Primary objective: To evaluate the safety and tolerability of SOBI003 at different dose levels.Secondary objectives:1. To characterize the pharmacokinetic (PK) properties of SOBI003 following single and repeated administration by the use of non-…
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint: Treatment Emergent Adverse Events (TEAEs) and Serious Adverse
Events (SAEs).
Secondary outcome
The secondary endpoints to evaluate the primary objective of the safety and
tolerability of SOBI003 are:
- Vital signs (blood pressure, heart rate, body temperature, respiratory rate
and oxygen saturation)
- Laboratory safety variables (hematology, coagulation, clinical chemistry and
urine analysis)
The endpoints relating to the 1st secondary objective are:
- Serum SOBI003 PK parameters at Weeks 1, 4, 12, and 24; tEnd of inf, CEnd of
inf, Cmax, tmax, CPre-dose, CTrough, CL, AUC0-168h, t1/2
- CSF SOBI003 concentration at Weeks 12 and 24
The endpoints relating to the 2nd secondary objective are:
- Occurrence of anti-drug antibodies (ADAs) against SOBI003 in serum
(seroconversion rate, time to seroconversion, transient/persistent). For
patients with confirmed ADA positive serum samples, the following additional
endpoints apply; ADA titers and IgG subclasses in serum and presence of
neutralizing antibodies (NAb) in serum.
- Occurrence of ADAs against SOBI003 in CSF (conversion rate, time to
occurrence, transient/persistent). For patients with confirmed ADA positive CSF
samples, the following additional endpoints apply; ADA titers and presence of
NAb in CSF.
The endpoints relating to the 3rd secondary objective are:
- Change from baseline in CSF HS at Weeks 12 and 24
- Change from baseline in serum HS at Weeks 2, 3, 4, 8, 12 and 24
- Change from baseline in urine HS at Weeks 2, 3, 4, 8, 12 and 24
The endpoints relating to the 4th secondary objective are neurocognitive
Development Quotient (DQ) and age-equivalence score (AEq) as assessed by the
Bayley Scales of Infant and Toddler Development®, third edition (BSID-III)
cognitive subtest or the Kaufman Assessment Battery for Children, Second
edition (KABC*-II); change from baseline at Week 24.
The endpoint relating to the 5th secondary objective is adaptive behavior
age-equivalence
score (AEq) as assessed by Vineland* Adaptive Behavior Scales, Expanded
Interview Form, Second edition (VABS-II); change from baseline at Week 24.
The endpoint relating to the 6th secondary objective is gray matter volume as
assessed by brain volumetric magnetic resonance imaging (MRI); change from
baseline at Week 24.
The endpoint relating to the 7th secondary objective is Pediatric Quality of
Life Inventory (PedsQL*) total score and PedsQL* Family Impact Module total
score; change from baseline at Week 24.
Background summary
MPS IIIA or Sanfilippo A, is an inherited LSD that is progressive,
life-shortening and rare. MPS IIIA is an autosomal recessive disorder caused by
mutations in the SGSH gene that result in absence of or a deficiency in the
enzyme sulfamidase (N-sulfoglucosamine sulfohydrolase). Lack of sulfamidase
activity leads to insufficient degradation of HS and lysosomal accumulationof
HS and its metabolites in lysosomes throughout the body
After an initial symptom-free interval, patients usually present with a slowing
of development and/or behavioral problems, followed by progressive intellectual
decline resulting in severe dementia and progressive motor disease. Acquisition
of speech is often slow and incomplete. The disease progresses to increasing
behavioural disturbance including temper tantrums, hyperactivity,
destructiveness, aggressive behaviour, pica and sleep disturbance. In the final
phase of the illness, children become increasingly immobile and unresponsive,
often require wheelchairs, and develop swallowing difficulties and seizures.
Depending on disease severity, patients have a median life-expectancy of about
15 years.
SOBI003 provides a potential clinical benefit by reducing the levels of stored
HS and its metabolites and thereby reducing neuroinflammation which potentially
could reduce the clinical manifestations. SOBI003 is predicted to gradually
achieve a brain HS reduction of ~ 35 % after 3 months and ~ 45 % after 6 months
treatment.
Study objective
Primary objective:
To evaluate the safety and tolerability of SOBI003 at different dose levels.
