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

• ClinicalTrials.gov Identifier: NCT04120493
• Recruitment Status: Recruiting
• First Posted: October 9, 2019
• Last Update Posted: March 17, 2023
• Sponsor: UniQure Biopharma B.V.
• Information provided by (Responsible Party): UniQure Biopharma B.V.

Study Description

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

Condition or disease	Intervention/treatment	Phase
Huntington's Disease	Genetic: intra-striatal rAAV5-miHTT; Other: Imitation (sham) surgery	Phase 1; Phase 2

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.

This trial consists of a blinded 12-month (Cohort 1 & 2) and 12-month (Cohort 3A & 3B) 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 (Cohort 1 & 2) or 12-month (Cohort 3A & 3B) blinded post treatment follow-up period, 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase I/II, Randomized, Double-Blind, Sham Control 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
• Actual Study Start Date: September 6, 2019
• Estimated Primary Completion Date: April 2029
• Estimated Study Completion Date: June 2029

Arms and Interventions

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 Name: 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 Name: AMT-130
Sham Comparator: Cohorts 1, 2, 3A & 3B; 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 3A; High dose rAAV5-miHTT (6x10^13 gc/subject).	Genetic: intra-striatal rAAV5-miHTT; Surgical adaptive approach; Other Name: AMT-130
Experimental: Cohort 3B; High dose rAAV5-miHTT (6x10^13 gc/subject).	Genetic: intra-striatal rAAV5-miHTT; Surgical adaptive approach; Other Name: AMT-130

Outcome Measures

Primary Outcome Measures :

1. Number and type of Adverse Events (AE) [ Time Frame: 12 months (Cohorts 1 & 2) and 24 months (Cohorts 3A and 3B) ]
   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.

Secondary Outcome Measures :

1. Duration of persistence of AMT-130 in the brain [ Time Frame: Collected for duration of study through month 60 ]
   Change over time in levels of AMT-130-derived Vector DNA and miRNA Expression in the Cerebrospinal Fluid (CSF)

Other Outcome Measures:

1. CSF Mutant Protein (fM) [ Time Frame: Collected for duration of study through month 60 ]
   Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment.
2. CSF/Serum Neurofilament Light Chain (pg/mL) [ Time Frame: Collected for duration of study through month 60 ]
   Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment.
3. Unified Huntington Disease Rating Scale (UHDRS) [ Time Frame: Collected for duration of study through month 60 ]
   The UHDRS will assess changes from baseline in summary scores of domains of motor function, cognitive function, behavioral function, and functional abilities.
4. Quantitative Motor (Q-Motor) Testing [ Time Frame: Collected for duration of study through month 60 ]
   Q-Motor testing will measure disease progression and responsiveness to AMT-130 treatment.
5. Huntington's Disease Cognitive Assessment Battery (HD-CAB) [ Time Frame: Collected for duration of study through month 60 ]
   The HD-CAB measures cognitive dysfunction in late premanifest and early manifest HD patients.
6. Magnetic Resonance Imaging (MRI) [ Time Frame: Collected for duration of study through month 60 ]
   MRI assessments will include whole brain volume, striatal region volumes, white matter volume, gray matter volume, ventricular volume, cortical thickness, and diffusion MRI measures.
7. Magnetic Resonance Spectroscopy (MRS) [ Time Frame: Collected for duration of study through month 60 ]
   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.
8. Neuro-QoL Measures [ Time Frame: Collected for duration of study through month 60 ]
   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.
9. HDQLIFE Measures [ Time Frame: Collected for duration of study through month 60 ]
   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.
10. Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Collected for duration of study through month 60 ]
    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.

