Spinal Muscular Atrophy Type I
Conditions
Keywords
Spinal Muscular Atrophy, SMN2, Onasemnogene Abeparvovec-xioi, Gene replacement therapy
Brief summary
This is a Phase 3, open-label, single-arm, single-dose, trial of onasemnogene abeparvovec-xioi (gene replacement therapy) in participants with spinal muscular atrophy (SMA) Type 1 and who are genetically defined by a biallelic pathogenic mutation of the survival motor neuron 1 gene (SMN1) with one or two copies of survival motor neuron 2 gene (SMN2). The primary objective of the study is to evaluate the efficacy of onasemnogene abeparvovec-xioi by assessing the proportion of symptomatic SMA Type 1 participants who achieve the ability to sit unaided for at least 10 seconds up to and including the 18 months of age trial visit. At least 6 participants aged \< 6 months (\< 180 days) at the time of gene replacement therapy (Day 1) will be enrolled.
Detailed description
This is a Phase 3, open-label, single-arm, single-dose trial of onasemnogene abeparvovec-xioi (gene replacement therapy) in participants with SMA Type 1 with one or 2 copies of SMN2. At least 6 participants \< 6 months (\< 180 days) of age at the time of gene replacement therapy (Day 1) will be enrolled. The trial includes 3 trial periods: screening, gene replacement therapy, and follow-up. During the screening period (Days -30 to -2), participants whose parent(s)/legal guardian(s) provide informed consent will undergo screening procedures to determine eligibility for trial enrollment. participants who meet the entry criteria will enter the in-patient gene replacement therapy period (Day -1 to Day 3). On Day -1, participants will be admitted to the hospital for pre-treatment baseline procedures. On Day 1, participants will receive a one-time intravenous (IV) infusion of the equivalent of onasemnogene abeparvovec-xioi cohort 2 dose received in the AVXS-101-CL-101 trial over approximately 60 minutes and will undergo in-patient safety monitoring over the next 48 hours. Participants may be discharged 48 hours after gene replacement therapy, based on Investigator judgment. During the outpatient follow-up period (Days 4 to End of Trial at 18 months of age), participants will return at regularly scheduled intervals for efficacy and safety assessments until the participant reaches 18 months of age.
Interventions
BIOLOGICALOnasemnogene Abeparvovec-xioi
Onasemnogene abeparvovec-xioi is a non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the human survival motor neuron (SMN) gene under the control of the cytomegalovirus (CMV) enhancer/chicken β-actin-hybrid promoter (CB). Onasemnogene abeparvovec-xioi will be administered as a one-time intravenous infusion over approximately 60 minutes. Dosage will be determined by the participants weight.
Sponsors
Novartis Gene Therapies
PRA Health Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Days to 6 Months
Healthy volunteers
No
Inclusion criteria
* Participants with SMA Type 1 as determined by diagnosis of SMA based on gene mutation analysis with biallelic SMN1 mutations (deletion or point mutations) and one or 2 copies of SMN2 \[inclusive of the known SMN2 gene modifier mutation (c.859G\>C)\] * Participants must be \< 6 months (\< 180 days) of age at the time of onasemnogene abeparvovec-xioi infusion * Participants must have a swallowing evaluation test performed prior to administration of gene replacement therapy * Up-to-date on childhood vaccinations as per local health authorities. * Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply with trial procedures and visit schedule
Exclusion criteria
* Previous, planned or expected scoliosis repair surgery/procedure prior to 18 months of age * Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry \< 95% saturation at screening: 1. Pulse oximetry saturation must not decrease ≥ 4 percentage points between screening and dosing with confirmatory oximetry reading 2. Participants may be put on non-invasive ventilatory support for less than 12 hours per day at the discretion of their physician or trial staff * Use or requirement of non-invasive ventilatory support for greater than or equal to 12 hours daily in the two weeks prior to dosing * Participant with signs of aspiration based on a swallowing test or whose weight-for-age falls below the 3rd percentile based on World Health Organization (WHO) Child Growth Standards and unwilling to use an alternative method to oral feeding * Active viral infection (includes human immunodeficiency virus \[HIV\] or positive serology for hepatitis B, C, or E, or known Zika virus infection) * Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within 2 weeks prior to screening * Upper or lower respiratory infection requiring medical attention, medical intervention, or increase in supportive care of any manner within 4 weeks prior to screening * Severe non-pulmonary/respiratory tract infection (eg, pyelonephritis, or meningitis) within 4 weeks before administration of gene replacement therapy or concomitant illness that, in the opinion of the Principal Investigator, creates unnecessary risks for gene replacement such as: 1. Major renal or hepatic impairment 2. Known seizure disorder 3. Diabetes mellitus 4. Idiopathic hypocalcuria 5. Symptomatic cardiomyopathy * Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients, or human, animal biological raw materials (human transferrin, human insulin, trypsin