Study of Safety, Tolerability and Efficacy of PBKR03 in Pediatric Subjects With Early Infantile Krabbe Disease

Leukodystrophy, Globoid Cell Clinical Trial

— GALax-C  

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)

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT04771416
• Other study ID #: PBKR03-001
• Secondary ID: 2020-005229-95
• Status: Suspended
• Phase: Phase 1/Phase 2
• Start date: February 24, 2022
• Est. completion date: January 2030

Study information

• Verified date: January 2024
• Source: Passage Bio, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 24
• Est. completion date: January 2030
• Est. primary completion date: January 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 9 Months

Eligibility

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.

Related Conditions & MeSH terms

• Leukodystrophy, Globoid Cell

Intervention

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

Locations

Country	Name	City	State
Brazil	Hospital De Clinicas De Porto Alegre	Porto Alegre
Canada	Montreal Children's Hospital	Montréal
Israel	Shaare Zadek Medical Center	Jerusalem
Netherlands	Amsterdam UMC	Amsterdam
United Kingdom	Manchester University	Manchester
United States	Ann & Robert Lurie	Chicago	Illinois
United States	New York-Presbyterian	New York	New York
United States	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of Utah School of Medicine	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Passage Bio, Inc.

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with treatment-related adverse events (AEs) and serious adverse events (SAEs) at Grade 3 or higher within 24 months of dosing	Assess the number of adverse events and serious adverse events at Grade 3 or higher as assessed by CTCAEv5.0	Up to 5 years (multiple visits)
Primary	Change from baseline in nerve conduction and velocity in motor nerve conduction studies	NCS will measure velocity and amplitude in distal segments of the median, peroneal and tibial motor nerves to evaluate effects on peripheral nerve integrity.	From baseline to 5 years (multiple visits)
Primary	Change from baseline in nerve conduction and velocity in sensory nerve conduction studies	NCS will measure velocity and amplitude in distal segments of the sural, radial and median sensory nerves to evaluate effects on peripheral nerve integrity	From baseline to 5 years (multiple visits)
Primary	Number of Participants with Clinically Significant Laboratory Abnormalities as Measured Using Hematology, Chemistry and Coagulation Tests	Assess the number of participants with clinically significant laboratory changes including hematology, serum chemistry, and coagulation tests	Up to 5 years (multiple visits)
Primary	Assess Humoral Response Against the Vector and Transgene in Serum	Assess serum antibody titers against AAVhu68 and against GALC following ICM administration of PBKR03	Up to 5 years (multiple visits)
Primary	Assess Humoral Response Against the Vector and Transgene in CSF	Assess antibody titers in the cerebrospinal fluid against AAVhu68 and against GALC following ICM administration of PBKR03	Up to 5 years (multiple visits)
Secondary	Change from Baseline in Developmental Milestones as Assessed by the Bayley Scale of Infant and Toddler Development, Third Edition	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	From baseline to 2 years (multiple visits)
Secondary	Change from Baseline in Developmental Milestones as Assessed by the Vineland Adaptive Behavior Scale-II	Assess changes in the developmental age and the total number of developmental milestones using the Vineland Adaptive Behavior Scale-II instrument	From baseline to 2 years (multiple visits)
Secondary	Change in Biomarkers of GALC Activity in Blood	Assess change in biomarkers of GALC activity in blood when compared with baseline	From baseline to 2 years (multiple visits)
Secondary	Change in Biomarkers of GALC Activity in CSF	Assess change in biomarkers of GALC activity when compared with baseline	From baseline to 2 years (multiple visits)
Secondary	Change in Biomarkers of GALC Substrates in Blood	Assess change in concentration of GALC substrates in blood	From baseline to 2 years (multiple visits)
Secondary	Change in Biomarkers of GALC Substrates in CSF	Assess change in concentration of GALC in CSF when compared with baseline	From baseline to 2 years (multiple visits)
Secondary	Change in Concentration of Biomarker of Disease Progression in Plasma	Assess change in neurofilament light chain (NfL) concentration as a marker for neurodegeneration and disease progression in plasma	From baseline to 2 years (multiple visits)
Secondary	Change in Concentration of Biomarker of Disease Progression in CSF	Assess change in neurofilament light chain concentration (NfL) as a marker for neurodegeneration and disease progression in CSF	From baseline to 2 years (multiple visits)
Secondary	Change in Brain Anatomy as Assessed by MRI	Assess change in disease severity, volumetric MRI measures, brain diffusivity, and white matter lesions by MRI imaging	From baseline to 2 years (multiple visits)
Secondary	Change in Quality of Life Using Pediatric Quality of Life Scale	Assess change in quality of life as measured by Pediatric Quality of Life Scale (Peds QL)	From baseline to 2 years (multiple visits)
Secondary	Change in Quality of Life Using Pediatric Quality of Life Scales	Assess change in quality of life as measured by the Pediatric Quality of Life - Infant Scale (PedsQL-IS)	From baseline to 2 years (multiple visits)
Secondary	Change in Ventilator-Free Survival Compared with Natural History Data	Assess change compared with natural history data in ventilator-free survival and chronic ventilatory support.	From baseline to 2 years (multiple visits)
Secondary	Incidence of Feeding Tube Placement at or Before Month 24	Though speech and swallowing assessment, study participants will be evaluated to determine whether a feeding tube is warranted	24 months