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Brand Name
Spinraza
Generic Name
Nusinersen
View Brand Information FDA approval date: December 23, 2016
Classification: Antisense Oligonucleotide
Form: Injection
What is Spinraza (Nusinersen)?
SPINRAZA is indicated for the treatment of spinal muscular atrophy in pediatric and adult patients. SPINRAZA is a survival motor neuron-2 -directed antisense oligonucleotide indicated for the treatment of spinal muscular atrophy in pediatric and adult patients
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Safety and Performance of the ThecaFlex DRx™ System Port and Catheter for Chronic Intrathecal Access, Cerebrospinal Fluid (CSF) Aspiration, and DElivery of Nusinersen in Spinal Muscular Atrophy (SMA) Patients Resistant to Lumbar PunctuRE Trial (PIERRE)
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Brand Information
Spinraza (Nusinersen)
1INDICATIONS AND USAGE
SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients.
2DOSAGE FORMS AND STRENGTHS
Injection: nusinersen is a clear and colorless solution supplied in single-dose vials in the following strengths:
- 12 mg/5 mL (2.4 mg/mL)
- 28 mg/5 mL (5.6 mg/mL)
- 50 mg/5 mL (10 mg/mL)
3CONTRAINDICATIONS
None.
4ADVERSE REACTIONS
The following serious adverse reactions are described in detail in other sections of the labeling:
- Thrombocytopenia and Coagulation Abnormalities
- Renal Toxicity
4.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of SPINRAZA cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice.
4.2Postmarketing Experience
The following adverse reactions have been identified during post-approval use of SPINRAZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serious infections associated with lumbar puncture, such as meningitis, have been reported. Hydrocephalus, aseptic meningitis, hypersensitivity reactions (e.g. angioedema, urticaria, rash), and arachnoiditis have also been reported.
5DESCRIPTION
Nusinersen is a modified antisense oligonucleotide, where the 2'-hydroxy groups of the ribofuranosyl rings are replaced with 2'-O-2-methoxyethyl groups and the phosphate linkages are replaced with phosphorothioate linkages. Nusinersen binds to a specific sequence in the intron downstream of exon 7 of the
SPINRAZA is supplied as a sterile, preservative-free, colorless solution for intrathecal use in a single-dose glass vial in the following strengths:
- 12 mg/5 mL (2.4 mg/mL)
- 28 mg/5 mL (5.6 mg/mL)
- 50 mg/5 mL (10 mg/mL)
Each 1 mL solution of the 12 mg/5 mL strength contains 2.4 mg of nusinersen (equivalent to 2.53 mg of nusinersen sodium salt). Each 1 mL also contains calcium chloride dihydrate (0.21 mg) USP, magnesium chloride hexahydrate (0.16 mg) USP, potassium chloride (0.22 mg) USP, sodium chloride (8.77 mg) USP, sodium phosphate dibasic anhydrous (0.10 mg) USP, sodium phosphate monobasic dihydrate (0.05 mg) USP, and Water for Injection USP.
Each 1 mL solution of the 28 mg/5 mL strength contains 5.6 mg of nusinersen (equivalent to 5.90 mg of nusinersen sodium salt). Each 1 mL also contains calcium chloride dihydrate (0.21 mg) USP, magnesium chloride hexahydrate (0.16 mg) USP, potassium chloride (0.22 mg) USP, sodium chloride (8.39 mg) USP, sodium phosphate dibasic anhydrous (0.10 mg) USP, sodium phosphate monobasic dihydrate (0.05 mg) USP, and Water for Injection USP.
Each 1 mL solution of the 50 mg/5 mL strength contains 10 mg of nusinersen (equivalent to 10.54 mg of nusinersen sodium salt). Each 1 mL also contains calcium chloride dihydrate (0.21 mg) USP, magnesium chloride hexahydrate (0.16 mg) USP, potassium chloride (0.22 mg) USP, sodium chloride (8.11 mg) USP, sodium phosphate dibasic anhydrous (0.10 mg) USP, sodium phosphate monobasic dihydrate (0.05 mg) USP, and Water for Injection USP.
For all strengths the product may contain hydrochloric acid or sodium hydroxide to adjust pH. The pH is ~7.2.
