Safety and Efficacy of AMT-130 in European Adults with Early Manifest Huntington Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

uniQure biopharma B.V.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

7 Oct 2021 → ongoing

Decision date (initial)

2024-07-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

uniQure biopharma B.V.

External identifiers

EU CT number

2024-511766-37-00

EudraCT number

2020-001461-36

ClinicalTrials.gov

NCT05243017

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Safety

Evaluate the safety and tolerability of bilateral striatal delivery of AMT 130 as a total HTT gene lowering therapy in adult participants with early manifest Huntington's Disease.

Secondary objectives 1

1. Determine the duration of persistence of AMT-130 in the brain

Conditions and MedDRA coding

Huntington’s Disease

Study design 4 periods

Regulatory references

Scientific advice from competent authorities

Paul-Ehrlich-Institut, Medicines And Healthcare Products Regulatory Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Able and willing to provide written informed consent prior to the study and any study-related procedure.
2. Male and female participants 25 to 65 years of age.
3. Cohorts 1 & 2: Early manifest HD as defined by a UHDRS TFC score of 9 to 13 and EITHER a. a DCL of 4 OR b. 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 (American Psychiatric Association, 2013; MDS Task Force criteria). Cohort 3: Early manifest HD as defined by a UHDRS TFC score of ≥11 and EITHER a. a DCL of 4 OR b. 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 (American Psychiatric Association, 2013; MDS Task Force criteria).
4. HTT gene expansion testing with the presence of ≥40 CAG repeats.
5. Striatal MRI volume requirements per hemisphere: a. Putamen ≥2.5 cm3 (per side) b. 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 (FOCPs) 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 17

1. Evidence of suicide risk, defined as: a. Suicide attempt within 1 year prior to Screening (Visit 1/1A). b. Suicidal ideation as defined by a positive response to question 5 on the C-SSRS Suicidal Ideation Section within 60 days prior to Screening (Visit 1/1A). c. Significant risk of suicide as judged by the Investigator.
2. Receipt of an experimental agent within 60 days or 5 half-lives prior to Screening or any time over the duration of this study.
3. Participation in an investigational study or investigational paradigm (e.g., exercise/physical activity, cognitive therapy, brain stimulation) within 60 days prior to Screening or any time 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 scans or lumbar punctures 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 (10+ hour surgical 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 >2 × upper limit of normal (ULN) b. Aspartate aminotransferase >2 × ULN c. Total bilirubin >2 × ULN d. Alkaline phosphatase >2 × ULN e. Creatinine >1.5 × ULN f. Platelet count <100,000/mm3 g. Prothrombin time >1.2 × ULN h. Partial thromboplastin time >1.2 × ULN
15. Additional Exclusion Criteria for Participants in Cohort 3: Known immunocompromised status including participants who have undergone organ transplantation or who test positive at Screening for the 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), hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc); 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. Additional Exclusion Criteria for Participants in Cohort 3: Known allergy, sensitivity, or other contraindication to medications in the immunosuppression regimen in this protocol.
17. Additional Exclusion Criteria for Participants in Cohort 3: 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 9

1. Type and incidence of AEs
2. Change from baseline in vital signs, electrocardiogram (ECG) parameters, physical examinations, and neurological examinations
3. Change from baseline in clinical chemistry and hematology safety laboratory tests
4. Change from baseline in routine urinalysis and CSF analysis
5. Change over time in AAV5 vector shedding
6. Change over time in antibodies against AAV5, cytokines, ELISpot, astroglial activation (glial fibrillary acidic protein [GFAP]), and microglial activation (YKL-40)
7. Prospective assessment of suicidality via the Columbia-Suicide Severity Rating Scale (C-SSRS)
8. Change from baseline to Day 14 and Month 1 in the MoCA
9. Change from baseline in edema, inflammation, volume loss and structural changes as measured by the following MRI pulse sequences: T1, T2, and diffusion magnetic resonance imaging (dMRI)

Secondary endpoints 2

1. Change over time in levels of AMT-130–derived vector DNA and miRNA expression in the CSF in Cohorts 1 and 2 through approval of CT-AMT-130-02 Protocol Amendment 6.0 Version 7.0
2. Change over time in levels of only AMT-130-derived vector DNA in Cohorts 1 and 2 post-approval, and throughout the trial in Cohort 3.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

uniQure biopharma B.V.

Sponsor organisation

uniQure biopharma B.V.

Address

Paasheuvelweg 25

City

Amsterdam

Postcode

1105 BP

Country

Netherlands

Scientific contact point

Organisation

uniQure biopharma B.V.

Contact name

Natascha Schillemans

Public contact point

Organisation

uniQure biopharma B.V.

Contact name

Natascha Schillemans

Third parties 15

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications