clinical and laboratory evaluations or could affect a subject's safety or their ability to undergo the neurosurgical procedure or comply with the procedures and study visit schedule

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The first cohort will be treated with low dose, and a total of 6 enrolled participants is anticipated. The second cohort will be treated with high dose, and a total of 9 enrolled participants is anticipated.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (Low Dose of AMT-130)<br>Low dose AMT-130 (6 × 10^12 gc/subject) | Genetic: intra-striatal rAAV5-miHTT<br>* One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain<br>* Other names: AMT-130;|
| Experimental: Cohort 2 (High Dose of AMT-130)<br>High dose AMT-130 (6 × 10^13 gc/subject) | Genetic: intra-striatal rAAV5-miHTT<br>* One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain<br>* Other names: AMT-130;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Adverse Events | Evaluation will be assessed by; - Type and incidence of Adverse Events (AEs) | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Vital Signs - Blood Pressure | Evaluation will be assessed by; - Changes from baseline in blood pressure (mmHg) | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Vital Signs - Respiratory Rate | Evaluation will be assessed by; - Changes from baseline in respiratory rate (BPM) | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Vital Signs - Heart Rate | Evaluation will be assessed by; - Changes from baseline in heart rate (BPM) | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Electrocardiograms | Evaluation will be assessed by; - Changes from baseline in electrocardiograms (ECGs) for any clinically significant abnormalities or clinically significant worsening. (normal or abnormal) | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by changes documented in the neurological examinations | Evaluation will be assessed by; - Changes from baseline in neurological examinations including mental status, cranial nerves, sensory, motor, fine motor, reflexes, and gait (normal or abnormal) | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by changes documented in the physical examinations | Evaluation will be assessed by; - Changes from baseline in physical examinations assessed by physical appearance, HEENT, Neck, Chest and Lungs, Cardiovascular, Abdomen, Musculoskeletal, and Genitourinary (normal or abnormal) | 6 months | 
| Evaluate the safety and tolerability by number of participants with clinically significant changes in laboratory tests - Clinical Chemistry | Evaluation will be assessed by; - Changes from baseline in Clinical Chemistry laboratory tests with clinical significance. | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by number of participants with clinically significant laboratory tests - hematology | Evaluation will be assessed by; - Changes from baseline in hematology laboratory tests with clinical significance. | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by number of participants with clinical significant laboratory tests - urinalysis | Evaluation will be assessed by; - Change from baseline in routine urinalysis test with clinical significance. | 6 months | 
| Evaluate the safety and tolerability o by number of participants with clinical significant changes in cerebrospinal fluid (CSF) analysis | Evaluation will be assessed by; - Change from baseline in CSF analysis with clinical significance. | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by vector shedding | Evaluation will be assessed by; - Change over time in AAV5 vector shedding | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers | Evaluation will be assessed by; - Change over time in microglial activation (YKL-40) (pg/mL) | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers | Evaluation will be assessed by; - Change over time in antibodies against AAV5 (g/L) | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers | Evaluation will be assessed by; - Change over time in cytokines (pg/mL) | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers | Evaluation will be assessed by; - Change over time in ELISpot | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers | Evaluation will be assessed by; - Change over time in astroglial activation (GFAP) (pg/mL) | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by cognitive assessment | Evaluation will be assessed by; - Change from baseline to Day 14 and Month 1 in the Montreal Cognitive Assessment (MoCA) | 6 months | 
| Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by number of participants with changes in MRI | Evaluation will be assessed by; - Change from baseline will be measured by edema, inflammation, volume loss, and structural changes as measured by the following MRI pulse sequences, T1, T2 and diffusion MRI (dMRI) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of persistence of AMT-130 in the brain | Change over time in levels of AMT-130-derived Vector DNA and miRNA Expression in the Cerebrospinal Fluid (CSF) | Collected for duration of study through month 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene therapy, AAV (adeno-associated virus), serotype 5 AAV (adeno-associated virus), serotype 5, Viral vector, miHTT, muHTT, Huntington's Disease (HD)