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

NCT05243017 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: CT-AMT-130-02
• Study Type: interventional
• Target: 14
• Locations: 2 countries
• Sites: 4

Brief Summary

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. Cohort 3 participants will receive either high or low dose (1:1 randomization). Participants enrolled in Cohort 3 will also receive an immunosuppression regimen consisting of dexamethasone, sirolimus, and rituximab.

Conditions

Huntington Disease

Keywords

Gene therapy; AAV (adeno-associated virus); serotype 5 AAV (adeno-associated virus); serotype 5; Viral vector; miHTT; muHTT; Huntington's Disease (HD)

Outcome Measures

Primary Outcomes (19)

• 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 Outcomes (1)

• Duration of persistence of AMT-130 in the brain

  Collected for duration of study through month 60

Other Outcomes (8)

• CSF Mutant Protein (fM)

  Collected for duration of study through month 60

• CSF/Serum Neurofilament Light Chain (pg/mL)

  Collected for duration of study through month 60

• Mean changes from baseline in summary scores for the Unified Huntington Disease Rating Scale (UHDRS)

  Collected for duration of study through month 60

Study Arms (3)

Cohort 1

EXPERIMENTAL

Low dose AMT-130 (6 × 10\^12 gc/subject)

Genetic: intra-striatal rAAV5-miHTT

Cohort 2

EXPERIMENTAL

High dose AMT-130 (6 × 10\^13 gc/subject)

Genetic: intra-striatal rAAV5-miHTT

Cohort 3

EXPERIMENTAL

Low dose AMT-130 (6 × 10\^12 gc/subject) High dose AMT-130 (6 × 10\^13 gc/subject)

Genetic: intra-striatal rAAV5-miHTT

Interventions

intra-striatal rAAV5-miHTT GENETIC

One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain

Also known as: AMT-130

Cohort 1; Cohort 2; Cohort 3

Eligibility Criteria

• Age: 25 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able and willing to provide written informed consent prior to the study and study-related procedure.
• Male and female participants 25-65 years of age.
• Cohorts 1 \& 2:
• a DCL of 4 OR
• a DCL of 3 with either a positive ("Yes") response to the UHDRS Question 80 (multidimensional manifest diagnosis on motor, cognitive, behavioral, functional) or DSM5 criteria for cognitive disorder (American Psychiatric Association, 2013; MDS Task Force criteria).
• Cohort 3:
• a DCL of 4 OR
• a DCL of 3 with either a positive ("Yes") response to the UHDRS Question 80 (multidimensional manifest diagnosis on motor, cognitive, behavioral, functional) or DSM5 criteria for cognitive disorder (American Psychiatric Association, 2013; MDS Task Force criteria).
• HTT gene expansion testing with the presence of ≥40 CAG repeats (confirmed by genetic testing at central laboratory).
• 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) must be stable for 3 months prior to Screening with no change in clinical symptoms requiring change in medication prior to anticipated administration procedure.
• Able and willing to comply with all procedures and the study visit schedule as outlined in the protocol.
• All female participants of childbearing potential (FCOP) must have negative serum pregnancy test at Screening (and Visit 1A, as appropriate), a negative pregnancy urine dipstick at Baseline, and not be breastfeeding. All FOCPs and sexually mature males must be compliant with highly effective birth control method as outlined in Section 4.5.

You may not qualify if:

• Evidence of suicide risk, defined as:
• Suicide attempt within 1 year prior to Screening (Visit 1/1A)
• Suicidal ideation as defined by a positive response to question 5 on Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation Section within 60 days prior to Screening (Visit 1/1A)
• Significant risk of suicide as judged by the Investigator
• 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 (ASOs), 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.
• Any contraindication to 3.0 Tesla MRI as per local guidelines
• 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 (including pre-existing cardiovascular or pulmonary conditions), infection, or other significant concurrent medical condition or medications that could confound clinical and laboratory evaluations or could affect a participant's safety or their ability to undergo a neurosurgical procedure (10+ hour surgical procedure) or comply with the procedures and study visit schedule.
• Known or suspected intolerance or hypersensitivity to the investigational product(s), closely related compounds, or any of the stated ingredients.

Sponsors & Collaborators

• UniQure Biopharma B.V.: lead

Study Sites (4)

Instytut Psychiatrii i Neurologii

Warsaw, Poland

Location

Interventional Neuro Center

Warsaw, Poland

Location

Cardiff University

Cardiff, United Kingdom

Location

National Hospital for Neurology & Neurosurgery

London, United Kingdom

Location

Related Publications (3)

• Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington's Disease Clinical Trials Corner: March 2024. J Huntingtons Dis. 2024;13(1):1-14. doi: 10.3233/JHD-240017.

  PMID: 38489195 DERIVED

• Ma YM, Zhao L. Mechanism and Therapeutic Prospect of miRNAs in Neurodegenerative Diseases. Behav Neurol. 2023 Nov 23;2023:8537296. doi: 10.1155/2023/8537296. eCollection 2023.

  PMID: 38058356 DERIVED

• Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington's Disease Clinical Trials Corner: November 2022. J Huntingtons Dis. 2022;11(4):351-367. doi: 10.3233/JHD-229006.

  PMID: 36463457 DERIVED

MeSH Terms

Conditions

Huntington Disease

Condition Hierarchy (Ancestors)

Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Chorea; Dyskinesias; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Study Officials

• David Margolin, MD, PhD

  UniQure Biopharma B.V.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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. The third cohort is randomized 1:1 high to low dose randomization.

Study Record Dates

• First Submitted: November 1, 2021
• First Posted: February 16, 2022
• Study Start: October 7, 2021
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): October 7, 2029
• Last Updated: March 10, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

PL (2); GB (2)