Study to assess safety, tolerability and efficacy of PBKR03 in pediatric subjects with Krabbe disease (GALax-C)

• Register: EUCTR
• Last refreshed on: 8 August 2022
• Main ID: EUCTR2020-005229-95-NL
• Date of registration: 19/03/2021
• Prospective Registration: Yes
• Primary sponsor: Passage Bio, Inc.
• Public title: Study to assess safety, tolerability and efficacy of PBKR03 in pediatric subjects with Krabbe disease (GALax-C)
• Scientific 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) (GALax-C) - Study of Safety, Tolerability and Efficacy of PBKR03 in Pediatric Subjects with Early Infantile Krab
• Date of first enrolment: 23/08/2021
• Target sample size: 28
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-005229-95
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Brazil, Canada, Israel, Netherlands, United Kingdom, United States

Contacts

• Contact type: Public
• Name: Samiah Al-Zaidy
• Affiliation: Passage Bio, Inc.

• Contact type: Scientific
• Name: Samiah Al-Zaidy
• Affiliation: Passage Bio, Inc.

Key inclusion & exclusion 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 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)

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:
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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

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)
MedDRA version: 20.0 Level: PT Classification code 10023492 Term: Krabbe's disease System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

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 human GALC gene
Concentration unit: Other
Concentration type: range
Concentration number: 14100000000000-80000000000000

Primary Outcome(s)

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

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

Secondary Outcome(s)

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 improved) since baseline to be assessed by an independent blinded expert panel review of in-home video recordings

Timepoint(s) of evaluation of this end point: At 12 months, 2 years and over 5 years

Secondary ID(s)

PBKR03-001

Source(s) of Monetary Support

Passage Bio, Inc.

Ethics review

• Status: Approved
• Approval date: 23/08/2021

Results

• Baseline characteristics: No results available
• Adverse events: No results available
• Outcome measures: No results available