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

NCT05302271 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 20-01021274R61HL151355
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

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

Keywords

Ataxia; Friedreich's ataxia; Pediatric; Gene therapy

Outcome Measures

Primary Outcomes (1)

• Safety of AAVrh.10hFXN

  To determine the safety of AAVrh.10hFXN, as measured by the number of subjects with any treatment-related adverse events for 5 years.

  5 Years

Other Outcomes (4)

• Change in cardiopulmonary exercise testing

  5 Years

• Change in cardiac-relevant parameters in cardiac-magnetic resonance scans

  5 Years

• Change in cardiac-relevant parameters in echocardiograms

  5 Years

Study Arms (4)

First Dose Cohort

EXPERIMENTAL

AAVrh.10hFXN will be administered intravenously.

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

Second Dose Cohort

EXPERIMENTAL

AAVrh.10hFXN will be administered intravenously.

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

Third Dose Cohort

EXPERIMENTAL

AAVrh.10hFXN will be administered intravenously.

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

Maximum Tolerated Dose Cohort

EXPERIMENTAL

AAVrh.10hFXN will be administered intravenously.

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

Interventions

Prednisone DRUG

All participants will remain immunosuppression therapy with prednisone for a total of 14 weeks.

First Dose Cohort; Maximum Tolerated Dose Cohort; Second Dose Cohort; Third Dose Cohort

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

AAVrh.10hFXN will be administered intravenously.

First Dose Cohort; Maximum Tolerated Dose Cohort; Second Dose Cohort; Third Dose Cohort

Eligibility Criteria

• Age: 12 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Weill Cornell Medicine

New York, New York, 10021, United States

RECRUITING

Related Publications (3)

• Crystal RG, Weinsaft JW, Kaminsky SM, Caragiulo A, Savage N, Patel A, Gavrilova RH, Perlman SL, Galbraith M, Kahlon U, Krishnan U, Kaner RJ, Sanders A, Vo M, Sarva H, Yoo A, Sondhi D, De BP, Mezey JG, Aubert G, Khan A, Selvan N, Bhalla N, Adler E, Zesiewicz T. AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich Ataxia: A Nonrandomized Clinical Trial. JAMA Cardiol. 2026 Aug 1;11(8):709-718. doi: 10.1001/jamacardio.2026.1699.

  PMID: 42307907 DERIVED

• Hendrickx N, Mentre F, Hamdan A, Karlsson MO, Hooker AC, Traschutz A, Gagnon C, Schule R, Synofzik M, Comets E; ARCA Study Group, EVIDENCE-RND consortium. Comparing randomized trial designs to estimate treatment effect in rare diseases with longitudinal models: a simulation study showcased by Autosomal Recessive Cerebellar Ataxias using the SARA score. BMC Med Res Methodol. 2025 Jul 30;25(1):179. doi: 10.1186/s12874-025-02626-x.

  PMID: 40739200 DERIVED

• De BP, Cram S, Lee H, Rosenberg JB, Sondhi D, Crystal RG, Kaminsky SM. Assessment of Residual Full-Length SV40 Large T Antigen in Clinical-Grade Adeno-Associated Virus Vectors Produced in 293T Cells. Hum Gene Ther. 2023 Aug;34(15-16):697-704. doi: 10.1089/hum.2023.032.

  PMID: 37171121 DERIVED

MeSH Terms

Conditions

Friedreich Ataxia; Cardiomyopathies; Cardiomegaly; Ataxia

Interventions

Prednisone

Condition Hierarchy (Ancestors)

Spinocerebellar Degenerations; Cerebellar Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Mitochondrial Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Heart Diseases; Cardiovascular Diseases; Hypertrophy; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Dyskinesias; Neurologic Manifestations; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Ronald G Crystal, MD

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maddie Galbraith, BS

CONTACT

646-962-2672; meg4013@med.cornell.edu

Niamh Savage, BS

CONTACT

646-962-5527; nis2049@med.cornell.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 21, 2022
• First Posted: March 31, 2022
• Study Start: February 22, 2022
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029
• Last Updated: September 28, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)