Gene Transfer Clinical Trial for Krabbe Disease (RESKUE)

• ClinicalTrials.gov Identifier: NCT04693598
• Recruitment Status: Recruiting
• First Posted: January 5, 2021
• Last Update Posted: September 17, 2021
• Sponsor: Forge Biologics, Inc
• Information provided by (Responsible Party): Forge Biologics, Inc

Study Description

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

Study Design

• 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: September 2021
• Estimated Primary Completion Date: April 2023
• Estimated Study Completion Date: April 2023

Arms and Interventions

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

Outcome Measures

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 ]

Eligibility Criteria

• 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

Contacts and Locations

Contacts

Contact: Medical Affairs; 3305549257; medicalaffairs@forgebiologics.com

Locations

United States, Pennsylvania

UPMC Children's Hospital of Pittsburgh; Recruiting

Pittsburgh, Pennsylvania, United States, 15224

Contact: Brie Yanniello 412-692-6350 yanniellob@upmc.edu

Principal Investigator: Randy M Windreich, MD

Sub-Investigator: Maria Escolar, MD

Sponsors and Collaborators

Forge Biologics, Inc

Investigators

• Principal Investigator: Randy Windreich; Clinical Director, Division of Blood and Marrow Transplantation and Cellular Therapies, UPMC Children's Hospital of Pittsburgh

More Information

Additional Information:

Bascou, N., DeRenzo, A., Poe, M. &amp; 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. &amp; Wenger, D., 2020. Conditions for combining gene therapy with bone marrow transplantation in murine Krabbe disease. BioImpacts, pp. 105-115. 

• Responsible Party: Forge Biologics, Inc
• ClinicalTrials.gov Identifier: NCT04693598
• Other Study ID Numbers: FBX-101
• First Posted: January 5, 2021
• Last Update Posted: September 17, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: There is no plan to share data

• 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:

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