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

NCT04771416 | Suspended Phase 1 DMC FDA Drug

• 2 other identifiers: PBKR03-0012020-005229-95
• Study Type: interventional
• Target: 24
• Locations: 6 countries
• Sites: 9

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.

Conditions

Leukodystrophy, Globoid Cell

Keywords

infantile; early infantile; Krabbe Disease; Rare disease; Leukodystrophy; GALC; Lysosomal storage disease

Outcome Measures

Primary Outcomes (6)

• 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)

• 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)

• 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)

• 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)

• 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)

• 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 Outcomes (13)

• Change from Baseline in Developmental Milestones as Assessed by the Bayley Scale of Infant and Toddler Development, Third Edition

  From baseline to 2 years (multiple visits)

• Change from Baseline in Developmental Milestones as Assessed by the Vineland Adaptive Behavior Scale-II

  From baseline to 2 years (multiple visits)

• Change in Biomarkers of GALC Activity in Blood

  From baseline to 2 years (multiple visits)

• Change in Biomarkers of GALC Activity in CSF

  From baseline to 2 years (multiple visits)

• Change in Biomarkers of GALC Substrates in Blood

  From baseline to 2 years (multiple visits)

Study Arms (2)

Part 1: Dose Escalation Cohorts designed to identify the optimal dose of PBKR03

EXPERIMENTAL

Cohort 1: Subjects aged \>4 to \<9 months Drug: PBKR03 1.5 x 10\^11 GC/g\* Single dose of PBKR03, via intra cisterna magna Cohort 2: Subjects aged \>4 to \<9 months Drug: PBKR03 5.0 x 10\^11 GC/g\* Single dose of PBKR03, via intra cisterna magna Cohort 3: Subjects aged \>1 to \<4 months Drug: PBKR03 1.5 x 10\^11 GC/g\* Single dose of PBKR03, via intra cisterna magna Cohort 4: Subjects aged \>1 to \<4 months Drug: PBKR03 5.0 x 10\^11 GC/g\* Single dose of PBKR03, via intra cisterna magna \*GC/g: genome copiesy per gram of estimated brain weight

Biological: PBKR03

Part 2: Expansion Cohort designed to confirm the safety and efficacy of PBKR03

EXPERIMENTAL

Cohort 5: Subjects aged \>1 to \<9 months Drug: PBKR03 Single dose of PBKR03, via intra cisterna magna Dose to be used for the confirmatory cohorts in Part 2 will be defined after a review of data from Part 1. \*GC/g: genome copiesy per gram of estimated brain weight

Biological: PBKR03

Interventions

PBKR03 BIOLOGICAL

Single dose of PBKR03, via intra cisterna magna

Part 1: Dose Escalation Cohorts designed to identify the optimal dose of PBKR03; Part 2: Expansion Cohort designed to confirm the safety and efficacy of PBKR03

Eligibility Criteria

• Age: 1 Month - 9 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• \> 1 month and \< 9 months of age at enrollment, either presymptomatic or symptomatic with first symptoms of Krabbe Disease at \< 6 months of age
• Leukocyte GALC activity below lower limit of normal (LLN)
• Whole blood psychosine \> 10 nM
• Biallelic pathogenic GALC gene variants previously associated with early infantile Krabbe Disease or variants classified as likely pathogenic
• Parents or the subject's legally authorized representative provide written informed consent prior to any study-related procedures, including screening evaluations
• 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

You may not qualify if:

• Any clinically significant neurocognitive deficit not attributable to Krabbe disease.
• An acute illness requiring hospitalization within 30 days of enrollment.
• 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.
• Intractable seizure or uncontrolled epilepsy defined as having had an episode of status epilepticus, or seizures requiring hospitalization.
• 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.
• 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.
• Any contraindication to MRI or lumbar puncture (LP).
• Prior gene therapy.
• 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.
• Prior Hematopoietic Stem Cell Transplantation (HSCT)
• Receipt of a vaccine within 14 days prior to or after dosing.
• Estimated glomerular filtration rate (eGFR) \<60 mL/minute/1.73 m2 based on creatinine
• Hematological abnormalities
• Coagulopathy (INR \> 1.5) or activated partial thromboplastin time \[aPTT\] \> 40 seconds
• WBC \< 5.5 x 103 cells/ μL

Sponsors & Collaborators

• Gemma Biotherapeutics: lead

Study Sites (9)

Ann & Robert Lurie

Chicago, Illinois, 60611, United States

Location

New York-Presbyterian

New York, New York, 10065, United States

Location

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

University of Utah School of Medicine

Salt Lake City, Utah, 84132, United States

Location

Hospital De Clinicas De Porto Alegre

Porto Alegre, Brazil

Location

Montreal Children's Hospital

Montreal, Canada

Location

Shaare Zadek Medical Center

Jerusalem, Israel

Location

Amsterdam UMC

Amsterdam, Netherlands

Location

Manchester University

Manchester, United Kingdom

Location

Related Publications (2)

• Heller G, Bradbury AM, Sands MS, Bongarzone ER. Preclinical studies in Krabbe disease: A model for the investigation of novel combination therapies for lysosomal storage diseases. Mol Ther. 2023 Jan 4;31(1):7-23. doi: 10.1016/j.ymthe.2022.09.017. Epub 2022 Oct 4.

  PMID: 36196048 DERIVED

• 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.

  PMID: 35333110 DERIVED

MeSH Terms

Conditions

Leukodystrophy, Globoid Cell; Rare Diseases; Lysosomal Storage Diseases

Condition Hierarchy (Ancestors)

Hereditary Central Nervous System Demyelinating Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Leukoencephalopathies; Demyelinating Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• May Orfali, MD

  Gemma Biotherapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open-label, multi-center, dose escalation

Study Record Dates

• First Submitted: February 23, 2021
• First Posted: February 25, 2021
• Study Start: February 24, 2022
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2030
• Last Updated: November 13, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1); IL (1); GB (1); US (4); BR (1); CA (1)