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Gene Transfer Clinical Trial for Krabbe Disease (RESKUE)

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ClinicalTrials.gov Identifier: NCT04693598
Recruitment Status : Not yet recruiting
First Posted : January 5, 2021
Last Update Posted : January 7, 2021
Sponsor:
Information provided by (Responsible Party):
Forge Biologics, Inc

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 compared as a control group.

Condition or disease Intervention/treatment Phase
Krabbe Disease Biological: FBX-101 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Dose escalation study from a low dose to a high dose following safety review
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Estimated Study Start Date : January 2021
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : April 2023


Arm Intervention/treatment
Experimental: Cohort 1 - Low Dose FBX-101 (aka AAVrh.10-GALC)
Participants will receive a single infusion at the lower dose (N=3 participants)
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.
Other Name: AAVrh.10-hGALC

Experimental: Cohort 2 - High Dose FBX-101 (aka AAVrh.10-GALC)
Participants will receive a single infusion at the higher dose (N=3 participants)
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.
Other Name: AAVrh.10-hGALC




Primary Outcome Measures :
  1. Safety as assessed by less than 3 incidents of organ specific AEs/SAEs at Grade 3 or higher based on CTCAE criteria attributed to the AAV administration. [ Time Frame: 12 months ]
  2. Safety as assessed by lack of HSCT engraftment. [ Time Frame: 12 months ]

Secondary Outcome Measures :
  1. Efficacy as assessed by improvement of the probability to achieve independent sitting compared to patients receiving HSCT. [ Time Frame: 24 months ]
  2. Efficacy as assessed by improvement of gross motor function as measured by PDMS above a functional age equivalent of 12 months by 2 years post treatment. [ Time Frame: 24 months ]

Other Outcome Measures:
  1. Exploratory endpoint as assessed by change in motor function as measured by GMFM88 and Adaptive Behavior compared to patients receiving HSCT only. [ Time Frame: 12 months and 24 months ]
  2. Exploratory endpoint as assessed by change in auditory brainstem responses compared to patients receiving HSCT only. [ Time Frame: 12 months and 24 months ]
    The brainstem auditory evoked responses are considered abnormal if either the interpeak latency of waves I to V is prolonged or if any of the obligate wave forms (I, III, or V) are missing.

  3. Exploratory endpoint as assessed by change in peripheral nerve conduction velocity compared to patients receiving HSCT only. [ Time Frame: 24 months ]
  4. Exploratory endpoint as assessed by change in brain MRI as measured by DTI compared to patients receiving HSCT only. [ Time Frame: 12 months and 24 months ]
  5. Exploratory endpoint as assessed by reduced diseased manifestation using biomarkers measuring reduction of psychosine levels and increase in GALC enzyme activities in the blood compared to patients receiving HSCT only. [ Time Frame: 12 months and 24 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 12 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Diagnosis of infantile Krabbe disease, characterized by the following criteria outlined below:

    • Galactocerebrosidase (GALC) activity < 0.20 nmol/h/mg protein in leukocytes; AND AT LEAST ONE OF THE FOLLOWING:
    • Elevated psychosine predictive of infantile disease ≥ 9.0 nmol/L; OR
    • Imaging or neurophysiological findings consistent with Krabbe disease (CSF, MRI, NCV, ABR); OR
    • Two predicted pathogenic GALC mutations.
  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)
  4. Participant's parent 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. Participants must have a 4/6, 5/6 or 6/6 HLA matched UCB unit available with a pre-cryopreservation total nucleated cell dose of ≥ 5 x 10^7 cells/kg
  7. Participant must have adequate organ function at time of screening as measured by:

    • Creatinine ≤ 0.6 mg/dL and creatinine clearance ≥ 60 mL/min/1.73 m2 by nuclear medicine GFR
    • 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 > 92% on room air Coagulation tests within 110% of normal ranges for age. (PT/INR and PTT)

Exclusion Criteria:

  1. History of allogeneic HCT within 4 months
  2. History of prior treatment with a gene therapy product
  3. Presence of major congenital anomaly affecting the neurological system
  4. Presence of any neurocognitive deficit not attributable to Krabbe disease
  5. Premature birth at less than 35 weeks' gestation
  6. Active aspiration
  7. Signs of infection or disease from active cytomegalovirus, adenovirus or other viruses
  8. HIV positive
  9. Uncontrolled and progressive bacterial, viral, or fungal infection.
  10. Presence of any contraindication for MRI
  11. Use of any investigational product prior to study enrollment or current enrollment in another study that involves clinical interventions
  12. Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the PI, would preclude participation in the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04693598


Contacts
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Contact: Medical Affairs 3305549257 medicalaffairs@forgebiologics.com

Locations
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United States, Pennsylvania
UPMC Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15224
Contact: Jodi Martin    412-692-6351    sausjl@upmc.edu   
Principal Investigator: Jessie Barnum, MD         
Sub-Investigator: Maria Escolar, MD         
Sponsors and Collaborators
Forge Biologics, Inc
Investigators
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Principal Investigator: Jessie Barnum, MD Div. of Blood & Marrow Transplantation & Cellular Therapies, UPMC Children's Hospital of Pittsburgh
Additional Information:
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Responsible Party: Forge Biologics, Inc
ClinicalTrials.gov Identifier: NCT04693598    
Other Study ID Numbers: FBX-101
First Posted: January 5, 2021    Key Record Dates
Last Update Posted: January 7, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no plan to share data

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Forge Biologics, Inc:
Lysosomal Storage Disorder
Globoid Cell Leukodystrophy
Leukodystrophy
GALC
Additional relevant MeSH terms:
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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