Spinal Muscular Atrophy
Conditions
Keywords
Spinal Muscular Atrophy, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS 396443
Brief summary
This study will test the safety, tolerability, and pharmacokinetics of escalating doses of nusinersen (ISIS 396443) administered into the spinal fluid either two or three times over the duration of the trial, in participants with spinal muscular atrophy (SMA). Four dose levels will be evaluated sequentially. Each dose level will be studied in a cohort of approximately 8 participants, where all participants will receive active drug.
Detailed description
This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc. In August 2016, sponsorship of the trial was transferred to Biogen.
Interventions
DRUGNusinersen
Single IT injection for each dose
Sponsors
Biogen
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 15 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Genetic documentation of 5q SMA (homozygous gene deletion or mutation) * Clinical signs attributable to SMA * Able to complete all study procedures, measurements, and visits and parent/patient has adequately supportive psychosocial circumstances, in the opinion of the Investigator * Estimated life expectancy \> 2 years from Screening * Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedure Key
Exclusion criteria
* Respiratory insufficiency defined by the medical necessity for invasive or non-invasive ventilation during a 24-hour period * Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Investigator * Previous scoliosis surgery that would interfere with the lumbar puncture injection procedure * Hospitalization for surgery (e.g. scoliosis surgery) or pulmonary event within 2 months of screening or planned during the duration of the study * Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period * History of brain or spinal cord disease that would interfere with lumbar puncture procedures or cerebrospinal fluid (CSF) circulation * Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system catheter * History of bacterial meningitis * Dosing with ISIS 396443 in clinical study ISIS 396443-CS1 Cohorts 2, 3, or 4 * Dosing with ISIS 396443 in clinical study ISIS 396443-CS10 * Clinically significant abnormalities in hematology or clinical chemistry parameters or electrocardiogram (ECG) at the Screening visit, as assessed by the Site Investigator that would render the subject unsuitable for inclusion * Treatment with investigational drug, biological agent, or device within 1-month of Screening or 5 half-lives of study agent, whichever is longer. Treatment with valproate or hydroxyurea within 3-months of screening. Any history of gene therapy or cell transplantation * Ongoing medical condition that would interfere with the conduct and assessments of the study. Examples are medical disability (e.g. wasting or cachexia, severe anemia) that would interfere with the assessment of safety or would compromise the ability of the patient to undergo study procedures. NOTE: Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of the investigational drug product, whether or not the AE is considered related to the investigational drug product. An SAE is any AE that, in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect; and is an important medical event in the judgment of the investigator. Drug-related is an event related or possibly related to study drug. Severity of AEs was assessed as mild, moderate, or severe. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax) | Day 1 and Day 85 | — |
| Plasma Pharmacokinetics: Time to Reach Cmax in Plasma | Day 1 and Day 85 | — |
| Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr) | Day 1 and Day 85 | — |
| Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations | Day 1, Day 29, and Day 85 | — |
| Urine Pharmacokinetics: Renal Clearance, Cohort 4 | Day 1 and Day 85 | Renal clearance of nusinersen for participants was assessed in the 12 mg reporting group only, per protocol. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nusinersen 3 mg 3 mg nusinersen on Days 1, 29, 85, IT injection | 8 |
| Nusinersen 6 mg 6 mg nusinersen on Days 1, 29, 85, IT injection | 8 |
| Nusinersen 9 mg 9 mg nusinersen on Days 1 and 85, IT injection | 9 |
| Nusinersen 12 mg 12 mg nusinersen on Days 1, 29, 85, IT injection | 9 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Investigator Judgment | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Nusinersen 3 mg | Nusinersen 6 mg | Nusinersen 9 mg | Nusinersen 12 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 8.6 years STANDARD_DEVIATION 5.4 | 8.1 years STANDARD_DEVIATION 5.2 | 6.0 years STANDARD_DEVIATION 4 | 6.9 years STANDARD_DEVIATION 4.3 | 7.4 years STANDARD_DEVIATION 4.6 |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 4 Participants | 3 Participants | 14 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 5 Participants | 6 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 6 / 8 | 9 / 9 | 9 / 9 |
| serious Total, serious adverse events | 2 / 8 | 0 / 8 | 0 / 9 | 1 / 9 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of the investigational drug product, whether or not the AE is considered related to the investigational drug product. An SAE is any AE that, in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect; and is an important medical event in the judgment of the investigator. Drug-related is an event related or possibly related to study drug. Severity of AEs was assessed as mild, moderate, or severe.
