Clinical trial NCT05302271: Phase IA and IB Study of AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich's Ataxia
Official title: Phase IA and IB Study of AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich's Ataxia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Friedreich Ataxia
Cardiomyopathies
Cardiac Hypertrophy
Myocardial Fibrosis
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2022-03-31
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: The clinical study design is a dose-escalation study with 4 cohorts of n=25, 5 subjects at each of 3 doses to establish the safety of the investigational drug product, and 1 cohort with n=10 at the maximum tolerated dose. The vector will be delivered intravenously.
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* Males and females, age 18 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, must meet the following criteria: must be abnormal in ≥2 of the following parameters, at least one of which is an abnormal cardiac MRI left ventricular mass index or abnormal cardiopulmonary exercise test

  1. 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)
  2. Cardiopulmonary arm crank testing with assessment of VO2 max ≤20 mL/kg-min, peak VO2 ≥10 mL/kg-min while maintaining revolutions of ≥40/min. To insure consistency of effort, peak RER ≥1.0
  3. Cardiac MRI stroke volume index \<45 mL/m2
  4. Cardiac MRI global longitudinal left ventricular strain \<20%
  5. Serum high-sensitivity cardiac troponin above the normal range
* 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)

Primary outcomes:
measure: Safety of AAVrh.10hFXN
timeFrame: 5 Years
Secondary outcomes:
Other outcomes:
measure: Change in cardiopulmonary exercise testing
timeFrame: 5 Years
measure: Change in cardiac-relevant parameters in cardiac-magnetic resonance scans
timeFrame: 5 Years
measure: Change in cardiac-relevant parameters in echocardiograms
timeFrame: 5 Years
measure: Change in arrhythmias with 24-hour monitoring.
timeFrame: 5 Years
Locations:
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
Study officials:
affiliation: Weill Medical College of Cornell University
name: Ronald G Crystal, MD
role: PRINCIPAL_INVESTIGATOR
References: