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    EudraCT Number:2020-005229-95
    Sponsor's Protocol Code Number:PBKR03-001
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-03-19
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2020-005229-95
    A.3Full title of the trial
    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) (GALax-C)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess safety, tolerability and efficacy of PBKR03 in pediatric subjects with Krabbe disease (GALax-C)
    A.3.2Name or abbreviated title of the trial where available
    Study of Safety, Tolerability and Efficacy of PBKR03 in Pediatric Subjects with Early Infantile Krab
    A.4.1Sponsor's protocol code numberPBKR03-001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPassage Bio, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPassage Bio, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPassage Bio, Inc.
    B.5.2Functional name of contact pointSamiah Al-Zaidy
    B.5.3 Address:
    B.5.3.1Street AddressOne Commerce Square, 2005 Market Street, 39th Floor
    B.5.3.2Town/ cityPhiladelphia
    B.5.3.3Post codePA 19103
    B.5.3.4CountryUnited States
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/21/2417
    D.3 Description of the IMP
    D.3.2Product code PBKR03
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntracisternal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available yet
    D.3.9.2Current sponsor codePBKR03
    D.3.9.3Other descriptive nameAdeno-associated virus serotype hu68 containing the human GALC gene
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number14100000000000 to 80000000000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D. cell therapy medicinal product No
    D. therapy medical product Yes
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive lysosomal storage disease (LSD) caused by mutations in the gene encoding the hydrolytic enzyme galactosylceramidase (galactocerebrosidase; GALC)
    E.1.1.1Medical condition in easily understood language
    In people suffering from Krabbe disease, the gene (GALC) that carries instructions to make a specific protein, called an enzyme, does not work properly
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10023492
    E.1.2Term Krabbe's disease
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety and tolerability of PBKR03 following administration of a single dose into the cisterna magna
    E.2.2Secondary objectives of the trial
    To assess the efficacy of PBKR03
    To assess the pharmacokinetics of PBKR03
    To assess the effects of PBKR03 on pharmacodynamic and disease biomarkers
    To assess the effects of PBKR03 on disease progression
    To assess the effects of PBKR03 on quality of life and healthcare resource utilization

    Explorative objective:
    To assess efficacy using in-home video recordings
    E.2.3Trial contains a sub-study No
    E.3Principal 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 the lower limit of normal (LLN) of the testing central laboratory (e.g., <0.30 nmol/hour/mg protein )
    3. Whole blood psychosine >10 nM
    4. Biallelic pathogenic GALC gene variants associated with early infantile Krabbe disease or variants classified as likely pathogenic (testing must be done at a Clinical Laboratory Improvement Amendments [CLIA] or CLIA-equivalent laboratory certified per local standard. If the GALC gene analysis is performed in the UK or the European Union (EU) a Conformité Européenne (CE) marked test will be used). See also Appendix 2, Classification of GALC Gene Variants.
    Note: Subjects without documentation of two pathogenic or likely pathogenic GALC variants but who meet all other inclusion criteria, including low GALC activity and high psychosine level, may be considered eligible for the study. In this case the totality of the available data, including relevant family history, must be consistent with a diagnosis of early infantile Krabbe disease.
    5. Parents or the subject’s legally authorized representative (LAR) provide(s) 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 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):
    a. Thrusting of legs in play (Bayley motor scale, gross motor subset, item 1)
    b. Lifting of head (Bayley motor scale, gross motor subset, item 3)
    c. Eyes follow moving person (Bayley motor scale, fine motor subset, item 2)
    d. Smiles in response to speaker’s attention (Bayley language scale, expressive, item 2)
    E.4Principal exclusion criteria
    1. Any clinically significant neurocognitive deficit not attributable to KD
    2. An acute illness requiring hospitalization within 30 days of enrollment, that, in the opinion of the Investigator, would interfere with the evaluation of the investigational product or interpretation of subject safety or study results.
    3. History of chronic ventilation assisted respiratory support (= use of more than 12 h/day of BiPap, Cpap or ventilator) or a need for tracheostomy as a result of their disease. Note: This does not exclude subjects who use respiratory vests.
    4. Intractable seizure/uncontrolled epilepsy defined as having had an episode of status epilepticus, or seizures requiring hospitalization
    a. This does not exclude subjects who have a history of staring spells that have not been associated with EEG findings
    5. Family history of seizure disorders/epilepsy of infantile or childhood onset, other than febrile seizures
    a. This does not exclude subjects with a family history of KD
    6. Any contraindication to ICM admin 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 space occupying lesion causing mass effect or signs of increased intracranial pressure, non-communicating hydrocephalus, space-occupying lesion in the posterior fossa or foramen magnum, aberrant vascular anatomy such as a large midline posterior inferior cerebellar artery, venous anomaly such as a large midline cerebellar vein or occipital sinus, congenital anatomical abnormalities such as Chiari malformation.
    7. Any contraindication to MRI or 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 HSCT
    11. Receipt of a vaccine within 14 days prior to and up to 30 days after dosing
    12. eGFR <60 mL/min/1.73 m2 based on creatinine, determined using the Bedside Schwartz equation
    13. Hematological abnormalities:
    a. Coagulopathy (INR > 1.5 or aPTT > 40 seconds)
    b. Thrombocytopenia (platelet count < 100,000 per μL)
    c. WBC <5.5 x 10^3 cells/μL
    d. Hemoglobin <10 g/dL.
    14. AST or ALT >3 x ULN or total bilirubin >1.5 x ULN.
    15. Abnormal respiratory function:
    a. Required suctioning in the absence of upper respiratory tract infection
    b. Hypoxemia (oxygen [O2] saturation awake < 96% or O2 saturation asleep < 96%, without ventilation support) as assessed during screening. Ventilatory support defined as dependence on supplemental O2 or use of a ventilator or BiPap or 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 ICM injection, anesthesia,
    fluoroscopy, LP, and/or MRI (Temp > 38°C, oxygen saturation < 95% on room air or baseline oxygen requirement, heart rate or respiratory rate
    abnormal for age of the subject, abnormal blood pressure for age, evidence of infection)
    18. Any condition (eg 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 interfere with evaluation of the investigational product or interpretation of subject safety or study results. This includes:
    a. Abnormal laboratory values considered clinically significant by the Investigator
    b. Underlying defect in immune function.
    c. History of multiple and severe life-threatening infections
    d. Any contraindication to treatment with corticosteroid medications
    e. Any evidence of hepatic abnormalities on ultrasound at screening
    f. Any clinical and/or neuroimaging signs that would increase the subject's risk of developing acute hydrocephalus including but not limited to abnormalities impacting the integrity of the CSF spaces (eg, septations, adhesions, or cystic changes in the arachnoid space) and abnormalities of the cerebral ventricular system that cannot be attributed to diminished cerebral volume due to the underlying disease and/or accompanied by signs of increased intracranial pressure.
    Subjects should be reevaluated throughout the course of the study to ensure that they have not acquired any condition that might qualify them for exclusion from study procedures. If they develop any condition(s) that would exclude them from the study prior to receiving PBKR03, they should be withdrawn from the study. If after receiving PBKR03, a subject develops a contraindication to a procedure (eg MRI), investigators should refrain from performing such procedures (which could potentially cause harm) for the duration of the study or until the contraindication resolves (all other study procedures and data collection will continue).
    E.5 End points
    E.5.1Primary end point(s)
    • Adverse events (AEs)
    • Physical and neurological examination
    • Nerve conduction studies (NCS)
    • Hematology
    • Serum chemistry including liver function tests
    • Coagulation tests (PT, aPTT, INR)
    • Serum and CSF anti AAVhu68 total antibodies (tAbs) and neutralizing antibodies (nAbs)
    • Serum and CSF anti-GALC tAbs
    • ELISpot for AAVhu68 capsid and GALC
    • Urinalysis
    • CSF cytology and chemistry (cell counts, protein, glucose)
    • Liver ultrasound
    E.5.1.1Timepoint(s) of evaluation of this end point
    Over 5 years
    E.5.2Secondary end point(s)
    The key secondary assessments will be at 2 years with additional evaluation to 5 years:
    • Bayley Scale of Infant and Toddler Development, Third Edition

