The purpose of this study is to characterize the safety and tolerability of OAV101 IT in participants who have discontinued treatment with nusinersen (Spinraza®) or risdiplam (Evrysdi®). The data from this study will expand on the data generated…
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To characterize the safety and tolerability of OAV101 IT over a 52-week period
in patients with SMA aged 2 to 18 years who have discontinued treatment with
nusinersen (Spinraza®) or risdiplam (Evrysdi®):
- Number and percentage of participants reporting AEs, related AEs, SAEs, and
AESIs
Secondary outcome
To assess the efficacy of OAV101 IT on motor function, and caregiver impact
over a 52-week period in patients with SMA aged 2 to 12 years who have
discontinued treatment with nusinersen (Spinraza®) or risdiplam (Evrysdi®):
* Change from baseline to Week 52 visit in the HFMSE total score
* Change from baseline to Week 52 visit in the RULM total Score
* Change from baseline to Week 52 visit in Assessment of Caregiver Experience
in ACEND instrument score
Background summary
Spinal muscular atrophy (SMA) is a neurogenetic disorder caused by a loss or
mutation in the survival motor neuron 1 gene (SMN1) on chromosome 5q13, leading
to decreased SMN protein levels and selective motor neuron dysfunction. SMA is
an autosomal recessive early childhood disease with an incidence of
approximately 1:10,000 live births. Before the available treatments, SMA was
the leading cause of infant mortality due to genetic diseases. A small amount
of SMN protein (about 10 - 15% of the total) is also produced by the SMN2 gene.
The SMN2 gene is nearly identical to SMN1, but only partially functional.
Disease severity and clinical prognosis generally correlate inversely with
variable copy number of SMN2.
Currently, several treatments have been approved for the treatment of SMA with
different mechanisms of action, such as splicing modulators (nusinersen
(Spinraza®) and risdiplam (Evrysdi®)) that modulate the splicing of the SMN2
gene and thus functionally converting tge SNB2 gene into SMN1 gene to increase
the level of SMN protein in the central nervous system (CNS), and gene therapy
(Zolgensma IV) that replaces a mutated or deleted SMN1 with a functional copy.
Unlike Zolgensma (OAV101), which is a single gene therapy, nusinersen
(Spinraza®) and risdiplam (Evrysdi®) require lifelong treatment to maintain
effectiveness. Therefore, targeting the major source of SMN protein and
ensuring sustained and uninterrupted SMN protein levels, OAV101 may provide an
important treatment option for patients who are unwilling or unable to commit
to chronic, lifelong therapy. In addition, individuals with SMA may discontinue
nusinersen (Spinraza®) or risdiplam (Evrysdi®) for other reasons (eg,
sub-optimal efficacy, safety, compliance, burden). The mechanism of action of
OAV101 is designed to address the root cause of (5q)SMA through the delivery of
a functional copy of the SMN1 gene encoding the SMN protein into target cells.
The goal is to increase the SMN proteins in motor neuron prior to development
of irreversible injury and motor neuron loss, thereby modyfying the patient's
SMA phenotype to a milder course with improved quality of life and prolonged
survival. The data from this study will expand on the data generated from other
studies of OAV101 IT in the treatment-naive SMA population. Specificallly, data
from this study may provide evidence in support in management and monitoring of
patients with SMA who discontinue nusinersen (Spinraza®) or risdiplam
(Evrysdi®) to receive OAV101 IT. In addition to collecting safety and
tolerability data, efficacy will be assessed to support the evaluation of
OAV101 IT for the treatment of this SMA population.
Study objective
The purpose of this study is to characterize the safety and tolerability of
OAV101 IT in participants who have discontinued treatment with nusinersen
(Spinraza®) or risdiplam (Evrysdi®). The data from this study will expand on
the data generated from other studies of OAV101 IT in the treatment naive SMA
population. Specifically, data from this study may provide evidence in support
of management and monitoring for patients with SMA who discontinue nusinersen
(Spinraza®) or risdiplam (Evrysdi®) to receive OAV101 IT. In addition to the
collection of safety and tolerability data, efficacy will be assessed to
support evaluation of OAV101 IT for the treatment of this SMA population.
Participants will receive a single dose of OAV101 (1.2 x 1014 vector genomes)
by lumbar IT injection after the defined period off nusinersen (Spinraza®) or
risdiplam (Evrysdi®); and safety, tolerability, and efficacy will be evaluated
over a 52-week period. Approximately 28 participants aged 2 to 18 years will be
enrolled. Age of participants enrolled will be stratified as 2 to 5 years
(inclusive of all 5-year-olds) and 6 to 18 years, with at least 12 subjects in
each stratum.
