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

A Phase I/II, Randomized, Double-Blind, Sham Control Study to Explore Safety, Tolerability, and Efficacy Signals of Multiple Doses of Striatally-Administered rAAV5-miHTT Total Huntingtin Gene (HTT) Lowering Therapy (AMT-130) in Early Manifest Huntington's Disease

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 I/II, randomized, multicenter, multiple dose, double-blind, imitation surgery, first-in-human (FIH) study.

Cohort 3 participants will receive either high or low dose (1:1 randomization).

Study Overview

• Status: Recruiting
• Conditions: Huntington's Disease
• Intervention / Treatment: Genetic: intra-striatal rAAV5-miHTT; Other: Imitation (sham) surgery

Detailed Description

AMT-130 is an investigational, single administration gene therapy intended to modify the disease course for HD. Preclinical studies have shown that AMT-130 lowers huntingtin protein and is associated with decreased progression of Huntington's Disease signs in animal models.

Cohort 1 & 2 consists of a blinded 12-month Core Study Period to evaluate the safety and potential impact of AMT-130 on disease progression and an unblinded 4-year Long-Term Period with periodic follow-up visits to evaluate the safety of AMT-130 and disease progression in treated individuals. Cohort 2 Sham participants who do not cross over to receive AMT-130 treatment will have the opportunity to participate in the Optional Extended Follow-Up Period and will be followed for an additional 2 years.

Following completion of the 12-month blinded post treatment follow-up period (Cohorts 1 & 2 only), once the crossover has been activated after review of data by the DSMB, subjects randomized to the imitation (sham) procedure who continue to meet inclusion/exclusion criteria will be allowed to crossover to receive AMT-130 treatment.

Cohort 3 participants will receive AMT-130 either high or low dose. Following completion of the Month 12 visit, they will be unblinded to their treatment arm. Cohort 3 will further evaluate the safety and exploratory efficacy data of low or high dose AMT-130 together with peri- and post-operative glucocorticoids.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Diane Lopez, MS; Phone Number: 781-777-3697; Email: amt130_clinical_trials@uniqure.com
• Study Contact Backup: Name: Elizabeth Eyler; Email: amt130_clinical_trials@uniqure.com

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-0111
      • Recruiting
      • University of Alabama at Birmingham
      • Contact: Jenna Smith; Phone Number: 205-996-2807; Email: jltidwell@uabmc.edu
      • Principal Investigator: Victor Sung, MD
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Not yet recruiting
      • University of Arizona
      • Contact: Paul Larson, MD
  • California
    • San Francisco, California, United States, 94158
      • Recruiting
      • University of California, San Francisco
      • Contact: Zach Lamson; Phone Number: 415-502-0670; Email: zach.lamson@ucsf.edu
      • Principal Investigator: Michael Geschwind, MD, Ph.D.
  • Colorado
    • Englewood, Colorado, United States, 80113
      • Recruiting
      • CenExel Rocky Mountain Clinical Research
      • Contact: Jessica Crall; Phone Number: 303-357-5456; Email: j.crall@cenexel.com
      • Principal Investigator: Rajeev Kumar, MD
  • Florida
    • Gainesville, Florida, United States, 32610
      • Withdrawn
      • University of Florida College of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • Rush University Medical Center
      • Principal Investigator: Deborah Hall, MD, Ph.D
      • Contact: Tyler Svymbersky; Phone Number: 312-563-0676; Email: tyler_svymbersky@rush.edu
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • Johns Hopkins University
      • Contact: Kia Ultz; Phone Number: 410-955-1349; Email: kcarte23@jhmi.edu
      • Contact: Mollie Webb Jenckes; Email: mjenckes@jhmi.edu
      • Principal Investigator: Christopher Ross, MD, Ph.D
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Withdrawn
      • Beth Israel Deaconess Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • Recruiting
      • University of Michigan Department of Neurology
      • Contact: Angela Stovall; Phone Number: 734-647-4787; Email: astovall@med.umich.edu
      • Principal Investigator: Praveen Dayalu, MD
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University
      • Contact: Nicole Vrettos; Email: Nicole.Vrettos@osumc.edu
      • Principal Investigator: Sandra Kostyk, M.D., Ph.D.
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University Medical Center
      • Contact: Danielle Buchanan; Phone Number: 615-875-3274; Email: danielle.a.buchanan@vumc.org
      • Principal Investigator: Daniel Claassen, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • The University Of Texas
      • Contact: Jamie Sims; Phone Number: 713-500-7763; Email: Jamie.Sims@uth.tmc.edu
      • Principal Investigator: Erin Furr-Stimming, MD
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Recruiting
      • Virginia Commonwealth University VCU School of Medicine, Department of Neurology
      • Principal Investigator: Matthew Barrett, MD
      • Contact: Kara L McHaney; Phone Number: 804-382-0076; Email: kara.mchaney@vcuhealth.org
  • Washington
    • Seattle, Washington, United States, 98195
      • Recruiting
      • University of Washington Medical Center
      • Contact: Debra Del Castillo; Phone Number: 206-543-3647; Email: debradel@uw.edu
      • Principal Investigator: Ali Samii, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Able and willing to provide written informed consent prior to the study and study-related procedure
2. Subjects 25 to 65 years of age of both sexes

3a. Cohort 1 & 2: 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

3b. 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).