    Other secondary assessments at 2 years with additional evaluation to 5 years as follows:
    • Vineland Adaptive Behavior Scales, Second Edition
    • Peabody Development Motor Scales, Second Edition
    • Kaufman Assessment Battery for Children Second Edition Nonverbal Index
    • Clinician Global Impression of Severity and change
    • Caregiver Global Impression of Severity and change
    • Speech and swallowing assessment

    The following will be assessed at the pre-specified time points:
    • Vector DNA levels (serum and CSF)
    • Vector Shedding (urine, feces, and saliva)

    The following fluid biomarkers will be assessed at pre-specified time points over 5 years:
    • CSF and blood GALC activity
    • CSF and blood psychosine levels
    • CSF and blood NfL level
    • CSF and blood cytokines

    The following will be assessed at pre-specified time points over 5 years:
    • Neurological examination
    • Nerve conduction studies, sensory and motor
    • Brain MRI with DTI
    • EEG
    • Seizure diary
    • Assessment of irritability while awake
    • Use of feeding tubes
    • Ventilation-free survival

    Instruments of quality of life and healthcare resource utilization will be assessed at pre-specified time points over 5 years as follows:
    • Quality of life: Pediatric Quality of Life Inventory/ Pediatric Quality of Life Inventory-Infant Scale
    • Healthcare resource utilization: chart review for hospital days, ER visits, ICU admissions, surgical procedures, need for hearing and visual aids

    Exploratory assessment of efficacy using in-home video recordings at 12 and 24 months:
    • The median change from baseline of in-home video recordings (based on ratings at each timepoint including baseline)
    • The proportion with improvement (slightly improved, improved, very improved, extremely improved) since baseline to be assessed by an independent blinded expert panel review of in-home video recordings
    E.5.2.1Timepoint(s) of evaluation of this end point
    At 12 months, 2 years and over 5 years
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA1
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 28
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F. of subjects for this age range: 28
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. of subjects incapable of giving consent
    Parents or an LAR will be required to sign an IRB/Institutional Ethics Committee (IEC) approved ICF prior to any study-related procedures, including screening evaluations.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 3
    F.4.2.2In the whole clinical trial 28
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    As the study is designed to be a single open-label dosing, there will be no other therapies provided after the end of the subject participation in the trial. The subject should continue seeking and receiving standard of care as clinically indicated.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-03-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-08-23
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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