Time frame: Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days
Population: Safety Population, defined as all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nusinersen 3 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Any AE | 8 Participants |
| Nusinersen 3 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Highest severity of AE=moderate | 4 Participants |
| Nusinersen 3 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Highest severity of AE=mild | 2 Participants |
| Nusinersen 3 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Any drug-related AE | 0 Participants |
| Nusinersen 3 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Highest severity of AE=severe | 2 Participants |
| Nusinersen 3 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Any SAE | 2 Participants |
| Nusinersen 3 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Discontinued due to an AE | 0 Participants |
| Nusinersen 6 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Highest severity of AE=moderate | 2 Participants |
| Nusinersen 6 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Discontinued due to an AE | 0 Participants |
| Nusinersen 6 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Any SAE | 0 Participants |
| Nusinersen 6 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Highest severity of AE=mild | 2 Participants |
| Nusinersen 6 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Highest severity of AE=severe | 2 Participants |
| Nusinersen 6 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Any drug-related AE | 0 Participants |
| Nusinersen 6 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Any AE | 6 Participants |
| Nusinersen 9 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Discontinued due to an AE | 0 Participants |
| Nusinersen 9 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Any AE | 9 Participants |
| Nusinersen 9 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Any drug-related AE | 0 Participants |
| Nusinersen 9 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Any SAE | 0 Participants |
| Nusinersen 9 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Highest severity of AE=mild | 6 Participants |
| Nusinersen 9 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Highest severity of AE=moderate | 3 Participants |
| Nusinersen 9 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Highest severity of AE=severe | 0 Participants |
| Nusinersen 12 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Any SAE | 1 Participants |
| Nusinersen 12 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Highest severity of AE=severe | 0 Participants |
| Nusinersen 12 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Highest severity of AE=moderate | 4 Participants |
| Nusinersen 12 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Any drug-related AE | 0 Participants |
| Nusinersen 12 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Any AE | 9 Participants |
| Nusinersen 12 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Highest severity of AE=mild | 5 Participants |
| Nusinersen 12 mg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | Discontinued due to an AE | 0 Participants |
Secondary
Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations
Time frame: Day 1, Day 29, and Day 85
Population: PK Population, defined as all enrolled participants who have evaluable PK data; number analyzed=participants with an assessment at given time point. (This study includes participants previously enrolled in Study ISIS 396443 - CS1 (NCT01494701).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nusinersen 3 mg | Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations | Day 1 | 0.0651 ng/mL | Standard Deviation 0.117 |
| Nusinersen 3 mg | Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations | Day 29 | 1.41 ng/mL | Standard Deviation 0.456 |
| Nusinersen 3 mg | Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations | Day 85 | 2.12 ng/mL | Standard Deviation 0.573 |
| Nusinersen 6 mg | Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations | Day 29 | 2.65 ng/mL | Standard Deviation 1.44 |
| Nusinersen 6 mg | Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations | Day 1 | 0.0560 ng/mL | Standard Deviation 0.104 |
| Nusinersen 6 mg | Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations | Day 85 | 3.76 ng/mL | Standard Deviation 2.05 |
| Nusinersen 9 mg | Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations | Day 1 | NA ng/mL | — |
| Nusinersen 9 mg | Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations | Day 85 | 1.50 ng/mL | Standard Deviation 0.447 |