Study design
This is a 52-week, open-label, single arm, multi-center study design in
pre-treated patients with SMA
Intervention
Name: OAV101 (formerly AVXS-101)
Unit Dose 1.2 x 1014 vector genomes
Route of administration Intrathecal (once)
The biological product is a non-replicating recombinant AAV9 containing the
cDNA of the human SMN gene under the control of the CMV enhancer/CB promoter.
The AAV inverted terminal repeats (ITR) has been modified to promote
intramolecular annealing of the transgene, thus forming a double-stranded
transgene ready for transcription. This modified ITR, termed a *self-
complementary* (sc) ITR, has been shown to significantly increase the speed of
which the transgene is transcribed, and the resulting protein is produced. The
biological product, called OAV101, expresses the human SMN protein in
transduced cells.
Study burden and risks
Risks: side-effects of the study medication and procedures (see E9)
Burden: amount of visits and examinations/procedures per visit (see E4)
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
* Written informed consent
* SMA diagnosis based on gene mutation analysis with bi-allelic SMN1 mutations
and any copy of SMN2 gene
* Aged 2 < 18 years (screening visit must occur before the patient's 18th
birthday) at time of Screening Visit 1
* Have had at least four loading doses of nusinersen (Spinraza®) or at least 3
months of treatment with risdiplam (Evrysdi®) at Screening
* Must be able to sit independently but must never have taken steps
independently
* Diagnosed through newborn or neonatal screening or patients clinically
diagnosed must have age of clinical symptom onset < 18 months
* Meets age-appropriate institutional criteria for use of anesthesia/sedation
* Female participants who are sexually active or have reached menarche must
have a negative pregnancy test at Screening. Those females who are sexually
active must also agree to use highly effective methods of contraception.
Exclusion criteria
* Excluding SMA, any medical condition considered clinically significant
* Positive for human immunodeficiency virus (HIV), hepatitis B or hepatitis
* Anti Adeno Associated Virus Serotype 9 (AAV9) antibody titer using an
immunoassay is reported as elevated at Screening (reference to >1:50 or a
validated result consistent with being elevated)
* Clinically significant abnormalities in test results during screening period
and/or at Baseline
* Platelet count less than the lower limit of normal (LLN), or platelet
transfusion within 1 month at Screening Visit 1
* Clinically significant abnormal coagulation panel results at Screening
* Hepatic dysfunction (i.e. alanine aminotransferase (ALT), total bilirubin
(TBL), gamma-glutamyl transferase (GGT) or glutamate dehydrogenase (GLDH) >
upper limit of normal (ULN) at Screening (with the exception of isolated AST
elevation: in the absence of other liver laboratory abnormalities, isolated
elevated AST is not considered exclusionary)
* Contraindications for lumbar puncture procedure
* At Baseline (Day-1), participants are excluded if they received:
* nusinersen (Spinraza®) within 4 months at Baseline
* risdiplam (Evrysdi®) within 15 days at Baseline
* Vaccinations 2 weeks prior to administration of OAV101
* Hospitalization for a pulmonary event, or for nutritional support within 2
months prior to Screening or inpatient major surgery planned.
* Presence of the following:
* An active infectious process requiring systemic antiviral or antimicrobial
therapy up to 30 days prior to OAV101 administration, or
* An active but untreated viral or bacterial infectious process up to 30 days
prior to administration of OAV101, or
* Any febrile illness up to 30 days prior to administration of OAV101
* Requiring invasive ventilation, awake noninvasive ventilation for > 6 hours
during a 24-hour period, noninvasive ventilation for >12 hours during a 24-hour
period or requiring tracheostomy, at Screening and up to OAV101 administration
* Concomitant use of any of the following medication categories within 90 days
prior to administration of OAV101
* Ongoing systemic immunosuppressive therapy (e.g., corticosteroids,
cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous
immunoglobulin, rituximab), plasmapheresis, immunomodulators (e.g., adalimumab)
* History of hypersensitivity to any of the study treatments or its excipients
or drugs of similar chemical classes
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 | EUCTR2021-0006709-3-NL |
| ClinicalTrials.gov | NCT05386680 |
| CCMO | NL81692.000.22 |