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
Conditions
Interventions
Product Code: PBKR03
Pharmaceutical Form: Injection
INN or Proposed INN: Not available yet
Current Sponsor code: PBKR03
Other descriptive name: Adeno-associated virus serotype hu68 containing the huma
Sponsors
Passage Bio, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. =1 month and 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) Are the trial subjects under 18? yes Number of subjects for this age range: 28 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
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 1.5 or aPTT > 40 seconds) b. Thrombocytopenia (platelet count 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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the safety and tolerability of PBKR03 following administration of a single dose into the cisterna magna;Secondary Objective: 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;Primary 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 ;Timepoint(s) of evaluation of this end point: Over 5 years | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: At 12 months, 2 years and over 5 years;Secondary 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 im | — |
Countries
Brazil, Canada, Israel, Netherlands, United Kingdom, United States
Contacts
Public ContactSamiah Al-Zaidy
Passage Bio, Inc.
Outcome results
None listed