Krabbe Disease Clinical Trial
— REKLAIMOfficial title:
A Phase 1b Clinical Study of Intravenous AAVrh10 Vector Expressing GALC in Krabbe Subjects Who Previously Received Hematopoietic Stem Cell Transplantation (REKLAIM)
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, after more than 21 days of the HSCT (UCBT preferred HSCT source). Data from previously transplanted patients with infantile and late infantile Krabbe disease will be used as a comparator group.
Status | Recruiting |
Enrollment | 9 |
Est. completion date | July 2026 |
Est. primary completion date | July 2026 |
Accepts healthy volunteers | No |
Gender | All |
Age group | N/A to 18 Years |
Eligibility | Inclusion Criteria: 1. 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: 1. Galactocerebrosidase (GALC) activity levels in leukocytes compatible with the diagnosis of infantile Krabbe disease; AND AT LEAST ONE OF THE FOLLOWING: 2. Psychosine levels predictive of infantile onset by Dried Blood Spot (DBS); OR 3. Imaging or neurophysiological findings consistent with Krabbe disease (CSF, MRI, NCV, ABR); OR 4. Two GALC mutations predictive to result in infantile onset phenotype. 2. 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: 1. Galactocerebrosidase (GALC) activity levels in leukocytes compatible with the diagnosis of late infantile Krabbe disease; AND AT LEAST ONE OF THE FOLLOWING: 2. Psychosine levels predictive of late infantile onset by DBS; OR 3. Imaging or neurophysiological findings consistent with Krabbe disease (CSF, MRI, NCV, ABR); OR 4. Two GALC mutations predictive to result in late infantile onset phenotype; OR 5. Neurological/developmental exam findings consistent with late infantile Krabbe disease 3. Participants must be considered candidates for HSCT or have received HSCT at least 21 days prior to dosing date 4. 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. 5. Participant must have adequate organ function at time of screening or evaluation as measured by: 1. Ejection fraction of > 50% by echocardiogram or other appropriate study without evidence of pulmonary hypertension. 2. Pulmonary evaluation testing demonstrating resting pulse oximeter > 95% on room air. 6. Absence of active aspiration 7. 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 8. Parent(s) and/or legal guardian able to comply with the clinical protocol Exclusion Criteria: 1. 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. 2. History of prior treatment with a gene therapy product 3. Inability to actively move upper extremities against gravity 4. Grade 2 or higher abnormalities in LFTs, bilirubin, creatinine, white count, hemoglobin, platelets, PT/INR and PTT according to latest version of CTCAE 5. Presence of any neurocognitive deficit, motor deficit, or brain damage not attributable to Krabbe disease 6. 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. 7. Active bacterial or fungal infection documented the preceding 7 days. 8. Presence of any contraindication for MRI or lumbar puncture (LP) 9. Use of any investigational product prior to study enrollment or current enrollment in another study that involves clinical interventions 10. Immunizations with live viruses in the 30 days prior to immune suppression 11. 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) 12. 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 |
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 |
Lead Sponsor | Collaborator |
---|---|
Forge Biologics, Inc |
United States,
Bascou N, DeRenzo A, Poe MD, Escolar ML. A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life. Orphanet J Rare Dis. 2018 Aug 9;13(1):126. doi: 10.1186/s13023-018-0872-9. — View Citation
Beltran-Quintero ML, Bascou NA, Poe MD, Wenger DA, Saavedra-Matiz CA, Nichols MJ, Escolar ML. Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months. Orphanet J Rare Dis. 2019 Feb 18;14(1):46. doi: 10.1186/s13023-019-1018-4. — View Citation
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. — View Citation
Escolar ML, Poe MD, Provenzale JM, Richards KC, Allison J, Wood S, Wenger DA, Pietryga D, Wall D, Champagne M, Morse R, Krivit W, Kurtzberg J. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med. 2005 May 19;352(20):2069-81. doi: 10.1056/NEJMoa042604. — View Citation
Escolar ML, Poe MD, Smith JK, Gilmore JH, Kurtzberg J, Lin W, Styner M. Diffusion tensor imaging detects abnormalities in the corticospinal tracts of neonates with infantile Krabbe disease. AJNR Am J Neuroradiol. 2009 May;30(5):1017-21. doi: 10.3174/ajnr.A1476. Epub 2009 Apr 22. — View Citation
Escolar ML, West T, Dallavecchia A, Poe MD, LaPoint K. Clinical management of Krabbe disease. J Neurosci Res. 2016 Nov;94(11):1118-25. doi: 10.1002/jnr.23891. — View Citation
Gupta A, Poe MD, Styner MA, Panigrahy A, Escolar ML. Regional differences in fiber tractography predict neurodevelopmental outcomes in neonates with infantile Krabbe disease. Neuroimage Clin. 2014 Sep 26;7:792-8. doi: 10.1016/j.nicl.2014.09.014. eCollection 2015. — View Citation
Rafi MA, Luzi P, Wenger DA. Conditions for combining gene therapy with bone marrow transplantation in murine Krabbe disease. Bioimpacts. 2020;10(2):105-115. doi: 10.34172/bi.2020.13. Epub 2020 Mar 24. — View Citation
Wright MD, Poe MD, DeRenzo A, Haldal S, Escolar ML. Developmental outcomes of cord blood transplantation for Krabbe disease: A 15-year study. Neurology. 2017 Sep 26;89(13):1365-1372. doi: 10.1212/WNL.0000000000004418. Epub 2017 Aug 30. — View Citation
Yoon IC, Bascou NA, Poe MD, Szabolcs P, Escolar ML. Long-term neurodevelopmental outcomes of hematopoietic stem cell transplantation for late-infantile Krabbe disease. Blood. 2021 Apr 1;137(13):1719-1730. doi: 10.1182/blood.2020005477. — View Citation
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 | ||
Secondary | Efficacy as assessed by improvement of gross motor function as measured longitudinally by PDMS-2, BOT-3, or by GMFM-88, depending on the age, compared to patients receiving HSCT only | 12 months and 24 months |
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