derived from porcine spleen, bovine derived protein (FBS, bovine milk-derived Benzonase, casamino acid, bovine pancreas), HEK 293 cells, Cosmic Calf Serum, HyQtase) used in manufacturing of onasemnogene abeparvovec-xioi product * Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, or immunosuppressive therapy within 3 months prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV immunoglobulin, rituximab) * Anti-AAV9 antibody titer \> 1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay. Should a potential participant demonstrate Anti-AAV9 antibody titer \> 1:50, he or she may receive retesting within 30 days of the screening period and will be eligible to participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50 * Clinically significant abnormal laboratory values (gamma-glutamyl transpeptidase \[GGT\], ALT, AST, total bilirubin \> 2x the ULN, creatinine ≥ 1.0 mg/dL, hemoglobin \[Hgb\] \< 8 or \> 18 g/dL; white blood cell \[WBC\] \> 20,000 per cmm) prior to gene replacement therapy. Patients with an elevated bilirubin level that is unequivocally the result of neonatal jaundice shall not be excluded * Participation in recent SMA treatment clinical trial (with the exception of observational cohort studies or non-interventional studies) or receipt of an investigational or commercial compound, product or therapy administered with the intent to treat SMA (e.g., nusinersen, valproic acid) at any time prior to screening for this trial. Oral beta-agonists must be discontinued at least 30 days prior to dosing. Inhaled albuterol specifically prescribed for the purposes of respiratory (bronchodilator) management is acceptable and not a contraindication at any time prior to screening for this trial * Expectation of major surgical procedures during the trial assessment period (e.g., spinal surgery or tracheostomy) * Parent(s)/legal guardian(s) unable or unwilling to comply with trial procedures or inability to travel for repeat visits * Parent(s)/legal guardian(s) unwilling to keep trial results/observations confidential or to refrain from posting confidential trial results/observations on social media sites * Parent(s)/legal guardian(s) refuses to sign consent form * Participants \< 35 weeks gestational age at time of birth
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved Sitting Alone for at Least 10 Seconds | From Baseline up to 18 Months of Age Visit | Independent sitting is defined by the World Health Organization Multicentre Growth Reference Study, confirmed by video recording, as a participant who sits up straight unsupported for at least 10 seconds. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival at 14 Months of Age | From Baseline up to 14 Months of Age | Event-free survival at 14 months of age was defined as the number of participants who did not die, did not require permanent ventilation and did not withdraw from the study by 14 months of age. |
Countries
Japan, South Korea, Taiwan
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
A total of 2 participants took part in the trial at a single site in Taiwan between May 2019 and June 2021.
Pre-assignment details
A total of 5 participants were screened, of which 3 were screen failures and 2 were enrolled and received study drug.
Participants by arm
| Arm | Count |
|---|---|
| AVXS-101 Participants received a single dose of AVXS-101 administered as an intravenous (IV) infusion over 60 minutes at a dose of 1.1 × 10\^14 vg/kg (vector genome per kilogram) on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued. | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | AVXS-101 |
|---|---|
| Age, Categorical <=18 years | 2 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
| SMN2 gene modifier mutation (c.859G>C) Present | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 2 |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
Primary
Number of Participants Who Achieved Sitting Alone for at Least 10 Seconds
Independent sitting is defined by the World Health Organization Multicentre Growth Reference Study, confirmed by video recording, as a participant who sits up straight unsupported for at least 10 seconds.
Time frame: From Baseline up to 18 Months of Age Visit
Population: Intent-to-Treat (ITT) population - Symptomatic participants with biallelic deletion mutations of survival of motor neuron 1 (SMN1) (exon 7/8 common homozygous deletions) and 2 copies of survival of motor neuron 2 (SMN2) without the known gene modifier mutation (c.859G\>C) who received an IV infusion of AVXS-101 at less than 180 days of age.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AVXS-101 | Number of Participants Who Achieved Sitting Alone for at Least 10 Seconds | 1 Participants |
Secondary
Event-free Survival at 14 Months of Age
Event-free survival at 14 months of age was defined as the number of participants who did not die, did not require permanent ventilation and did not withdraw from the study by 14 months of age.
Time frame: From Baseline up to 14 Months of Age
Population: ITT population - Symptomatic participants with biallelic deletion mutations of SMN1 (exon 7/8 common homozygous deletions) and 2 copies of SMN2 without the known gene modifier mutation (c.859G\>C) who received an IV infusion of AVXS-101 at less than 180 days of age.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AVXS-101 | Event-free Survival at 14 Months of Age | 2 Participants |