The molecular formula of SPINRAZA is C
6CLINICAL STUDIES
The efficacy of SPINRAZA Low Dose Regimen was demonstrated in two double-blind, sham-procedure controlled clinical trials in patients with symptomatic infantile-onset and later-onset SMA (Study 1 and Study 2) and was supported by open-label clinical trials conducted in patients with presymptomatic (Study 3) and symptomatic SMA
6.1Infantile-Onset SMA
Study 1 (NCT02193074) was a multicenter, randomized, double-blind, sham-procedure controlled study in 121 symptomatic infants ≤ 7 months of age at the time of first dose, diagnosed with SMA (symptom onset before 6 months of age). Patients were randomized 2:1 to receive either SPINRAZA Low Dose Regimen or sham injection as a series of loading doses administered intrathecally followed by maintenance doses administered every 4 months. Patients in this study were deemed most likely to develop Type 1 SMA.
A planned interim efficacy analysis was conducted based on patients who died, withdrew, or completed at least 183 days of treatment. Of the 82 patients included in the interim analysis (52 patients in the SPINRAZA-treated group and 30 in the sham-control group), 44% were male, 87% were Caucasian, 2% were Black, and 4% were Asian. Age at first treatment ranged from 30 to 262 days (median 181). Length of treatment ranged from 6 to 442 days (median 261 days). Baseline demographics were balanced between the SPINRAZA and control groups with the exception of age at first treatment (median age 175 vs. 206 days, respectively). The SPINRAZA and control groups were balanced with respect to gestational age, birth weight, disease duration, and SMN2 copy number. Median disease duration was 14 weeks. There was some imbalance in age at symptom onset with 88% of subjects in the SPINRAZA group and 77% in the control group experiencing symptoms within the first 12 weeks of life.
The primary endpoint assessed at the time of interim analysis was the proportion of responders: patients with an improvement in motor milestones according to Section 2 of the Hammersmith Infant Neurologic Exam (HINE). This endpoint evaluates seven different areas of motor milestone development, with a maximum score between 2-4 points for each, depending on the milestone, and a total maximum score of 26. A treatment responder was defined as any patient with at least a 2-point increase (or maximal score of 4) in ability to kick (consistent with improvement by at least 2 milestones), or at least a 1-point increase in the motor milestones of head control, rolling, sitting, crawling, standing or walking (consistent with improvement by at least 1 milestone). To be classified as a responder, patients needed to exhibit improvement in more categories of motor milestones than worsening. Of the 82 patients who were eligible for the interim analysis, a statistically significantly greater percentage of patients achieved the definition of a motor milestone responder in the SPINRAZA group (40%) compared to the sham-control group (0%). Results from the final analysis were consistent with those from the interim analysis (
The primary endpoint assessed at the final analysis was time to death or permanent ventilation (≥ 16 hours ventilation/day continuously for > 21 days in the absence of an acute reversible event or tracheostomy). Statistically significant effects on event-free survival and overall survival were observed in patients in the SPINRAZA group compared to those in the sham-control group (
At the final analysis, the study also assessed treatment effects on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), which is an evaluation of motor skills in patients with infantile-onset SMA. The CHOP-INTEND results are displayed in
Figure 1. Percent of Patients Who Died and Net Change from Baseline in Total Motor Milestone Score (HINE) Among Patients Alive in the Final Efficacy Set of Study 1 *
*For subjects who were alive and ongoing in the study, the change in total motor milestone score was calculated at the later of Day 183, Day 302, or Day 394.
Figure 2. Event-Free Survival in the Intent to Treat Set
Study 4 (NCT04089566) Part B was a multicenter, double-blind, randomized, controlled study, which included 75 patients with infantile-onset SMA (2 SMN2 copies; symptom onset before 6 months of age). Part B was powered to assess efficacy in infantile-onset patients by evaluating the change in CHOP-INTEND at Day 183 in the patients receiving SPINRAZA High Dose Regimen (n=50) as compared to a prespecified matched sham group from Study 1 (n=20; matched on baseline disease duration and baseline CHOP-INTEND score).
Baseline demographic characteristics of the SPINRAZA group and matched sham group were balanced. Of the 70 patients 50% were male, 64% were Caucasian, and 16% were Asian. Relative to the infantile-onset population in Study 1, patients enrolled in Study 4 had shorter disease duration (time from symptom onset to screening) and lower baseline CHOP-INTEND scores, suggesting they were progressing more quickly and further into their disease course.
