Safety and Proof-of-Concept (POC) Study With AMT-130 in Adults With Early Manifest Huntington's Disease

NCT04120493 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: CT-AMT-130-01
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 12

Brief Summary

This is the first study of AMT-130 in patients with early manifest HD and is designed to establish safety and proof-of-concept (PoC). CT-AMT-130-01 is a Phase 1/2, multicenter, first-in-human (FIH) study. The first three cohorts of the study have completed enrollment, including the randomized, double-blind, sham-controlled cohorts. Cohort 4 is open-label. Cohort 4 participants will receive high dose AMT-130.

Conditions

Huntington's 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 (1)

• Number and type of Adverse Events (AE)

  Safety will be assessed by adverse events (AEs) related to clinical safety laboratory tests, vital signs, electrocardiograms (ECGs), neurological and physical examinations, rAAV5 vector shedding, immunogenicity response (Cohorts 1, 2 \& 3), suicidality risk \[Columbia-Suicide Severity Rating Scale \[C-SSRS)\], changes in global cognitive functioning \[Montreal Cognitive Assessment Scale (MoCA)\] and MRI measures of edema, inflammation, volume loss and structural changes.

  12 months (Cohorts 1 & 2) and 12 months (Cohort 3)

Secondary Outcomes (1)

• Duration of persistence of AMT-130 in the brain

  Collected for duration of study through month 72 (Cohorts 1 & 2) and through month 16 (Cohorts 3 & 4)

Other Outcomes (6)

• CSF Mutant Protein (fM)

  Collected for duration of study through month 72

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

  Collected for duration of study through month 72

• Unified Huntington Disease Rating Scale (UHDRS)

  Collected for duration of study through month 72

Study Arms (5)

Cohort 1

EXPERIMENTAL

Low dose rAAV5-miHTT (6x10\^12 gc/subject). Note: gc = genome copies

Genetic: intra-striatal rAAV5-miHTT

Cohort 2

EXPERIMENTAL

High dose rAAV5-miHTT (6x10\^13 gc/subject).

Genetic: intra-striatal rAAV5-miHTT

Cohorts 1, 2

SHAM COMPARATOR

Imitation (sham) surgery

Other: Imitation (sham) surgery

Cohort 3

EXPERIMENTAL

Low dose rAAV5-miHTT (6x10\^12 gc/subject). High dose rAAV5-miHTT (6x10\^13 gc/subject).

Genetic: intra-striatal rAAV5-miHTT

Cohort 4

EXPERIMENTAL

High dose rAAV5-miHTT (6x10\^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; Cohort 4

Imitation (sham) surgery OTHER

Simulated surgical procedure with skin incisions only; no intrastriatal injections and no burr holes through the skull

Cohorts 1, 2

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
• Participants 25 to 65 years of age of both sexes
• Cohorts 1, 2, \& 4: Early manifest HD as defined by a UHDRS total functional capacity (TFC) score of 9 to 13 and EITHER a diagnostic confidence level (DCL) of 4 OR a DCL of 3 if the subject either meets the definition of multidimensional manifest HD (UHDRS question 80) or has cognitive symptoms
• Cohort 3: Early manifest HD as defined by a UHDRS TFC score of ≥ 11 and EITHER a DCL of 4 or a DCL of 3 with either a positive "Yes" response to UHDRS Question 80 (multidimensional manifest diagnosis on motor, cognitive, behavioral, functional) or DSM5 criteria for cognitive disorder (Movement Disorder Society Task Force criteria).
• HTT gene expansion testing with the presence of ≥40 CAG repeats
• Striatal MRI volume requirements per hemisphere:
• Cohorts 1, 2, \& 3: Putamen ≥2.5 cm\^3 (per side); Caudate ≥2.0 cm\^3 (per side)
• Cohort 4: Putamen \<2.5 cm\^3 (on either side); Caudate \<2.0 cm\^3 (on either 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 (FOCP) must have a 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 a highly effective birth control method.

You may not qualify if:

• 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) 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 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 lumbar puncture 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 the neurosurgical 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
• Any known allergy to gadoteridol (ProHance)
• Screening laboratory values (as measured by the central laboratory): a. Alanine aminotransferase (ALT) \>2 × upper limit of normal (ULN) b. Aspartate aminotransferase (AST) \>2 × ULN c. Total bilirubin \>2 × ULN d. Alkaline phosphatase (ALP) \>2 × ULN e. Creatinine \>1.5 × ULN f. Platelet count \<100,000/mm3g.Prothrombin time (PT) \>1.2 × ULN h. Partial thromboplastin time (PTT) \>1.2 × ULN
• Known allergy, sensitivity, or other contraindication to medications in the immunosuppression regimen in this protocol.

Sponsors & Collaborators

• UniQure Biopharma B.V.: lead

Study Sites (12)

University of Alabama at Birmingham

Birmingham, Alabama, 35294-0111, United States

Location

University of Arizona (Surgical Site Only)

Tucson, Arizona, 85724, United States

Location

University of California, San Francisco

San Francisco, California, 94158, United States

Location

CenExel Rocky Mountain Clinical Research

Englewood, Colorado, 80113, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

University of Michigan Department of Neurology

Ann Arbor, Michigan, 48105, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

The University of Texas

Houston, Texas, 77030, United States

Location

Virginia Commonwealth University VCU School of Medicine, Department of Neurology

Richmond, Virginia, 23298, United States

Location

University of Washington Medical Center

Seattle, Washington, 98195, United States

Location

Related Publications (4)

• Pala M, Yilmaz SG. Circular RNAs, miRNAs, and Exosomes: Their Roles and Importance in Amyloid-Beta and Tau Pathologies in Alzheimer's Disease. Neural Plast. 2025 Apr 8;2025:9581369. doi: 10.1155/np/9581369. eCollection 2025.

  PMID: 40235521 DERIVED

• 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

• 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

• Rodrigues FB, Wild EJ. Huntington's Disease Clinical Trials Corner: April 2020. J Huntingtons Dis. 2020;9(2):185-197. doi: 10.3233/JHD-200002.

  PMID: 32250312 DERIVED

MeSH Terms

Conditions

Huntington Disease

Interventions

salicylhydroxamic acid; Surgical Procedures, Operative

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 H. Margolin, MD, PhD

  uniQure, Inc.

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: September 30, 2019
• First Posted: October 9, 2019
• Study Start: September 6, 2019
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): December 1, 2029
• Last Updated: October 21, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (12)