Summary

Eligibility
for people ages 25-65 (full criteria)
Location
at San Francisco 5391959, California 5332921 and other locations
Dates
study started
study ends around
Principal Investigator
by Michael Geschwind
Headshot of Michael Geschwind
Michael Geschwind

Description

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.

Official Title

A Phase 1/2, Randomized, Double-Blind, Sham Control and Open-Label 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

Details

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.

All participants continue follow-up visits through 5 years after receipt of AMT-130.

Keywords

Huntington's Disease, Gene therapy, AAV (adeno-associated virus), serotype 5 AAV (adeno-associated virus), serotype 5, Viral vector, miHTT, muHTT, Huntington's Disease (HD), Huntington Disease, salicylhydroxamic acid, Operative Surgical Procedures, intra-striatal rAAV5-miHTT

Eligibility

You can join if…

Open to people ages 25-65

  • 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, & 3: 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 cm3 (per side); Caudate ≥2.0 cm3 (per side)
  • Cohort 4: Putamen <2.5 cm3 (on either side); Caudate <2.0 cm3 (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 CAN'T join 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.
  • 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.

Locations

  • UCSF accepting new patients
    San Francisco 5391959 California 5332921 94158 United States
  • University of Arizona (Surgical Site Only) in progress, not accepting new patients
    Tucson 5318313 Arizona 5551752 85724 United States
  • University of Washington Medical Center accepting new patients
    Seattle 5809844 Washington 5815135 98195 United States

Lead Scientist at UCSF

  • Michael Geschwind
    Dr. Geschwind received his M.D.and Ph.D. in neuroscience through the National Institutes of Health (NIH)-sponsored Medical Scientist Training Program (MSTP) at the Albert Einstein College of Medicine in New York.

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
UniQure Biopharma B.V.
ID
NCT04120493
Phase
Phase 1/2 Huntington's Disease Research Study
Study Type
Interventional
Participants
Expecting 43 study participants
Last Updated