Gene Transfer Clinical Trial for Krabbe Disease

Krabbe Disease Clinical Trial

— RESKUE  

Official title:

A Phase 1/2 Clinical Study of Intravenous Gene Transfer With an AAVrh10 Vector Expressing GALC in Krabbe Subjects Receiving Hematopoietic Stem Cell Transplantation (RESKUE)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04693598
• Other study ID #: FBX-101-RESKUE
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: November 5, 2021
• Est. completion date: July 2024

Study information

• Verified date: April 2024
• Source: Forge Biologics, Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 6
• Est. completion date: July 2024
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Day to 12 Months

Eligibility

Inclusion Criteria:

1. 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.

2. Age at the time of screening: 1 day to 12 months

3. 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

4. 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

5. Parent(s) and/or legal guardian able to comply with the clinical protocol

6. 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)

Exclusion Criteria:

1. History of prior treatment with a gene therapy product

2. Presence of major congenital anomaly or any other condition that affects neurodevelopmental function

3. Presence of any neurocognitive deficit or brain damage not attributable to Krabbe disease

4. Active aspiration

5. Signs of active infection or disease from cytomegalovirus, adenovirus or other viruses

6. HIV positive

7. Uncontrolled and progressive bacterial or fungal infection

8. Presence of any contraindication for MRI

9. Use of any investigational product prior to study enrollment or current enrollment in another study that involves clinical interventions

10. Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the PI, would preclude participation in the study

11. 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.

Related Conditions & MeSH terms

• Krabbe Disease
• Leukodystrophy, Globoid Cell

Intervention

Biological:
• FBX-101
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.

Locations

Country	Name	City	State
United States	University of Michigan Hospitals - Michigan Medicine	Ann Arbor	Michigan
United States	Children's Hospital of Orange County (CHOC)	Orange	California

Sponsors (1)

Lead Sponsor	Collaborator
Forge Biologics, Inc

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety as assessed by incidence and severity of adverse events and serious adverse events that are attributed to FBX-101.		24 months
Primary	Safety as assessed by HSCT incident of engraftment.		24 months
Secondary	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
Secondary	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

External 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 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.
•   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.
•   Yoon, I., et al., 2021. Long-term neurodevelopmental outcomes of hematopoietic stem cell transplantation for late-infantile Krabbe disease. Blood, pp. 1719-1730