4. HTT gene expansion testing with the presence of ≥40 CAG repeats

5. Striatal MRI volume requirements per hemisphere: Putamen ≥2.5 cm3 (per side); Caudate ≥2.0 cm3 (per side)

6. 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

7. Able and willing to comply with all procedures and the study visit schedule as outlined in the protocol

8. All female subjects 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.

Exclusion Criteria:

1. Evidence of suicide risk
2. Receipt of an experimental agent within 60 days or five half-lives prior to Screening or anytime over the duration of this study.
3. 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.
4. Presence of an implanted deep brain stimulation device, ventriculoperitoneal or other CSF shunt, or other implanted catheter
5. 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.
6. Any contraindication to 3.0 Tesla MRI as per local guidelines
7. Brain and spinal pathology that may interfere with the surgical delivery of AMT-130 or represents a significant neurologic comorbid disorder
8. Any contraindication to lumbar puncture as per local guidelines
9. 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
10. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study
11. 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 subject's safety or their ability to undergo the neurosurgical procedure or comply with the procedures and study visit schedule
12. Known or suspected intolerance or hypersensitivity to the investigational product(s), closely-related compounds, or any of the stated ingredients
13. 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
14. Known, documented infection with coronavirus disease 2019 (COVID-19) based upon any testing methodology: a. Within 8 weeks of anticipated Visit 2 (Baseline) for an asymptomatic patient or a patient who recovered from only mild, non-respiratory symptoms b. Within 12 weeks of anticipated Visit 2 (Baseline) for an asymptomatic patient (e.g. cough, dyspnea) who did not require hospitalization c. At any time for a symptomatic patient who is diabetic, immunocompromised, or hospitalized d. For any patient not already excluded by 14 a-c above: i. within 8 weeks of anticipated Visit 2 (Baseline) for any patient with residual respiratory or cardiac symptoms, such as fatigue, shortness of breath, and chest pain ii. Any patient with neurological symptoms associated with a symptomatic COVID-19 infection that might complicate assessment of HD progression

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Low dose rAAV5-miHTT (6x10^12 gc/subject).	Genetic: intra-striatal rAAV5-miHTT; One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain; Other Names: AMT-130
Experimental: Cohort 2; High dose rAAV5-miHTT (6x10^13 gc/subject).	Genetic: intra-striatal rAAV5-miHTT; One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain; Other Names: AMT-130
Sham Comparator: Cohorts 1, 2; Imitation (sham) surgery	Other: Imitation (sham) surgery; Simulated surgical procedure with skin incisions only; no intrastriatal injections and no burr holes through the skull
Experimental: Cohort 3; Low dose rAAV5-miHTT (6x10^12 gc/subject). High dose rAAV5-miHTT (6x10^13 gc/subject).	Genetic: intra-striatal rAAV5-miHTT; One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain; Other Names: AMT-130

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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, 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 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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CSF Mutant Protein (fM)	Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment.	Collected for duration of study through month 60
CSF/Serum Neurofilament Light Chain (pg/mL)	Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment.	Collected for duration of study through month 60
Unified Huntington Disease Rating Scale (UHDRS)	The UHDRS will assess changes from baseline in summary scores of domains of motor function, cognitive function, behavioral function, and functional abilities.	Collected for duration of study through month 60
Quantitative Motor (Q-Motor) Testing	Q-Motor testing will measure disease progression and responsiveness to AMT-130 treatment.	Collected for duration of study through month 60
Huntington's Disease Cognitive Assessment Battery (HD-CAB)	The HD-CAB measures cognitive dysfunction in late premanifest and early manifest HD patients.	Collected for duration of study through month 60
Magnetic Resonance Imaging (MRI)	MRI assessments will include whole brain volume, striatal region volumes, white matter volume, gray matter volume, ventricular volume, cortical thickness, and diffusion MRI measures.	Collected for duration of study through month 60
Magnetic Resonance Spectroscopy (MRS)	MRS will be collected using single-voxel point resolved spectroscopy of the left putamen and white matter region immediately adjacent to the left putamen. Neuronal health and gliosis will be evaluated by measuring total N-acetylaspartic acid (neuronal integrity marker) and myoinisitol (reactive astrocytosis marker) levels.	Collected for duration of study through month 60
Neuro-QoL Measures	The Neuro-QoL is a brief, reliable, valid, standardized set of patient reported, Health Related Quality of Life (HRQoL) measures for people living with neurological conditions.	Collected for duration of study through month 60
HDQLIFE Measures	The HDQLIFE is a measurement system that was designed to provide a brief, reliable and valid assessment of HRQoL in HD and consists of NeuroQoL measures that have been validated in the HD population and several new HD specific measures.	Collected for duration of study through month 60
Hospital Anxiety and Depression Scale (HADS)	The HADS is a 14-item, self-report measure that has been shown to be reliable and valid for identifying depression and anxiety in adults who are physically ill. Each item is scored from 0 (no anxiety or depression) to 3 (abnormal anxiety or depression) for a maximum total score of 21.	Collected for duration of study through month 60

Collaborators and Investigators

• Sponsor: UniQure Biopharma B.V.
• Investigators: Principal Investigator: Kenechi Ejebe, MD, UniQure Biopharma B.V.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 6, 2019
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: September 30, 2019
• First Submitted That Met QC Criteria: October 7, 2019
• First Posted (Actual): October 9, 2019

Study Record Updates

• Last Update Posted (Actual): October 18, 2023
• Last Update Submitted That Met QC Criteria: October 16, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Gene therapy; Viral vector; AAV (adeno-associated virus); serotype 5 AAV (adeno-associated virus); serotype 5; miHTT; muHTT; Huntington's Disease (HD)
• 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: CT-AMT-130-01

Drug and device information, study documents

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