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Study of Safety, Tolerability and Efficacy of PBKR03 in Pediatric Subjects With Early Infantile Krabbe Disease (GALax-C)

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ClinicalTrials.gov Identifier: NCT04771416
Recruitment Status : Not yet recruiting
First Posted : February 25, 2021
Last Update Posted : February 25, 2021
Sponsor:
Information provided by (Responsible Party):
Passage Bio, Inc.

Brief Summary:
PBKR03 is a gene therapy for Krabbe Disease (Globoid cell leukodystrophy) intended to deliver a functional copy of the GALC gene to the brain and peripheral tissues. This study will evaluate the safety, tolerability and efficacy of this treatment by first evaluating two different doses in two different age groups, then confirming the optimal dose to be used for confirmation of safety and efficacy.

Condition or disease Intervention/treatment Phase
Leukodystrophy, Globoid Cell Biological: PBKR03 Phase 1 Phase 2

Detailed Description:

PBKR03 is an adeno-associated viral vector serotype Hu68 carrying the gene encoding for human galactosylceramidase, GALC, formulated as a solution for injection into the cisterna magna.

This is a global interventional, multicenter, single-arm, dose escalation, study of PBKR03 delivered as a one-time dose administered into the cisterna magna of subjects with early infantile Krabbe Disease.

The dose-ranging portion of the study will enroll independent dose escalation cohorts in two age groups of subjects with early infantile Krabbe disease:

  • Cohort 1: 3 subjects aged ≥4 to <9 months will receive the low dose (Dose I)
  • Cohort 2: 3 subjects aged ≥4 to <9 months will receive the high dose (Dose II)
  • Cohort 3: 3 subjects aged ≥1 to <4 months will receive the low dose (Dose I)
  • Cohort 4: 3 subjects aged ≥1 to <4 months will receive the high dose (Dose II)

Part 1 of the study will enroll a total of four cohorts, enrolled sequentially with separate age-based dose-escalation cohorts. Enrollment will initiate in Cohort 1. Following completion of Cohort 1, simultaneous enrollment in Cohort 2 and Cohort 3 will occur. Cohort 4 will follow completion of cohort 3.

The confirmatory cohort, Part 2, will enroll subjects with early infantile Krabbe Disease, aged >1 to <9 months. These subjects will receive a dose chosen based on the data obtained in part 1 of the study This will be a 2-year study with a 3-year safety extension.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Open-label, multi-center, dose escalation
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Open-Label, Multicenter Dose-Ranging and Confirmatory Study to Assess the Safety, Tolerability and Efficacy of PBKR03 Administered to Pediatric Subjects With Early Infantile Krabbe Disease (Globoid Cell Leukodystrophy)
Estimated Study Start Date : June 2021
Estimated Primary Completion Date : January 2027
Estimated Study Completion Date : January 2030


Arm Intervention/treatment
Experimental: Part 1: Dose Escalation Cohorts designed to identify the optimal dose of PBKR03

Cohort 1: Subjects aged >4 to <9 months Drug: PBKR03 1.5 x 10^11 GC/g* Single dose of PBKR03, via intra cisterna magna

Cohort 2: Subjects aged >4 to <9 months Drug: PBKR03 5.0 x 10^11 GC/g* Single dose of PBKR03, via intra cisterna magna

Cohort 3: Subjects aged >1 to <4 months Drug: PBKR03 1.5 x 10^11 GC/g* Single dose of PBKR03, via intra cisterna magna

Cohort 4: Subjects aged >1 to <4 months Drug: PBKR03 5.0 x 10^11 GC/g* Single dose of PBKR03, via intra cisterna magna

*GC/g: genome copiesy per gram of estimated brain weight

Biological: PBKR03
Single dose of PBKR03, via intra cisterna magna

Experimental: Part 2: Expansion Cohort designed to confirm the safety and efficacy of PBKR03

Cohort 5: Subjects aged >1 to <9 months Drug: PBKR03 Single dose of PBKR03, via intra cisterna magna Dose to be used for the confirmatory cohorts in Part 2 will be defined after a review of data from Part 1.

*GC/g: genome copiesy per gram of estimated brain weight

Biological: PBKR03
Single dose of PBKR03, via intra cisterna magna




Primary Outcome Measures :
  1. Number of participants with treatment-related adverse events (AEs) and serious adverse events (SAEs) at Grade 3 or higher within 24 months of dosing [ Time Frame: Up to 5 years (multiple visits) ]
    Assess the number of adverse events and serious adverse events at Grade 3 or higher as assessed by CTCAEv5.0

  2. Change from baseline in nerve conduction and velocity in motor nerve conduction studies [ Time Frame: From baseline to 5 years (multiple visits) ]
    NCS will measure velocity and amplitude in distal segments of the median, peroneal and tibial motor nerves to evaluate effects on peripheral nerve integrity.

