Huntington's Disease
Conditions
Keywords
Gene therapy, AAV (adeno-associated virus), serotype 5 AAV (adeno-associated virus), serotype 5, Viral vector, miHTT, muHTT, Huntington's Disease (HD)
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.
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, and 3 evaluated low dose and high dose AMT-130. Cohort 4 will further evaluate the safety of high dose AMT-130 in participants with low striatal volume. All participants in Cohort 4 will receive high dose AMT-130 and will receive pre- and post-operative dexamethasone. Cohorts 1 and 2 participants continue follow-up visits through 6 years after receipt of AMT-130. Cohorts 3 and 4 participants continue follow-up visits through 5 years after receipt of AMT-130.
Interventions
GENETICintra-striatal rAAV5-miHTT
One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain
OTHERImitation (sham) surgery
Simulated surgical procedure with skin incisions only; no intrastriatal injections and no burr holes through the skull
Sponsors
UniQure Biopharma B.V.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
25 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 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.
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) 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. * Any participant with an active infection (e.g., coronavirus disease 2019 \[COVID-19\]) at Screening or at the time of treatment that requires medical intervention. Participants may rescreen, or if screened eligible and an open surgical slot is available, may receive treatment after recovery. * Cohort 4 ONLY: Inability to establish a safe trajectory to administer AMT-130 to the target structures, as assessed by neuroimaging.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number and type of Adverse Events (AE) | 12 months (Cohorts 1 & 2) and 12 months (Cohort 3) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Change over time in levels of AMT-130-derived Vector DNA Expression in the Cerebrospinal Fluid (CSF) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Unified Huntington Disease Rating Scale (UHDRS) | Collected for duration of study through month 72 | The UHDRS will assess changes from baseline in summary scores of domains of motor function, cognitive function, behavioral function, and functional abilities. |
| Quantitative Motor (Q-Motor) Testing | Collected for duration of study through month 72 (Cohorts 1, 2 & 3) | Q-Motor testing will measure disease progression and responsiveness to AMT-130 treatment. |
| CSF Mutant Protein (fM) | Collected for duration of study through month 72 | Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment. |
| Neuro-QoL Measures | Collected for duration of study through month 72 | 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. |
| Magnetic Resonance Imaging (MRI) | Collected for duration of study through month 72 | MRI assessments will include whole brain volume, striatal region volumes, white matter volume, gray matter volume, ventricular volume, cortical thickness, and diffusion MRI measures. |
| CSF/Serum Neurofilament Light Chain (pg/mL) | Collected for duration of study through month 72 | Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment. |
Countries
United States
Outcome results
None listed