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

Phase 1

Active, not recruiting

• Conditions: Huntington's Disease
• Interventions: Genetic: intra-striatal rAAV5-miHTT; Other: Imitation (sham) surgery

• Registration Number: NCT04120493
• Lead Sponsor: UniQure Biopharma B.V.

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, multiple dose, double-blind, imitation surgery, first-in-human (FIH) study.

Cohort 3 participants will receive either high or low dose (1:1 randomization). Participants enrolled in Cohort 3 will also receive an immunosuppression regimen consisting of dexamethasone, sirolimus, and rituximab.

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 either high or low dose AMT-130. Following completion of the Month 36 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. Cohort 3 participants will also receive pre and post-operative immunosuppressant therapies composed of dexamethasone, sirolimus, and rituximab.

Study Timeline

• Study Start: 2019-09-06
• Study First Submitted: 2019-09-30
• Study First Submitted QC: 2019-10-07
• Study First Posted: 2019-10-09
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-05
• Last Update Posted: 2025-03-10
• Primary Completion: 2029-04
• Study Completion: 2029-06

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 37

Inclusion Criteria

1. Able and willing to provide written informed consent prior to the study and study-related procedure
2. Participants 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 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

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 (ASOs), 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 participant'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. Any known allergy to gadoteridol (ProHance)
14. 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
15. Known immunocompromised status including participants who have undergone organ transplantation; or who test positive at Screening for human immunodeficiency virus (HIV); or who are at risk of pathogen reactivation if immunosuppressed, including participants who test positive at Screening for hepatitis C virus antibody (anti-HCV), hepatitis C virus ribonucleic acid (HCV RNA), or hepatitis B surface antigen (HBsAg); or who have history of active tuberculosis or a positive tuberculosis blood test during Screening. For participants with an indeterminate tuberculosis blood test result or positive tuberculosis test result, repeat testing is recommended.
16. Known allergy, sensitivity, or other contraindication to medications in the immunosuppression regimen in this protocol.
17. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 1	intra-striatal rAAV5-miHTT	Low dose rAAV5-miHTT (6x10\^12 gc/subject).
Cohort 2	intra-striatal rAAV5-miHTT	High dose rAAV5-miHTT (6x10\^13 gc/subject).
Cohorts 1, 2	Imitation (sham) surgery	Imitation (sham) surgery
Cohort 3	intra-striatal rAAV5-miHTT	Low dose rAAV5-miHTT (6x10\^12 gc/subject). High dose rAAV5-miHTT (6x10\^13 gc/subject).

Primary Outcome Measures

Name	Time	Method
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, 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

Name	Time	Method
Duration of persistence of AMT-130 in the brain	Collected for duration of study through month 60	Change over time in levels of AMT-130-derived Vector DNA Expression in the Cerebrospinal Fluid (CSF)

Trial Locations

Locations (12)

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

Ohio State University; 🇺🇸 Columbus, Ohio, United States

Virginia Commonwealth University VCU School of Medicine, Department of Neurology; 🇺🇸 Richmond, Virginia, United States

University of Arizona (Surgical Site Only); 🇺🇸 Tucson, Arizona, United States

University of California, San Francisco; 🇺🇸 San Francisco, California, United States

CenExel Rocky Mountain Clinical Research; 🇺🇸 Englewood, Colorado, United States

The University of Texas; 🇺🇸 Houston, Texas, United States

University of Washington Medical Center; 🇺🇸 Seattle, Washington, United States

Rush University Medical Center; 🇺🇸 Chicago, Illinois, United States

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

University of Michigan Department of Neurology; 🇺🇸 Ann Arbor, Michigan, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States