  3. Change from baseline in nerve conduction and velocity in sensory nerve conduction studies [ Time Frame: From baseline to 5 years (multiple visits) ]
    NCS will measure velocity and amplitude in distal segments of the sural, radial and median sensory nerves to evaluate effects on peripheral nerve integrity

  4. Number of Participants with Clinically Significant Laboratory Abnormalities as Measured Using Hematology, Chemistry and Coagulation Tests [ Time Frame: Up to 5 years (multiple visits) ]
    Assess the number of participants with clinically significant laboratory changes including hematology, serum chemistry, and coagulation tests

  5. Assess Humoral Response Against the Vector and Transgene in Serum [ Time Frame: Up to 5 years (multiple visits) ]
    Assess serum antibody titers against AAVhu68 and against GALC following ICM administration of PBKR03

  6. Assess Humoral Response Against the Vector and Transgene in CSF [ Time Frame: Up to 5 years (multiple visits) ]
    Assess antibody titers in the cerebrospinal fluid against AAVhu68 and against GALC following ICM administration of PBKR03


Secondary Outcome Measures :
  1. Change from Baseline in Developmental Milestones as Assessed by the Bayley Scale of Infant and Toddler Development, Third Edition [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess changes in the developmental age and the total number of developmental milestones using the Bayley Scale of Infant and Toddler Development, Third Edition instrument

  2. Change from Baseline in Developmental Milestones as Assessed by the Vineland Adaptive Behavior Scale-II [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess changes in the developmental age and the total number of developmental milestones using the Vineland Adaptive Behavior Scale-II instrument

  3. Change in Biomarkers of GALC Activity in Blood [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in biomarkers of GALC activity in blood when compared with baseline

  4. Change in Biomarkers of GALC Activity in CSF [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in biomarkers of GALC activity when compared with baseline

  5. Change in Biomarkers of GALC Substrates in Blood [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in concentration of GALC substrates in blood

  6. Change in Biomarkers of GALC Substrates in CSF [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in concentration of GALC in CSF when compared with baseline

  7. Change in Concentration of Biomarker of Disease Progression in Plasma [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in neurofilament light chain (NfL) concentration as a marker for neurodegeneration and disease progression in plasma

  8. Change in Concentration of Biomarker of Disease Progression in CSF [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in neurofilament light chain concentration (NfL) as a marker for neurodegeneration and disease progression in CSF

  9. Change in Brain Anatomy as Assessed by MRI [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in disease severity, volumetric MRI measures, brain diffusivity, and white matter lesions by MRI imaging

  10. Change in Quality of Life Using Pediatric Quality of Life Scale [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in quality of life as measured by Pediatric Quality of Life Scale (Peds QL)

  11. Change in Quality of Life Using Pediatric Quality of Life Scales [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in quality of life as measured by the Pediatric Quality of Life - Infant Scale (PedsQL-IS)

  12. Change in Ventilator-Free Survival Compared with Natural History Data [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change compared with natural history data in ventilator-free survival and chronic ventilatory support.

  13. Incidence of Feeding Tube Placement at or Before Month 24 [ Time Frame: 24 months ]
    Though speech and swallowing assessment, study participants will be evaluated to determine whether a feeding tube is warranted



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Month to 9 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. > 1 month and < 9 months of age at enrollment, either presymptomatic or symptomatic with first symptoms of Krabbe Disease at < 6 months of age
  2. Leukocyte GALC activity below lower limit of normal (LLN)
  3. Whole blood psychosine > 10 nM
  4. Biallelic pathogenic GALC gene variants previously associated with early infantile Krabbe Disease or variants classified as likely pathogenic
  5. Parents or the subject's legally authorized representative provide written informed consent prior to any study-related procedures, including screening evaluations
  6. Symptomatic subjects must exhibit a minimum level of neurological and developmental function that indicates that they have the potential to benefit from treatment, at least with slowing or stabilization of their disease. In particular, the subject must demonstrate the following clinical features (when age-appropriate):

    • Thrusting of legs in play
    • Lifting of head
    • Eyes follow moving person
    • Smiles in response to speaker's attention

Exclusion Criteria:

