This first-in-human study is planned to include both a dose ranging phase and a confirmatory phase, with the intention that all data collected throughout the study may support registration. The dose ranging phase will be conducted in cohorts of 3-4…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess the safety and tolerability of PBKR03
Secondary outcome
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
Background summary
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;
EC#3.2.1.46; Wenger et al 2000). This enzyme is responsible for the degradation
of certain galactolipids, including galactosylceramide (ceramide) and
galactosylsphingosine (psychosine). In Krabbe disease, GALC deficiency causes
toxic accumulation of psychosine in the lysosomes of cells throughout the
nervous system (Svennerholm et al 1980). The myelin-producing oligodendrocytes
in the central nervous system (CNS) and Schwann cells in the peripheral nervous
system (PNS) are particularly sensitive to the accumulation of psychosine,
resulting in widespread death of these cells. The resulting myelin breakdown in
both the CNS and PNS is accompanied by reactive astrocytic gliosis and the
infiltration of giant multinucleated macrophages (*globoid cells*) (Suzuki
2003). Aggressive forms of Krabbe disease, such as the early infantile form,
are associated with extensive central and peripheral effects including brain
atrophy, spasticity, loss of hearing and vision, seizures, weight loss,
aspiration, loss of development milestones and early mortality.
Study objective
This first-in-human study is planned to include both a dose ranging phase and a
confirmatory phase, with the intention that all data collected throughout the
study may support registration. The dose ranging phase will be conducted in
cohorts of 3-4 subjects with early infantile Krabbe disease in which the
assessment of safety will be the primary objective. Doses selected for
administration in the dose ranging phase are expected to be safe and have the
potential to confer therapeutic benefit to study subjects as determined from
the nonclinical development program. If the safety and biomarker data from the
dose ranging phase supports progression to the confirmatory phase of the study,
the primary objectives for the confirmatory component will include both safety
and efficacy.
Study design
Overview of Study Design:
Pediatric subjects aged >=1 to <9 months (maximum of 28 subjects) with early
infantile Krabbe disease, either presymptomatic or symptomatic with onset of
symptoms at <=6 months of age, will be enrolled.
All subjects will receive a single dose of PBKR03 administered by ICM injection
and will be assessed for 2 years for safety, tolerability and efficacy, and
then for an additional 3 years of follow-up for safety and durability of
effect. Starting 1 day prior to PBKR03 administration, systemic corticosteroids
will be administered for approximately 1 month, and then the corticosteroid
dose will be tapered gradually over approximately 1 month until normal adrenal
function has been documented. Subjects may be followed beyond 5 years in
accordance with local regulations.
The dose ranging portion of this study will enroll independent dose escalation
cohorts in 2 age groups of subjects with early infantile Krabbe disease, for a
planned total of 12 subjects in 4 cohorts:
• 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)
Due to limited clinical experience with the ICM procedure in children, this
study will initially enroll subjects aged >=4 months. Three subjects will be
enrolled into the low dose cohort (Cohort 1, Dose I) prior to consideration of
dose escalation. Safety will be monitored by the Sponsor and an Independent
Data Monitoring Committee (IDMC), and ongoing safety management of subjects
will be based on adverse events (AEs) and stopping rules prospectively defined
in this protocol. After safety and pharmacodynamic (PD) data are reviewed from
all subjects in Cohort 1 and determined to be acceptable by the IDMC, the study
may proceed to enroll additional subjects of the same age group into the high
dose cohort (Cohort 2, Dose II). Also, at that time, subjects aged <4 months
and as young as 1 month of age can then be enrolled in the low dose cohort
(Cohort 3, Dose I). Enrollment of subjects aged <4 months and as young as 1
month of age into the high dose cohort (Cohort 4, Dose II) will proceed if
criteria outlined above are met.
