Gene Transfer Clinical Trial for Krabbe Disease

NCT04693598 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: FBX-101-RESKUE
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

This is a nonblinded, non-randomized dose escalation study of intravenous AAVrh10 after hematopoietic stem cell transplantation (HSCT) in which subjects will receive standard of care hematopoietic cell transplantation for Krabbe disease, followed by a single infusion of an adeno-associated virus gene therapy product. Extensive natural history subjects will be used to compare as control group.

Conditions

Krabbe Disease

Keywords

Lysosomal Storage Disorder; Globoid Cell Leukodystrophy; Leukodystrophy; GALC

Outcome Measures

Primary Outcomes (2)

• Safety as assessed by incidence and severity of adverse events and serious adverse events that are attributed to FBX-101.

  24 months

• Safety as assessed by HSCT incident of engraftment.

  24 months

Secondary Outcomes (2)

• Efficacy as assessed by improvement of probability to achieve independent sitting compared to untreated patients or those receiving HSCT only.

  12 months and 24 months

• Efficacy as assessed by improvement of gross motor function as measured by Peabody Developmental Motor Scale 2nd Edition (PDMS-2) above a functional age equivalent of 12 months compared to untreated patients or those receiving HSCT only

  24 months

Study Arms (2)

Cohort 1 - Low Dose FBX-101 (aka AAVrh.10-GALC)

EXPERIMENTAL

Participants will receive a single infusion at the lower dose (N=3 participants)

Biological: FBX-101

Cohort 2 - High Dose FBX-101 (aka AAVrh.10-GALC)

EXPERIMENTAL

Participants will receive a single infusion at the higher dose (N=3 participants)

Biological: FBX-101

Interventions

FBX-101 BIOLOGICAL

A replication-deficient adeno-associated virus gene transfer vector expressing the human galactocerebrosidase (GALC) cDNA will be delivered one-time through a venous catheter inserted into a peripheral limb vein.

Also known as: AAVrh.10-hGALC

Cohort 1 - Low Dose FBX-101 (aka AAVrh.10-GALC); Cohort 2 - High Dose FBX-101 (aka AAVrh.10-GALC)

Eligibility Criteria

• Age: 1 Day - 12 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Diagnosis of infantile Krabbe disease, characterized by the following criteria outlined below:
• Galactocerebrosidase (GALC) activity levels in leukocytes compatible with the diagnosis of Krabbe disease; AND AT LEAST ONE OF THE FOLLOWING:
• Elevated psychosine levels predictive of infantile disease onset by DBS; OR
• Imaging or neurophysiological findings consistent with Krabbe disease (CSF, MRI, NCV, ABR); OR
• Two GALC mutations predictive to result in infantile onset phenotype.
• Age at the time of screening: 1 day to 12 months
• Participant has been deemed eligible for treatment with HSCT (standard of care) and a fully myeloablative reduced intensity/toxicity conditioning regimen (RIC/RTC) is/has been used
• Participant's parents or legal guardian consents to participate in the study and provides informed consent according to IRB guidelines prior to any study procedures being performed
• Parent(s) and/or legal guardian able to comply with the clinical protocol
• Participant must have adequate organ function at time of screening as measured by:
• Creatinine ≤ 1.5x upper limit of age appropriate normal and creatinine clearance ≥ 60 mL/min/1.73 m2
• Hepatic transaminases (ALT/AST) ≤ 2x age related upper limit of normal
• Ejection fraction of \> 50% by echocardiogram or other appropriate study without evidence of pulmonary hypertension
• Pulmonary evaluation testing demonstrating resting pulse oximeter \> 95% on room air
• Coagulation tests within 110% of normal ranges for age. (PT/INR and PTT)

You may not qualify if:

• History of prior treatment with a gene therapy product
• Presence of major congenital anomaly or any other condition that affects neurodevelopmental function
• Presence of any neurocognitive deficit or brain damage not attributable to Krabbe disease
• Active aspiration
• Signs of active infection or disease from cytomegalovirus, adenovirus or other viruses
• HIV positive
• Uncontrolled and progressive bacterial or fungal infection
• Presence of any contraindication for MRI
• Use of any investigational product prior to study enrollment or current enrollment in another study that involves clinical interventions
• Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the PI, would preclude participation in the study
• Ongoing veno-occlusive disease (VOD) as determined by liver ultrasound (moderate ascites and static or retrograde portal vein flow) the day before FBX-101 infusion.

Sponsors & Collaborators

• Forge Biologics, Inc: lead

Study Sites (1)

University of Michigan Hospitals - Michigan Medicine

Ann Arbor, Michigan, 48109, United States

Location

Related Publications (2)

• Bradbury AM, Bagel J, Swain G, Miyadera K, Pesayco JP, Assenmacher CA, Brisson B, Hendricks I, Wang XH, Herbst Z, Pyne N, Odonnell P, Shelton GD, Gelb M, Hackett N, Szabolcs P, Vite CH, Escolar M. Combination HSCT and intravenous AAV-mediated gene therapy in a canine model proves pivotal for translation of Krabbe disease therapy. Mol Ther. 2024 Jan 3;32(1):44-58. doi: 10.1016/j.ymthe.2023.11.014. Epub 2023 Nov 11.

  PMID: 37952085 DERIVED

• Heller G, Bradbury AM, Sands MS, Bongarzone ER. Preclinical studies in Krabbe disease: A model for the investigation of novel combination therapies for lysosomal storage diseases. Mol Ther. 2023 Jan 4;31(1):7-23. doi: 10.1016/j.ymthe.2022.09.017. Epub 2022 Oct 4.

  PMID: 36196048 DERIVED

Related Links

• Bascou, N., DeRenzo, A., Poe, M. \& Escolar, M., 2018. A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life. Orphanet Journal of Rare Diseases, pp. 1-17.
• Beltran-Quintero, M. et al., 2019. Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months. Orphanet Journal of Rare Diseases, pp. 1-13.
• Bradbury, A. et al., 2018. AAVrh10 Gene Therapy Ameliorates Central and Peripheral Nervous System Disease in Canine Globoid Cell Leukodystrophy (Krabbe Disease). Human Gene Therapy, pp. 785-801.
• Escolar, M. et al., 2005. Transplantation of Umbilical-Cord Blood in Babies with Infantile Krabbe's Disease. The New England Journal of Medicine, pp. 2069-2081.
• Escolar, M. et al., 2016. Clinical management of Krabbe disease. Journal of Neuroscience Research, pp. 1118-1125.
• Rafi, M., Luzi, P. \& Wenger, D., 2020. Conditions for combining gene therapy with bone marrow transplantation in murine Krabbe disease. BioImpacts, pp. 105-115.
• Bradbury et al. 2023.Combination HSCT and intravenous AAV-mediated gene therapy in a canine model proves pivotal for translation of Krabbe disease therapy. Molecular Therapy, November 2023:S1525-0016(23)00615-9.

MeSH Terms

Conditions

Leukodystrophy, Globoid Cell; Lysosomal Storage Diseases

Condition Hierarchy (Ancestors)

Hereditary Central Nervous System Demyelinating Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Leukoencephalopathies; Demyelinating Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Study Design

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

Model Details: Dose escalation study from a low dose to a high dose following safety review

Study Record Dates

• First Submitted: December 30, 2020
• First Posted: January 5, 2021
• Study Start: November 5, 2021
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2026
• Last Updated: January 30, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)