  1. Any clinically significant neurocognitive deficit not attributable to Krabbe Disease or any other condition that may, in the opinion of the investigator, confound interpretation of study results.
  2. If a subject had an acute illness requiring hospitalization within 30 days of enrollment, the history must be discussed with the sponsor's medical monitor before allowing the subject to be enrolled.
  3. History of chronic ventilation assisted respiratory support (defined as more than 12 hours/day of bilevel positive airway pressure, continuous positive airway pressure (CPAP) or ventilator) or a need for tracheostomy as a result of their disease. Note: This does not exclude patients who use respiratory vests.
  4. Intractable seizure or uncontrolled epilepsy defined as having had an episode of status epilepticus, or seizures requiring hospitalization.
  5. Family history of seizures or epilepsy of infantile or childhood onset, other than febrile seizures. This does not exclude subjects with a family history of Krabbe disease.
  6. Any contraindication to the ICM administration procedure, including contraindications to fluoroscopic imaging, intrathecal contrast and anesthesia or any condition that would increase the risk of adverse outcomes from the ICM procedure including, but not limited to, the presence of a space occupying lesion, aberrant vascular anatomy or congenital anatomical abnormalities such as a Chiari malformation.
  7. Any contraindication to MRI or lumbar puncture (LP).
  8. Prior gene therapy.
  9. Enrollment in any other clinical study with an investigational product within 4 weeks prior to Screening or within 5 half-lives of the investigational product used in that clinical study, whichever is longer.
  10. Prior Hematopoietic Stem Cell Transplantation (HSCT)
  11. Receipt of a vaccine within 14 days prior to or after dosing.
  12. Estimated glomerular filtration rate (eGFR) <60 mL/minute/1.73 m2 based on creatinine
  13. Hematological abnormalities

    • Coagulopathy (INR > 1.5) or activated partial thromboplastin time [aPTT] > 40 seconds
    • WBC < 5.5 x 103 cells/ μL
    • Hemoglobin <10 g/dL
    • Thromobcytopenia (platelet count < 100,000 per μL.)
  14. AST or ALT > 3 times the upper limit of normal (ULN) or total bilirubin > 1.5x ULN
  15. Abnormal respiratory function

    1. Required suctioning in the absence of upper respiratory tract infection
    2. Hypoxemia (oxygen [O2] saturation awake less than 96% or O2 saturation asleep less than 96%, without ventilation support) as assessed during screening. Ventilatory support is defined as dependence on supplemental O2 or use of a ventilator or bilevel positive airway pressure (BiPap) or continuous positive airway pressure (Cpap) machine.
  16. Poor peripheral perfusion or temperature instability in the absence of intercurrent illness
  17. Medical conditions or laboratory or vital sign abnormalities that would increase risk of complications from intra-cisterna magna injection, anesthesia, fluoroscopy, LP, and/or MRI
  18. Any condition (e.g., history of any disease, evidence of any current disease, any finding upon physical examination, or any laboratory abnormality) that, in the opinion of the investigator, would put the subject at undue risk during the administration procedure or would interfere with evaluation of PBKR01 or interpretation of subject safety or study results.

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): NCT04771416


Contacts
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Contact: Patient/Family Inquiries 267-866-0133 patientservices@passagebio.com
Contact: Physician Inquiries medinfo@passagebio.com

Locations
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United States, Illinois
Ann & Robert Lurie
Chicago, Illinois, United States, 60611
United States, New York
New York-Presbyterian
New York, New York, United States, 10065
United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Utah
University of Utah School of Medicine
Salt Lake City, Utah, United States, 84132
Brazil
Hospital De Clinicas De Porto Alegre
Porto Alegre, Brazil
Canada
Montreal Children's Hospital
Montréal, Canada
Israel
Shaare Zadek Medical Center
Jerusalem, Israel
Netherlands
Amsterdam UMC
Amsterdam, Netherlands
United Kingdom
Manchester University
Manchester, United Kingdom
Sponsors and Collaborators
Passage Bio, Inc.
Investigators
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Study Director: D. Elizabeth McNeil, MD, MSc Passage Bio, Inc.
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Responsible Party: Passage Bio, Inc.
ClinicalTrials.gov Identifier: NCT04771416    
Other Study ID Numbers: PBKR03-001
2020-005229-95 ( EudraCT Number )
First Posted: February 25, 2021    Key Record Dates
Last Update Posted: February 25, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Passage Bio, Inc.:
infantile
early infantile
Krabbe Disease
Rare disease
Leukodystrophy
GALC
Lysosomal storage disease
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