| Nusinersen 12 mg | Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations | Day 29 | 2.22 ng/mL | Standard Deviation 0.924 |
| Nusinersen 12 mg | Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations | Day 85 | 3.36 ng/mL | Standard Deviation 1.04 |
| Nusinersen 12 mg | Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations | Day 1 | NA ng/mL | — |
Secondary
Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax)
Time frame: Day 1 and Day 85
Population: Pharmacokinetic (PK) Population, defined as all enrolled participants who have evaluable PK data; number analyzed=participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nusinersen 3 mg | Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax) | Day 1 | 51.5 ng/mL | Standard Deviation 72.7 |
| Nusinersen 3 mg | Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax) | Day 85 | 32.5 ng/mL | Standard Deviation 32.3 |
| Nusinersen 6 mg | Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax) | Day 85 | 52.8 ng/mL | Standard Deviation 33.5 |
| Nusinersen 6 mg | Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax) | Day 1 | 79.8 ng/mL | Standard Deviation 57.2 |
| Nusinersen 9 mg | Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax) | Day 1 | 141.0 ng/mL | Standard Deviation 52.8 |
| Nusinersen 9 mg | Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax) | Day 85 | 127.0 ng/mL | Standard Deviation 37.7 |
| Nusinersen 12 mg | Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax) | Day 1 | 208.0 ng/mL | Standard Deviation 110 |
| Nusinersen 12 mg | Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax) | Day 85 | 132.0 ng/mL | Standard Deviation 85.6 |
Secondary
Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr)
Time frame: Day 1 and Day 85
Population: PK Population, defined as all enrolled participants who have evaluable PK data; number analyzed=participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nusinersen 3 mg | Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr) | Day 1 | 181 ng*hr/mL | Standard Deviation 225 |
| Nusinersen 3 mg | Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr) | Day 85 | 110 ng*hr/mL | Standard Deviation 107 |
| Nusinersen 6 mg | Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr) | Day 85 | 179 ng*hr/mL | Standard Deviation 135 |
| Nusinersen 6 mg | Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr) | Day 1 | 306 ng*hr/mL | Standard Deviation 259 |
| Nusinersen 9 mg | Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr) | Day 1 | 601 ng*hr/mL | Standard Deviation 249 |
| Nusinersen 9 mg | Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr) | Day 85 | 524 ng*hr/mL | Standard Deviation 185 |
| Nusinersen 12 mg | Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr) | Day 1 | 823 ng*hr/mL | Standard Deviation 442 |
| Nusinersen 12 mg | Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr) | Day 85 | 555 ng*hr/mL | Standard Deviation 398 |
Secondary
Plasma Pharmacokinetics: Time to Reach Cmax in Plasma
Time frame: Day 1 and Day 85
Population: PK Population, defined as all enrolled participants who have evaluable PK data; number analyzed=participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nusinersen 3 mg | Plasma Pharmacokinetics: Time to Reach Cmax in Plasma | Day 1 | 5.09 hours |
| Nusinersen 3 mg | Plasma Pharmacokinetics: Time to Reach Cmax in Plasma | Day 85 | 6.08 hours |
| Nusinersen 6 mg | Plasma Pharmacokinetics: Time to Reach Cmax in Plasma | Day 85 | 6.04 hours |
| Nusinersen 6 mg | Plasma Pharmacokinetics: Time to Reach Cmax in Plasma | Day 1 | 5.93 hours |
| Nusinersen 9 mg | Plasma Pharmacokinetics: Time to Reach Cmax in Plasma | Day 1 | 3.92 hours |
| Nusinersen 9 mg | Plasma Pharmacokinetics: Time to Reach Cmax in Plasma | Day 85 | 4.12 hours |
| Nusinersen 12 mg | Plasma Pharmacokinetics: Time to Reach Cmax in Plasma | Day 1 | 4.05 hours |
| Nusinersen 12 mg | Plasma Pharmacokinetics: Time to Reach Cmax in Plasma | Day 85 | 5.92 hours |
Secondary
Urine Pharmacokinetics: Renal Clearance, Cohort 4
Renal clearance of nusinersen for participants was assessed in the 12 mg reporting group only, per protocol.
Time frame: Day 1 and Day 85
Population: Pharmacokinetic (PK) Population, defined as all enrolled participants who have evaluable PK data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nusinersen 3 mg | Urine Pharmacokinetics: Renal Clearance, Cohort 4 | Day 1 | 0.674 mL/hr | Standard Deviation 0.602 |
| Nusinersen 3 mg | Urine Pharmacokinetics: Renal Clearance, Cohort 4 | Day 85 | 77.5 mL/hr | Standard Deviation 92.5 |