Gene Transfer Clinical Trial for Infantile and Late Infantile Krabbe Disease Treated in the Past With HSCT (REKLAIM)

• ClinicalTrials.gov Identifier: NCT05739643
• Recruitment Status: Recruiting
• First Posted: February 22, 2023
• Last Update Posted: August 25, 2023
• Sponsor: Forge Biologics, Inc
• Information provided by (Responsible Party): Forge Biologics, Inc

Tracking Information

• First Submitted Date: February 13, 2023
• First Posted Date: February 22, 2023
• Last Update Posted Date: August 25, 2023
• Actual Study Start Date: February 3, 2023
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 13, 2023): Safety as assessed by incidence and severity of adverse events and serious adverse events that are attributed to FBX-101 [ Time Frame: 24 months ]
• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures (submitted: May 10, 2023): Efficacy as assessed by improvement of gross motor function as measured longitudinally by Gross Motor Function Measure 88 (GMFM-88) compared to untreated patients or those receiving HSCT only [ Time Frame: 12 months and 24 months ]
• Original Secondary Outcome Measures (submitted: February 13, 2023): Efficacy as assessed by improvement of gross motor function as measured longitudinally by Gross Motor Function Measure 88 (GMFM-88) compared to untreated patients of those receiving HSCT only [ Time Frame: 12 months and 24 months ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Gene Transfer Clinical Trial for Infantile and Late Infantile Krabbe Disease Treated in the Past With HSCT
• Official Title: A Phase 1b Clinical Study of Intravenous AAVrh10 Vector Expressing GALC in Krabbe Subjects Who Previously Received Hematopoietic Stem Cell Transplantation (REKLAIM)
• Brief Summary: This is a non-blinded, non-randomized dose escalation study of intravenous FBX-101 in which subjects who have previously received hematopoietic stem cell transplant will receive a single infusion of an adeno-associated virus gene therapy product. Data from untreated and previously transplanted patients with infantile and late infantile Krabbe disease will be used as a comparator group.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

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

• Condition: Krabbe Disease

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.

Other Name: AAVrh.10-hGALC

Study Arms

• Experimental: Cohort 1 - Low Dose FBX-101 (aka AAVrh.10-GALC)
  Group 1: N=3 patients with Infantile Krabbe disease with previous HSCT will receive a single infusion at the low dose Group 2: N=3 patients with Late Infantile Krabbe disease with previous HSCT will receive a single infusion at the low dose
  Intervention: Biological: FBX-101
• Experimental: Cohort 2 - High Dose FBX-101 (aka AAVrh.10-GALC)
  Group 1: N=3 patients with Infantile Krabbe disease with previous HSCT will receive a single infusion at the high dose Group 2: N=3 patients with Late Infantile Krabbe disease with previous HSCT will receive a single infusion at the high dose
  Intervention: Biological: FBX-101

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 13, 2023): 12
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Group 1: Subjects transplanted for infantile onset Krabbe disease (IKD onset <12 months) 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. Elevated 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 2: Subjects transplanted for late infantile onset Krabbe (LIKD onset 12-47 months) with signs or symptoms of Krabbe disease, and 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. Elevated 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 have received HSCT at least 90 days prior to dosing date
4. Chimerism should reflect at least 30% of myeloid cells from the donor by month 3 post-transplant or 10% by one-year post-transplant that result in GALC leukocyte levels > or equal to 0.2 nmol/h/mg.
5. 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
6. 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
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
7. Active bacterial or fungal infection documented in 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. Ejection fraction of <50% by echocardiogram or other appropriate study without evidence of pulmonary hypertension
12. 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)
13. 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No

Contacts

Contact: Michelle Salvo; 380-239-2013; advocacy@forgebiologics.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05739643
• Other Study ID Numbers: FBX-101-REKLAIM
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Forge Biologics, Inc
• Original Responsible Party: Same as current
• Current Study Sponsor: Forge Biologics, Inc
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Forge Biologics, Inc
• Verification Date: August 2023