Clinical trial NCT04771416: Study of Safety, Tolerability and Efficacy of PBKR03 in Pediatric Subjects With Early Infantile Krabbe Disease
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)
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE1
PHASE2
Conditions: Leukodystrophy, Globoid Cell
Keywords: infantile
early infantile
Krabbe Disease
Rare disease
Leukodystrophy
GALC
Lysosomal storage disease
Lead sponsor: Passage Bio, Inc.
Sponsor class: INDUSTRY
First posted: 2021-02-25
Enrollment: 24
Sex: ALL
Minimum age (years): 1
Maximum age (years): 9
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Open-label, multi-center, dose escalation
Primary purpose: TREATMENT

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.

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.

Eligibility 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.
2. An acute illness requiring hospitalization within 30 days of enrollment.
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.

Primary outcomes:
measure: Number of participants with treatment-related adverse events (AEs) and serious adverse events (SAEs) at Grade 3 or higher within 24 months of dosing
timeFrame: Up to 5 years (multiple visits)
measure: Change from baseline in nerve conduction and velocity in motor nerve conduction studies
timeFrame: From baseline to 5 years (multiple visits)
measure: Change from baseline in nerve conduction and velocity in sensory nerve conduction studies
timeFrame: From baseline to 5 years (multiple visits)
measure: Number of Participants with Clinically Significant Laboratory Abnormalities as Measured Using Hematology, Chemistry and Coagulation Tests
timeFrame: Up to 5 years (multiple visits)
measure: Assess Humoral Response Against the Vector and Transgene in Serum
timeFrame: Up to 5 years (multiple visits)
measure: Assess Humoral Response Against the Vector and Transgene in CSF
timeFrame: Up to 5 years (multiple visits)
Secondary outcomes:
measure: Change from Baseline in Developmental Milestones as Assessed by the Bayley Scale of Infant and Toddler Development, Third Edition
timeFrame: From baseline to 2 years (multiple visits)
measure: Change from Baseline in Developmental Milestones as Assessed by the Vineland Adaptive Behavior Scale-II
timeFrame: From baseline to 2 years (multiple visits)
measure: Change in Biomarkers of GALC Activity in Blood
timeFrame: From baseline to 2 years (multiple visits)
measure: Change in Biomarkers of GALC Activity in CSF
timeFrame: From baseline to 2 years (multiple visits)
measure: Change in Biomarkers of GALC Substrates in Blood
timeFrame: From baseline to 2 years (multiple visits)
measure: Change in Biomarkers of GALC Substrates in CSF
timeFrame: From baseline to 2 years (multiple visits)
measure: Change in Concentration of Biomarker of Disease Progression in Plasma
timeFrame: From baseline to 2 years (multiple visits)
measure: Change in Concentration of Biomarker of Disease Progression in CSF
timeFrame: From baseline to 2 years (multiple visits)
measure: Change in Brain Anatomy as Assessed by MRI
timeFrame: From baseline to 2 years (multiple visits)
measure: Change in Quality of Life Using Pediatric Quality of Life Scale
timeFrame: From baseline to 2 years (multiple visits)
measure: Change in Quality of Life Using Pediatric Quality of Life Scales
timeFrame: From baseline to 2 years (multiple visits)
measure: Change in Ventilator-Free Survival Compared with Natural History Data
timeFrame: From baseline to 2 years (multiple visits)
measure: Incidence of Feeding Tube Placement at or Before Month 24
timeFrame: 24 months
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Ann & Robert Lurie
state: Illinois
city: New York
country: United States
facility: New York-Presbyterian
state: New York
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah School of Medicine
state: Utah
city: Porto Alegre
country: Brazil
facility: Hospital De Clinicas De Porto Alegre
city: Montréal
country: Canada
facility: Montreal Children's Hospital
city: Jerusalem
country: Israel
facility: Shaare Zadek Medical Center
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Manchester
country: United Kingdom
facility: Manchester University
Study officials:
affiliation: Passage Bio, Inc.
name: Samiah Al-Zaidy, MD
role: STUDY_DIRECTOR
References:
citation: Hordeaux J, Jeffrey BA, Jian J, Choudhury GR, Michalson K, Mitchell TW, Buza EL, Chichester J, Dyer C, Bagel J, Vite CH, Bradbury AM, Wilson JM. Efficacy and Safety of a Krabbe Disease Gene Therapy. Hum Gene Ther. 2022 May;33(9-10):499-517. doi: 10.1089/hum.2021.245. Epub 2022 Mar 22.