AAVrh.10hFXNPhase IA and IB Study of AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich's Ataxia

Sponsor:

Weill Medical College of Cornell University

Code:

NCT05302271

Conditions

Friedreich Ataxia

Cardiomyopathies

Cardiac Hypertrophy

Myocardial Fibrosis

Eligibility Criteria

Sex: All

Age: 12 - 50

Healthy Volunteers: Not accepted

Interventions

AAVrh.10hFXN, serotype rh.10 adeno-associated virus (AAV) gene transfer vector expressing the cDNA coding for human FXN

Prednisone

Study Details

Brief summary:

The purpose of this study is to test the safety and preliminary efficacy of AAVrh.10hFXN to treat the cardiomyopathy associated with Friedreich's ataxia (FA). AAVrh.10hFXN is a serotype rh.10 adeno-associated virus gene transfer vector coding for Frataxin (FXN). The drug is administered intravenously. This is a phase 1, open label, dose escalation study with a total of 25 participants.

Conditions

Friedreich Ataxia

Cardiomyopathies

Cardiac Hypertrophy

Myocardial Fibrosis

Study ID

NCT05302271

Start date

Feb 22, 2022

Status verified date

Sep, 2026

Completion date

Dec 31, 2029

Anticipated

Primary completion date

Dec 31, 2028

Anticipated

Eligibility Criteria

Sex: All

Age: 12 - 50

Healthy Volunteers: Not accepted

Inclusion Criteria:

Males and females, age 12 to 50
Willing and able to provide informed consent
Definitive diagnosis of FA, based on clinical phenotype and genotype (GAA expansion on both alleles)
>600 GAA repeats in intron 1 in at least one allele
FARS and SARA neurologic scores consistent with diagnosis of Friedreich's ataxia
Left ventricle ejection fraction (EF) measured by cardiac MRI of ≥35% to 75%
Evidence of FA-related cardiac disease that falls into one of the 2 categories: Early disease (defined by serum high sensitivity troponin above the normal range, without increased LVMI) or Advanced disease (defined as high sensitivity troponin above the normal range and increased LVMI).

Increased LVMI in adults: In the absence of other factors known to cause left ventricular hypertrophy, cardiac MRI left ventricular mass index >2 standard deviations above the normal range (males >84 gm/m², females >69 gm/m²)
Increased LVMI in pediatrics: In the absence of other factors known to cause left ventricular hypertrophy, cardiac MRI left ventricular mass index >95ᵗʰ centile based on normal BSA for their age and gender
Fibrosis ≤10% in the left ventricular wall on late gadolinium enhancement cardiac MRI
Resting O2 saturation ≥95%
Serum neutralizing anti-AAVrh.10 titer <1:125
Hematocrit >30%
White blood cell levels within normal limits
Normal prothrombin, partial thromboplastin time
Normal liver-related serum parameters (ALT, AST, ALP, bilirubin); normal liver ultrasound and serum alpha fetoprotein
Normal kidney function as assessed by plasma urea and creatinine; estimated GFR >30 mL/min/1.73m²
No evidence of active infection of any types, including hepatitis virus (A, B or C), human immunodeficiency virus (HIV-1 and HIV-2), or SARS-CoV2
Fertile individuals should utilize barrier birth control measures to prevent pregnancy for up to 6 months after vector administration
Individuals not receiving experimental medications or participating in another experimental protocol for at least 12 wk prior to entry to the study (individuals who are/have received approved therapy will be included).
Capable of undergoing cardiac MRI
No contraindications to receiving corticosteroid immunosuppression

Exclusion Criteria:

Individuals receiving corticosteroids or other immunosuppressive medications
Individuals with uncontrolled diabetes (glycated hemoglobin, HbA1c levels >7%)
Genotype FA missense mutation on one or both alleles
Evidence of infection defined by elevated white blood cell count, temperature >38.5̊ C, infiltrate on chest x-ray
Decompensated heart failure (NY4A class III-IV at time of baseline clinical assessment)
Hemoglobin <10 g/dl
Absolute neutrophil count <1500 cells/mm3
Platelet count <100,000 cells/mm3
Hemodynamically unstable atrial or ventricular arrhythmias which require medical intervention
Contraindication to cardiac MRI (e.g., non-MRI compatible pacemaker/defibrillator) or gadolinium (known or suspected hypersensitivity, glomerular filtration rate <30 mL/min/1.73m2)
Any malignancy during the last five years, except basal cell skin cancer
Unrelated clinical condition with life expectancy <12 months (prohibiting follow-up)
Concomitant conditions (other than FA) known to produce left ventricular hypertrophy, including aortic stenosis, systemic hypertension (BP ≥140/90 on noninvasive blood pressure), or genetically mediated hypertrophic cardiomyopathy
Use of oxygen supplementation
Risk for thromboembolic disease, including history of thromboembolic disease hospitalization within the last 90 days, recent trauma and/or recent surgical procedure. If the history of thromboembolic disease is not definitive, the subject will be excluded if laboratory testing suggests a risk for thromboembolic disease because of mutations in the protein-S, protein C, antithrombin, factor V Leiden or prothrombin gene
Any uncontrolled psychiatric disease
Pregnant or breastfeeding woman
Prior participation in any gene and/or cell therapy
Known obstructive coronary artery disease (as documented by clinical history of myocardial infarction, prior coronary revascularization or angina symptoms (Canadian Cardiovascular Society grade ≥2 at time of baseline clinical assessment), or epicardial obstructive coronary artery disease (≥ 50% left main, ≥ 70% of other major coronary arteries)
Any lung function abnormalities that would affect cardiopulmonary testing
Any condition, disorder, or abnormal laboratory test findings at screening which, in the judgment of the investigator, would interfere with the individual's ability to comply with all study requirements, or would require the administration of treatment during the study that could potentially affect the interpretation of the study data, or would place the individual at an unacceptable risk by his/her participation in the study
If prior infection with SARS-CoV2, any related residual cardiac or pulmonary abnormalities
Alcoholism or drug addiction (see reference 71 for alcoholism, reference 72 for drug addiction)

Study Design

Enrollment

25 participants

Anticipated

Allocation

Non randomized

Intervention Model

Sequential

Primary purpose

Treatment