Muscular Atrophy, Spinal
Conditions
Keywords
Zolgensma, OAV101, AVXS 101, gene therapy, Muscle atrophy, SBMA, spinal and bulbar muscular atrophy, spinal muscular atrophy, bulbar muscular atrophy, muscle function, myopathy, muscle wasting, atrophied muscle, loss of muscle strength
Brief summary
This was a phase IV Open-label, single-arm, single-dose, multicenter study, to evaluate the safety, tolerability and efficacy of intravenous administration of OAV101 (AVXS-101) in patients with SMA with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene ≤ 24 months and weighing ≤ 17 kg, over a 18-month period post infusion.
Detailed description
This is an open-label, single arm, multi-center study to evaluate the safety, tolerability, and efficacy of IV OAV101 in symptomatic SMA pediatric participants. The study enrolled participants ≤ 24 months old that weigh ≤ 17 kg. Participants who met eligibility criteria at Screening and Baseline visits received a single dose of IV OAV101 t the approved dose of 1.1e14 vg/kg and were followed for 18 months. The study included a 20-day screening period in which there were 2 Screening visits, during which, eligibility was assessed (Screening 1), weight was collected for dose calculation (Screening 2), and baseline assessments were performed prior to treatment. On Day -1, participants were admitted to the hospital for pre-treatment baseline procedures including prednisolone treatment per study protocol. On Day 1, participants received a single IV infusion of OAV101. Participants were discharged 12-48 hours after the infusion, based on Investigator judgment. Safety monitoring was performed on an ongoing basis per protocol requirement and was evaluated by the clinical safety team as well as DMC (Data monitoring committee).
Interventions
GENETICOAV101
A single Gene Therapy IV infusion at 1.1e14 vector genome (vg)/kg over approximately 60 minutes
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
OAV101 will be administered as a single IV infusion at 1.1e14 vg/kg over approximately 60 minutes
Eligibility
Sex/Gender
ALL
Age
No minimum to 24 Months
Healthy volunteers
No
Inclusion criteria
1. Written informed consent/assent obtained prior to any assessment performed 2. Symptomatic SMA diagnosis based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point mutations) and any copy of SMN2 gene. 3. Age ≤ 24 months of age at time of treatment 3\. Weight ≤17 kg at the time of Screening Period 4. Naïve to treatment or have discontinued an approved drug/therapy 5. Up-to date on recommended childhood vaccinations and RSV prophylaxis with palivizumab (also known as Synagis), per local standard of care Key
Exclusion criteria
1. Previous use of OAV101 or any AAV9 gene therapy 2. Participant with history of aspiration pneumonia or signs of aspiration (eg, coughing or sputtering of food) within 4 weeks prior to Screening 3. Participant dependent on gastrostomy feeding tube for 100% of nutritional intake. 4. Anti-AAV9 antibody titer \> 1:50 as determined by ligand binding immunoassay at the time of screening 5. Inability to take corticosteroids 6. Concomitant use of immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, or immunosuppressive therapy within 3 months prior to gene replacement therapy (eg, cyclosporine, tacrolimus, methotrexate, rituximab cyclophosphamide, IV immunoglobulin) 7. Hepatic dysfunction (i.e. AST, ALT, bilirubin, GGT or GLDH, ≥ ULN; CTCAE ≥ 1) at Screening (with the exception of isolated AST elevation: in the absence of other liver laboratory abnormalities, isolated AST elevation is not considered exclusionary) 8. Previously treated with nusinersen (Spinraza®) within 4 months prior to Screening 9. Previously treated with risdiplam (EvrysdiTM) within 15 days prior to Screening (washout period of at least 5 half-lives before Screening)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent AEs and SAEs | Up to Month 18 | An AE is any untoward medical occurrence (eg any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. Changes from baseline in vital signs, cardiac safety assessments, and clinical laboratory results are reported as Adverse Events if clinically significant and as applicable, per investigator assessment. |
| Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | Up to Month 18 | An AE is any untoward medical occurrence (eg any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. Adverse events of special interest (AESI) are defined by the important identified risk and important potential risk: Hepatotoxicity, Thrombocytopenia, Cardiac adverse events, Sensory abnormalities suggestive of ganglionopathy, and Thrombotic microangiopathy. These were assessed by the investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Baseline (Screening), and at Weeks 26, 52 and 78 | The World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) was used to measure developmental motor milestones. This was assessed via the milestone checklist. The 6 developmental milestones are: sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone and walking alone. A yes response indicates that the patient reached a particular development milestone. |
Countries
Argentina, Brazil
Participant flow
Recruitment details
16 participants were enrolled into the study, at five sites from Brazil (three sites) and Argentina (two sites). Six participants were from Argentina and 10 from Brazil.
Pre-assignment details
On Day -1, participants were admitted to the hospital for pre-treatment baseline procedures including prednisolone treatment per study protocol.
