Gene Transfer Clinical Trial for Infantile and Late Infantile Krabbe Disease Treated Previously With HSCT

Study Overview
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Brief Summary
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This is a non-blinded, non-randomized dose escalation study of intravenous FBX-101 in which subjects will receive a single infusion of an adeno-associated virus gene therapy product. Data from previously transplanted patients with infantile and late infantile Krabbe disease will be used as a comparator group.

Detailed Description
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The FBX-101-REKLAIM study has been modified on Q4 2023 to allow a broader patient recruitment of infantile and late infantile Krabbe patients. The updated REKLAIM study merges the recruitment populations of the previous FBX-101-RESKUE clinical trial (NCT04693598) and the FBX-101-REKLAIM clinical trial (NCT05739643).

Official Title
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A Phase 1b Clinical Study of Intravenous AAVrh10 Vector Expressing GALC in Krabbe Subjects Who Previously Received Hematopoietic Stem Cell Transplantation (REKLAIM)

Conditions
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Krabbe Disease

Intervention / Treatment
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* Biological: FBX-101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Group Infantile Krabbe: Subjects who are going to be transplanted or have already been transplanted for asymptomatic infantile onset Krabbe disease with initial diagnosis based on: Galactocerebrosidase (GALC) activity levels in leukocytes compatible with the diagnosis of infantile Krabbe disease; AND AT LEAST ONE OF THE FOLLOWING: Psychosine levels predictive of infantile onset by Dried Blood Spot (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. Group Late Infantile Krabbe: Subjects who are going to be transplanted or have already been transplanted for symptomatic late infantile onset Krabbe with initial diagnosis based on: Galactocerebrosidase (GALC) activity levels in leukocytes compatible with the diagnosis of late infantile Krabbe disease; AND AT LEAST ONE OF THE FOLLOWING: Psychosine levels predictive of late infantile onset by DBS; OR Imaging or neurophysiological findings consistent with Krabbe disease (CSF, MRI, NCV, ABR); OR Two GALC mutations predictive to result in late infantile onset phenotype; OR Neurological/developmental exam findings consistent with late infantile Krabbe disease Participants must be considered candidates for HSCT or have received HSCT at least 21 days prior to dosing date For patients already transplanted and followed for more than 3 months chimerism should reflect at least 30% of myeloid cells from the donor by month 3 post-transplant, from 30 to 10% between 3 months and one year post-transplant or 10% by one year post-transplant. Participant must have adequate organ function at time of screening or evaluation as measured by: 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. Absence of active aspiration Participant's parents or legal guardian consent to participate in the study and provide informed consent according to IRB/IEC guidelines prior to any study procedures being performed Parent(s) and/or legal guardian able to comply with the clinical protocol Exclusion Criteria: Immunoassay with total anti-AAVrh10 antibody titers of >1:100. This criteria will not apply to children screened before they have received HSCT or for children who sign the inform consent within 60 days from HSCT. History of prior treatment with a gene therapy product Inability to actively move upper extremities against gravity Grade 2 or higher abnormalities in LFTs, bilirubin, creatinine, white count, hemoglobin, platelets, PT/INR and PTT according to latest version of CTCAE Presence of any neurocognitive deficit, motor deficit, or brain damage not attributable to Krabbe disease Signs of active infections or disease from cytomegalovirus, adenovirus, EBV, hepatitis B or C, and HIV or other viruses excluding rhinovirus from RVP and asymptomatic norovirus presence in stool. Patients showing HIV positive results will be excluded from the study. Active bacterial or fungal infection documented the preceding 7 days. Presence of any contraindication for MRI or lumbar puncture (LP) Use of any investigational product prior to study enrollment or current enrollment in another study that involves clinical interventions Immunizations with live viruses in the 30 days prior to immune suppression Active acute Graft Versus Host Disease (GvHD) Grade II or higher according to modified Glucksberg criteria (Przepiorka et al., 1995) or active, moderate or severe, chronic GvHD according to revised NIH criteria (Jagasia et al., 2015) Any other medical condition, serious intercurrent illness, other genetic condition or extenuating circumstance that, in the opinion of the PI, would preclude participation in the study
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation study from a low dose to a high dose following safety review
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - Low Dose FBX-101 (aka AAVrh.10-GALC)<br>N=3 patients with Infantile or Late Infantile Krabbe disease will receive a single infusion at the low dose | Biological: FBX-101<br>* 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.<br>* Other names: AAVrh.10-hGALC;|
| Experimental: Cohort 2 - High Dose FBX-101 (aka AAVrh.10-GALC)<br>N=3-6 patients with Infantile or Late Infantile Krabbe disease will receive a single infusion at the high dose | Biological: FBX-101<br>* 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.<br>* Other names: AAVrh.10-hGALC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as assessed by incidence and severity of adverse events and serious adverse events that are attributed to FBX-101 |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as assessed by improvement of gross motor function as measured longitudinally by PDMS-2, BOTMP2, or by GMFM-88, depending on the age, compared to patients receiving HSCT only |  | 12 months and 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukodystrophy, Globoid Cell, 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, Lipidoses, Lipid Metabolism, Inborn Errors, Lysosomal Storage Diseases, Metabolic Diseases, Lipid Metabolism Disorders