Secondary objectives:
1. To characterize the pharmacokinetic (PK) properties of SOBI003 following
single and repeated administration by the use of non-compartmental analysis
(NCA)
2. To assess the immunogenicity of SOBI003
3. To assess the pharmacodynamic (PD) effect of different dose levels and
treatment duration of SOBI003 on heparan sulfate (HS) levels in cerebrospinal
fluid (CSF), serum and urine
4. To assess the effect of SOBI003 at different dose levels on neurocognition
5. To assess the effect of SOBI003 at different dose levels on adaptive behavior
6. To assess the effect of SOBI003 at different dose levels on gray matter
volume
7. To assess the effect of SOBI003 at different dose levels on Quality of Life
Study design
An open, non-controlled, parallel, ascending multiple-dose, multicenter study
Intervention
SOBI003 solution, 20 mg/mL, is administered as 4-hour i.v. infusions given once
weekly for a duration of 24 weeks.
The planned lowest dose level is 3 mg/kg (cohort 1). For cohorts 2 and 3,
the dose levels will be selected on basis of at least 4-week safety, PK,
immunogenicity, and PD data of prior dose cohort(s) as well as applicable
toxicology data. An additional cohort comprising 3 patients may be added, if
deemed necessary for safety, tolerability, PK or PD evaluation.
Study burden and risks
The main burden for the patients consists of the following:
- physical examination at each visit,neurological examination, ECG and
echcardiography multiple times
- The patient is expected to visit the hospital 15 times
- a venous access port is used for blood samples and drug administration. It
will be inserted under general anesthesia.
- one X-ray will be performed. The radiation exposure in this study is
considered small. .
- a venous line will be placed in the patients arm, about 14 blood samples will
be taken, either using the post or venous line to minimize needle punctures.
- A lumbar puncture will be done twice, this will be done under general
anesthesia
- A skin biopsy will be taken once. This will be taken under
sedation/anesthesia, if possible at the same time as the MRI/port insertion.
- Hospitalization. The patient must be hospitalized for certain timeframes:
• from the day before the first infusion until 2 days after the third infusion
(18 days)
• for infusions on weeks 4 to 8, 12 and 24: from the day of the infusion until
2 days after the infusion
• for infusions on weeks 9 to 11, and 13 to 23: from the day of the infusion
until 12 hours after the beginning of the infusion.
- an MRI will be done twice, under sedation/general anesthesia
Every effort will be made to combine the procedures so that as few
anesthesia/sedation procedures as possible have to be performed.
See section E for more information
MPSIIIA is an irreversible, progressive, life-shortening disease with no
existing effective therapeutic alternative. The nonclinical safety evaluation
of SOBI003 did not show any signs of adverse effects, thus SOBI003 was
well-tolerated. Given the observed pharmacological and toxicological profile in
the non-clinical studies, it is judged that SOBI003 can be given to man in a
carefully monitored First-In-Human study. Adherence to study
inclusion/exclusion criteria, staggered dose escalation, close clinical
monitoring, and stopping rules will be applied. the dose-levels applied in this
study are expected to be sufficiently pharmacologically active to result in
peripheral and central reduction of HS, potentially also reducing or
stabilizing neuroinflammation, and neurodegeneration with potential effect on
clinical manifestations including amelioration of neurocognitive dysfunction in
these patients with MPS IIIA. These predictions are based on current
nonclinical data, and are thus to be confirmed in clinical studies. In summary,
the potential benefits of SOBI003 treatment are considered to outweigh the
foreseeable risks.
Tomtebodavägen 23a 23a
Stockholm SE-112 76
SE
Tomtebodavägen 23a 23a
Stockholm SE-112 76
SE
Listed location countries
Age
Inclusion criteria
1. Informed consent obtained from the patient*s legally authorized representative(s)
2. Patients with MPS IIIA, as confirmed by both:
- A documented deficiency in sulfamidase enzyme activity in concordance with a diagnosis of MPS IIIA*, and
-Normal enzyme activity level of at least one other sulfatase measured in leukocytes
3. Chronological age of >=12 and <=72 months (i.e., 1 to 6 years) at the time of the first SOBI003 infusion and has a developmental age >=12 months at screening as assessed by the Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
4. Medically stable patient who is expected to be able to comply with study procedures;* as determined by the reference ranges applied by the Greenwood Genetic Center
Exclusion criteria
1. At least one S298P mutation in the SGSH gene
2. Contraindications for anesthetic procedures, surgical procedure (venous access port) MRI
scans and/or lumbar punctures
3. History of poorly controlled seizures
4. Patients is currently receiving psychotropic or other medications which in the investigator's opinion, would be likely to substantially confound test results
5. Significant non-MPS IIIA-related CNS impairment or behavioral disturbances, which in the investigator's opinion, would confound the scientific integrity or interpretation of study assessments
6. Prior administration of stem cell or gene therapy, or ERT for MPS IIIA
7. Concurrent or prior (within 30 days of enrolment into this study) participation in a study
involving invasive procedures
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 | EUCTR2017-002806-10-NL |
| ClinicalTrials.gov | NCT03423186 |
| CCMO | NL67533.018.18 |