Participants by arm
| Arm | Count |
|---|---|
| OAV101 A single IV infusion at 1.1e14 vg/kg over approximately 60 minutes | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
Baseline characteristics
| Characteristic | OAV101 | — |
|---|---|---|
| Age, Continuous Age at dosing | 15.79 months STANDARD_DEVIATION 5.89 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 11 Participants | — |
| Sex: Female, Male Male | 5 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 16 |
| other Total, other adverse events | 16 / 16 |
| serious Total, serious adverse events | 11 / 16 |
Outcome results
Primary
Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest
An AE is any untoward medical occurrence (eg any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. Adverse events of special interest (AESI) are defined by the important identified risk and important potential risk: Hepatotoxicity, Thrombocytopenia, Cardiac adverse events, Sensory abnormalities suggestive of ganglionopathy, and Thrombotic microangiopathy. These were assessed by the investigator.
Time frame: Up to Month 18
Population: Full analysis set (FAS) - all treated patients.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | Risk name: Hepatotoxicity | 11 Participants |
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | -Preferred term: Aspartate aminotransferase increased | 5 Participants |
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | -Preferred term: Alanine aminotransferase increased | 5 Participants |
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | -Preferred term: Blood alkaline phosphatase increased | 2 Participants |
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | -Preferred term: Bilirubin conjugated increased | 2 Participants |
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | -Preferred term: Gamma-glutamyltransferase increased | 5 Participants |
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | -Preferred term: Hepatic enzyme increased | 3 Participants |
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | -Preferred term: Hepatic failure | 1 Participants |
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | -Preferred term: Transaminases increased | 2 Participants |
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | Risk name: Thrombocytopenia | 5 Participants |
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | -Preferred term: Platelet count decreased | 4 Participants |
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | -Preferred term: Thrombocytopenia | 1 Participants |
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | Risk name: Thrombotic microangiopathy | 2 Participants |
| OAV101 | Evaluation of Important Identified and Important Potential Risks - Treatment-emergent Adverse Events of Special Interest | -Preferred term: Thrombotic microangiopathy | 2 Participants |
Primary
Number of Participants With Treatment Emergent AEs and SAEs
An AE is any untoward medical occurrence (eg any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. Changes from baseline in vital signs, cardiac safety assessments, and clinical laboratory results are reported as Adverse Events if clinically significant and as applicable, per investigator assessment.
Time frame: Up to Month 18
Population: Full analysis set (FAS) - all treated patients.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| OAV101 | Number of Participants With Treatment Emergent AEs and SAEs | Any treatment-emergent adverse events | 16 Participants |
| OAV101 | Number of Participants With Treatment Emergent AEs and SAEs | Any treatment-emergent adverse events related to OAV101 | 11 Participants |
| OAV101 | Number of Participants With Treatment Emergent AEs and SAEs | Any serious treatment-emergent adverse events | 11 Participants |
| OAV101 | Number of Participants With Treatment Emergent AEs and SAEs | Serious treatment-emergent adverse events related to OAV101 | 3 Participants |
| OAV101 | Number of Participants With Treatment Emergent AEs and SAEs | Treatment-emergent adverse events leading to study discontinuation | 0 Participants |
| OAV101 | Number of Participants With Treatment Emergent AEs and SAEs | Treatment-emergent adverse events leading to death | 2 Participants |
| OAV101 | Number of Participants With Treatment Emergent AEs and SAEs | Treatment-emergent adverse events of special interest | 12 Participants |
Secondary
Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS)
The World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) was used to measure developmental motor milestones. This was assessed via the milestone checklist. The 6 developmental milestones are: sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone and walking alone. A yes response indicates that the patient reached a particular development milestone.
Time frame: Baseline (Screening), and at Weeks 26, 52 and 78
Population: Full analysis set (FAS) - all treated patients with evaluable assessments at the respective assessment time points.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Screening - Sitting without support | 6 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Screening - Hands-and-knees crawling | 2 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Screening - Standing with assistance | 1 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Screening - Walking with assistance | 0 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Screening - Standing alone | 0 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Screening - Walking alone | 0 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 26 Sitting without support (n=14) | 12 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 26 Hands-and-knees crawling (n=14) | 2 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 26 Standing with assistance (n=14) | 2 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 26 Walking with assistance (n=14) | 2 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 26 Standing alone (n=14) | 1 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 26 Walking alone (n=14) | 0 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 52 Sitting without support (n=13) | 10 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 52 Hands-and-knees crawling (n=13) | 4 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 52 Standing with assistance (n=13) | 7 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 52 Walking with assistance (n=13) | 3 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 52 Standing alone (n=13) | 6 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 52 Walking alone (n=13) | 2 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 78 Sitting without support (n=12) | 10 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 78 Hands-and-knees crawling (n=12) | 3 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 78 Standing with assistance (n=12) | 7 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 78 Walking with assistance (n=12) | 2 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 78 Standing alone (n=12) | 3 Participants |
| OAV101 | Number of Participants Who Achieve Development Motor Milestones According to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) | Week 78 Walking alone (n=12) | 1 Participants |