A statistically significant improvement in the mean change from baseline in CHOP-INTEND at Day 183 was observed in the SPINRAZA High Dose Regimen group (15.1 point improvement) compared to the matched sham group (11.1 point worsening) (LS mean difference:26.19 points (95% CI: 20,7, 31.7)) p= <0.0001 (
A statistically significantly greater percentage of patients in the SPINRAZA High Dose Regimen group met the HINE-2 responder definition at Day 183 as compared to the matched sham group (58% vs. 0%; p<0.0001).
Similar to Study 1, the SPINRAZA High Dose Regimen group experienced a nominally statistically significant 67% reduction in the risk of death or permanent ventilation relative to the matched sham group (p = 0.0006). The median time to death or permanent ventilation was not reached in the SPINRAZA group and was 19.1 weeks in the matched sham group. Similar observations were seen for overall survival.
6.2Later-Onset SMA
Study 2 (NCT02292537) was a multicenter, randomized, double-blind, sham-procedure controlled study in 126 symptomatic children with later-onset SMA (symptom onset after 6 months of age). Patients were randomized 2:1 to either SPINRAZA Low Dose Regimen or sham injection as a series of loading doses administered intrathecally followed by maintenance doses administered every 6 months.
The median age at screening was 3 years (range 2-9 years), and the median age of onset of clinical signs and symptoms of SMA was 11 months (range 6-20 months). Of the 126 patients included in the study, 47% were male, 75% were Caucasian, 2% were Black, and 18% were Asian. Length of treatment ranged from 324 to 482 days (median 450 days). At baseline, patients had a mean Hammersmith Functional Motor Scale – Expanded (HFMSE) score of 21.6, all had achieved independent sitting, and no patients had achieved independent walking. Patients in this study were deemed most likely to develop Type 2 or 3 SMA.
The primary endpoint assessed was the change from baseline score at Month 15 on the HFMSE. The HFMSE evaluates motor function in patients with SMA who have limited ambulation, comprising of 33 scored activities that give objective information on motor ability and clinical progression, such as the ability to sit unassisted, stand, or walk. Each item is scored from 0-2, with a maximum total score of 66. Higher scores indicate better motor function. The primary analysis was conducted in the Intent to Treat (ITT) population, which included all subjects who were randomized and received at least 1 dose of SPINRAZA or at least one sham procedure. At the final analysis, a statistically significant improvement in HFMSE scores from baseline to Month 15 was observed in the group treated with SPINRAZA Low Dose Regimen compared to the sham-control group (
Figure 3. Mean Change from Baseline in HFMSE Score Over Time in the Intent to Treat Set1, 2(Study 2)
1Data for patients without a Month 15 visit were imputed using the multiple imputation method
2Error bars denote +/- standard error
Study 4 (NCT04089566) Part B was a double-blind, randomized, controlled study, which included 24 patients with later-onset SMA (symptom onset after six months of age) who were randomized 2:1 to receive SPINRAZA High Dose Regimen (n=16) or SPINRAZA Low Dose Regimen treatment (n=8)
Baseline demographic characteristics between all groups were generally balanced.
The efficacy endpoints for the later-onset population in Study 4 were the change from baseline to Day 302 in the HFMSE and in the Revised Upper Limb Module (RULM) score. The RULM test assesses functional ability of the upper limbs in patients with SMA and is comprised of 19 items scored on a 3-point scale. The maximum score is 37 points. The change from baseline to Day 302 in HFMSE score and RULM score showed a slight numerical difference favoring the SPINRAZA High Dose Regimen, though the comparison was not powered to achieve statisitical significance.
6.3Presymptomatic SMA
The results of the sham-controlled trial in patients with infantile-onset (Study 1) (NCT02193074) and later-onset (Study 2) (NCT02292537) SMA were supported by an open-label uncontrolled trial conducted in 25 patients with presymptomatic SMA who had a genetic diagnosis of 5q SMA and 2 or 3 copies of SMN2 (Study 3) (NCT02386553). In Study 3, 15 patients (60%) who had 2 SMN2 copies, and 10 patients (40%) who had 3 SMN2 copies; 48% were male, 56% were Caucasian, 12% were Asian, 4% were American Indian or Alaska Native, and 28% were of another race, or had no race reported. Patients ranged in age from 3 days to 42 days (median 22 days) at the time of first dose. Patients received SPINRAZA Low Dose Regimen