Eligibility Criteria

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

Criteria

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
3. 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 has cognitive symptoms
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, 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 COVID-19 requiring hospitalization, with a history of symptomatic diabetes or immune compromise, or with residual respiratory or cardiac symptom associated with COVID-19

Contacts and Locations

Contacts

Contact: Diane Lopez, MS; 781-777-3697; amt130_clinical_trials@uniqure.com

Contact: Lee Rushton; 781-528-7716; amt130_clinical_trials@uniqure.com

Locations

United States, Alabama

University of Alabama at Birmingham; Recruiting

Birmingham, Alabama, United States, 35294-0111

Contact: Jenna Smith 205-996-2807 jltidwell@uabmc.edu

Principal Investigator: Victor Sung, MD

United States, California

University of California, San Francisco; Recruiting

San Francisco, California, United States, 94158

Contact: Zach Lamson 415-502-0670 zach.lamson@ucsf.edu

Principal Investigator: Michael Geschwind, MD, Ph.D.

United States, Colorado

CenExel Rocky Mountain Clinical Research; Recruiting

Englewood, Colorado, United States, 80113

Contact: Jessica Crall 303-357-5456 j.crall@cenexel.com

Principal Investigator: Rajeev Kumar, MD

United States, Florida

University of Florida College of Medicine; Recruiting

Gainesville, Florida, United States, 32610

Contact: Kyle Rizer 352-733-2426 kyle.rizer@neurology.ufl.edu

Principal Investigator: Nikolaus McFarland, MD, Ph.D.

United States, Illinois

Rush University Medical Center; Recruiting

Chicago, Illinois, United States, 60612

Contact: Jacob Hawkins 312-563-5563 Jacob_Hawkins@rush.edu

Principal Investigator: Deborah Hall, MD, Ph.D

United States, Maryland

Johns Hopkins University; Recruiting

Baltimore, Maryland, United States, 21287

Contact: Kia Ultz 410-955-1349 kcarte23@jhmi.edu

Contact: Mollie Webb Jenckes mjenckes@jhmi.edu

Principal Investigator: Christopher Ross, MD, Ph.D

United States, Massachusetts

Beth Israel Deaconess Medical Center; Withdrawn

Boston, Massachusetts, United States, 02215

United States, Michigan

University of Michigan Department of Neurology; Recruiting

Ann Arbor, Michigan, United States, 48105

Contact: Angela Stovall 734-647-4787 astovall@med.umich.edu

Principal Investigator: Praveen Dayalu, MD

United States, Ohio

Ohio State University; Recruiting

Columbus, Ohio, United States, 43210

Contact: Nicole Vrettos Nicole.Vrettos@osumc.edu

Principal Investigator: Sandra Kostyk, M.D., Ph.D.

United States, Tennessee

Vanderbilt University Medical Center; Recruiting

Nashville, Tennessee, United States, 37232

Contact: Danielle Buchanan 615-875-3274 danielle.a.buchanan@vumc.org

Principal Investigator: Daniel Claassen, MD

United States, Texas

The University of Texas; Recruiting

Houston, Texas, United States, 77030

Contact: Jamie Sims 713-500-7763 Jamie.Sims@uth.tmc.edu

Principal Investigator: Erin Furr-Stimming, MD

United States, Virginia

Virginia Commonwealth University VCU School of Medicine, Department of Neurology; Recruiting

Richmond, Virginia, United States, 23298

Contact: Heather L Ward 804-382-0076 heather.ward@vcuhealth.org

Principal Investigator: Matthew Barrett, MD

United States, Washington

University of Washington Medical Center; Recruiting

Seattle, Washington, United States, 98195

Contact: Debra Del Castillo 206-543-3647 debradel@uw.edu

Principal Investigator: Ali Samii, MD

Sponsors and Collaborators

UniQure Biopharma B.V.

Investigators

• Principal Investigator: Anke Post, MD, PhD; UniQure Biopharma B.V.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: UniQure Biopharma B.V.
• ClinicalTrials.gov Identifier: NCT04120493
• Other Study ID Numbers: CT-AMT-130-01
• First Posted: October 9, 2019
• Last Update Posted: March 17, 2023
• Last Verified: October 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by UniQure Biopharma B.V.:

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

Additional relevant MeSH terms:

Huntington Disease; 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; Cognition Disorders; Neurocognitive Disorders; Mental Disorders