If a treatment-related PD response (i.e., change in levels of GALC activity or
psychosine) is not certain because of variability of the response in the first
3 subjects dosed in Cohort 1 or Cohort 3, an additional subject may be enrolled
at the same dose level before dose escalation. If a treatment-related moderate
AE (Common Terminology Criteria for Adverse Events [CTCAE] Grade 2) occurs in 1
of the first 3 subjects dosed in a cohort, an additional subject will be
enrolled in the same dose cohort.
Occurrence of certain AEs that are prospectively defined in this protocol
suggests that the Maximum Tolerated Dose (MTD) may have been reached or
exceeded, and further dosing will not continue until the IDMC is convened to
review all available data, determine whether the MTD was reached, and made a
recommendation whether the study should continue in its original design,
continue with modification (e.g, dose de-escalation), or cease enrollment.
Review of all available data from one of the low dose cohorts may also lead the
IDMC to recommend escalation to a dose that is lower than the one originally
planned (e.g., smaller incremental increase). During the ongoing dose ranging
phase of the study the IDMC will review data pooled from both low dose cohorts
(Cohort 1 and Cohort 3) or from both high dose cohorts (Cohort 2 and Cohort 4)
to assess the effects of Dose I and Dose II and help inform recommendations on
study conduct.
Enrollment of individual subjects within a cohort will be separated by a
minimum of 60 days to allow assessment of 30-day biomarker and nerve conduction
study (NCS) data and 60-day safety data.
The dose ranging cohorts are intended to define a dose for further evaluation
in an expanded, confirmatory cohort. The optimal dose for the confirmatory
cohort (which will not exceed the doses tested in the dose escalation cohorts)
will be chosen based on available safety, tolerability, biomarker, and clinical
data collected in the dose ranging cohorts. This optimal dose will be further
characterized in the confirmatory cohort, in which 12 subjects are expected to
be enrolled. All subjects in the confirmatory cohorts may be enrolled
simultaneously. It is anticipated that an integrated analysis of pooled data
from all cohorts will be sufficient to make conclusions regarding the safety
and efficacy of PBKR03 in this rare disease.
Intervention
In order to more effectively deliver GALC to cells throughout the CNS while
minimizing procedure-related morbidity, AAV vector delivery into the CSF has
been evaluated.
PBKR03 to be administered by ICM injection
Study burden and risks
In summary, when comparing the risks of PBKR03 administration, additional risk
of procedures that may be invasive or require anesthesia/sedation such as MRIs,
LPs, or nerve conduction testing versus the devastating clinical course of
early infantile Krabbe disease, the anticipated benefit of correcting the
underlying pathophysiology and improving developmental potential and survival
outweigh the potential risks associated with PBKR03 and study procedures all
listed in the protocol chapter 5.3.2
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Philadelphia PA 19103
US
Commerce Square Two 2001 Market Street
Philadelphia PA 19103
US
Listed location countries
Age
Inclusion criteria
1. >= 1 month and <9 months of age at enrollment, and are presymptomatic or
symptomatic with first symptoms of Krabbe disease at <=6 months of age
2. Leukocyte GALC activity <=lower limit of normal (LLN)
3. Whole blood (dried blood spot) 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 of Protocol, 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 available data, including relevant family history,
must be consistent with a diagnosis of early infantile Krabbe disease. For the
full list of inclusion criteria see chapter 6.1 of the protocol
Exclusion criteria
1. Any clinically significant neurocognitive deficit not attributable to Krabbe
disease
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 (defined as use
of more than 12 hours/day of bilevel positive airway pressure, continuous
positive airway pressure, 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 or 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 or epilepsy of infantile or childhood
onset, other than febrile seizures
a. This does not exclude subjects with a family history of Krabbe disease
6. Any contraindication to ICM administration procedure, including
contraindications to fluoroscopic imaging, IT 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.For the full list of exclusion criteria see chapter 6.2 of the
protocol
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005229-95-NL |
| CCMO | NL76430.000.21 |