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

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)

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.

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.

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.