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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05243017
Recruitment Status : Recruiting
First Posted : February 16, 2022
Last Update Posted : September 14, 2022
Sponsor:
Information provided by (Responsible Party):
UniQure Biopharma B.V.

Study Description
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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.

Condition or disease Intervention/treatment Phase
Huntington Disease Genetic: intra-striatal rAAV5-miHTT Phase 1 Phase 2

Detailed Description:
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
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 7, 2021
Estimated Primary Completion Date : March 2027
Estimated Study Completion Date : October 7, 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 1 (Low Dose of AMT-130)
Low dose AMT-130 (6 × 10^12 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 of AMT-130)
High dose AMT-130 (6 × 10^13 gc/subject)
 Genetic: intra-striatal rAAV5-miHTT
One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain
Other Name: AMT-130


Outcome Measures
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Primary Outcome Measures :
  1. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Type and incidence of Adverse Events (AEs)


  2. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in blood pressure (mmHg)


  3. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in respiratory rate (BPM)


  4. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in heart rate (BPM)


  5. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in electrocardiograms (ECGs) for any clinically significant abnormalities or clinically significant worsening. (normal or abnormal)


  6. 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 [ Time Frame: 6 months ]

    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)


  7. 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 [ Time Frame: 6 months ]

    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)


  8. Evaluate the safety and tolerability by number of participants with clinically significant changes in laboratory tests - Clinical Chemistry [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in Clinical Chemistry laboratory tests with clinical significance.


  9. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in hematology laboratory tests with clinical significance.


  10. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change from baseline in routine urinalysis test with clinical significance.


  11. Evaluate the safety and tolerability o by number of participants with clinical significant changes in cerebrospinal fluid (CSF) analysis [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change from baseline in CSF analysis with clinical significance.


  12. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change over time in AAV5 vector shedding


  13. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change over time in microglial activation (YKL-40) (pg/mL)


  14. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change over time in antibodies against AAV5 (g/L)


  15. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change over time in cytokines (pg/mL)


  16. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change over time in ELISpot


  17. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change over time in astroglial activation (GFAP) (pg/mL)


  18. 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 [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change from baseline to Day 14 and Month 1 in the Montreal Cognitive Assessment (MoCA)


  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 number of participants with changes in MRI [ Time Frame: 6 months ]

    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)



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. Mean changes from baseline in summary scores for the 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 to capture the current disease status.

  4. Changes over time in 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. Changes over time in 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. Mean changes from baseline in 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.

  7. Changes over time in Neurological Disorders Quality of Life in Neurological Disorder Measures (Neuro-QoL) [ 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.

  8. Magnetic Resonance Imaging (MRI) - Brain Volumes [ 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(cm^3)

  9. Magnetic Resonance Imaging (MRI) - Cortical Thickness [ Time Frame: Collected for duration of study through month 60 ]
    MRI assessments will include cortical thickness (mm)

  10. Diffusion Magnetic Resonance Imaging (MRI) [ Time Frame: Collected for duration of study through month 60 ]
    MRI assessments will include diffusion MRI measures mm2/s

  11. Mean changes from baseline for 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.


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

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05243017


Contacts
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Contact: Diane Lopez, MS 781-777-3697 amt130_clinical_trials@uniqure.com
Contact: Christopher Sullivan 339-970-7611 amt130_clinical_trials@uniqure.com

Locations
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Germany
Universitaetsklinikum Düsseldorf Not yet recruiting
Düsseldorf, Germany
Contact: Andrea Dreyer    +49 211 81-17246    andrea.dreyer@med.uni-duesseldorf.de   
Principal Investigator: Jan Vesper         
George Huntington Institute Not yet recruiting
Münster, Germany
Contact: Dorothee Schulte to Bühne    +49 251 788 7880    dorothee.schultetobuehne@ghi-muenster.de   
Principal Investigator: Ralf Reilmann         
Poland
Interventional Neuro Center Active, not recruiting
Warsaw, Poland
Instytut Psychiatrii i Neurologii Recruiting
Warszawa, Poland
Contact: Malgorzata Dusza-Rowinska    +48 698 250 623    neurol1@ipin.edu.pl   
Principal Investigator: Grzegorz Witkowski         
United Kingdom
Cardiff University Recruiting
Cardiff, United Kingdom
Contact: Hel Hughes    +44 2920 745302    Helen.Hughes10@wales.nhs.uk   
Principal Investigator: William Gray         
National Hospital for Neurology & Neurosurgery Recruiting
London, United Kingdom
Contact: Miguel Alvarez       miguel.alvarez.13@ucl.ac.uk   
Principal Investigator: Sarah Tabrizi         
Sponsors and Collaborators
UniQure Biopharma B.V.
Investigators
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Principal Investigator: Anke Post, MD, PhD UniQure Biopharma B.V.
More Information
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Responsible Party: UniQure Biopharma B.V.
ClinicalTrials.gov Identifier: NCT05243017    
Other Study ID Numbers: CT-AMT-130-02
First Posted: February 16, 2022    Key Record Dates
Last Update Posted: September 14, 2022
Last Verified: September 2022

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