These highlights do not include all the information needed to use

SPINRAZA is administered intrathecally by, or under the direction of, healthcare professionals experienced in performing lumbar punctures.

Two dosing regimen options for SPINRAZA, which consist of loading followed by maintenance dosages, are presented in Table 1.

SPINRAZA is for intrathecal use only.

Prepare and use SPINRAZA according to the following steps using aseptic technique. Each vial is intended for single dose only.

Use the vial strength that corresponds to the prescribed dose. Do not combine SPINRAZA vials of different strengths and concentrations or use partial vials to achieve the prescribed dose.

Preparation

• Store SPINRAZA in the carton in a refrigerator until time of use.
• Allow the SPINRAZA vial to warm to room temperature (25^o C/77^o F) prior to administration. Do not use external heat sources.
• Inspect the SPINRAZA vial for particulate matter and discoloration prior to administration. Do not administer SPINRAZA if visible particulates are observed or if the liquid in the vial is discolored. The use of external filters is not required.
• Withdraw 5 mL of SPINRAZA from the single-dose vial into a syringe and discard unused contents of the vial.
• Administer SPINRAZA within 4 hours of removal from vial.

Administration

• Consider sedation as indicated by the clinical condition of the patient.
• Consider ultrasound or other imaging techniques to guide intrathecal administration of SPINRAZA, particularly in younger patients.
• Prior to administration, remove 5 mL of cerebrospinal fluid.
• Administer SPINRAZA as an intrathecal bolus injection over 1 to 3 minutes using a spinal anesthesia needle [see Dosage and Administration (2.1)]. Do not administer SPINRAZA in areas of the skin where there are signs of infection or inflammation [see Adverse Reactions (6.3)].

Conduct the following laboratory tests at baseline and prior to each dose of SPINRAZA and as clinically needed [see Warnings and Precautions (5.1, 5.2)]:

• Platelet count
• Prothrombin time; activated partial thromboplastin time
• Quantitative spot urine protein testing

If transitioning from SPINRAZA Low Dose Regimen to High Dose Regimen, administer a single 50 mg bolus dose at least four months (+/- 14 days) after the last 12 mg maintenance dose, followed by a 28 mg maintenance dose once every 4 months thereafter. Additional clinical benefit in patients who transition from the Low Dose Regimen to the High Dose Regimen has not been established in a controlled study. 

Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides.

In the sham-controlled studies for patients with infantile-onset (Study 1) and later-onset (Study 2) SMA who received Low Dose Regimen [see Clinical Studies (14.1,14.2)], 24 of 146 (16%) SPINRAZA-treated patients with high, normal, or unknown platelet count at baseline developed a platelet level below the lower limit of normal, compared to 10 of 72 (14%) sham-controlled patients.

In Study 2, two SPINRAZA-treated patients developed platelet counts less than 50,000 cells per microliter, with a lowest level of 10,000 cells per microliter recorded on study day 28.

In patients who received High Dose Regimen, decreases in platelet counts were also observed.

Because of the risk of thrombocytopenia and coagulation abnormalities from SPINRAZA, patients may be at increased risk of bleeding complications.

Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed.

Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides.

SPINRAZA is present in and excreted by the kidney [see Clinical Pharmacology (12.3)]. In Study 1 and Study 2, 71 of 123 (58%) of SPINRAZA-treated patients had elevated urine protein, compared to 22 of 65 (34%) sham-controlled patients. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration greater than 0.2 g/L, consider repeat testing and further evaluation.

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.

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.

The safety and effectiveness of SPINRAZA in pediatric patients from newborn to 17 years have been established [see Clinical Studies (14.1)].

Clinical studies of SPINRAZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

SPINRAZA is an antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Using in vitro assays and studies in transgenic animal models of SMA, SPINRAZA was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein.

Autopsy samples from patients (n=3) had higher levels of SMN2 messenger ribonucleic acid (mRNA) containing exon 7 in the thoracic spinal cord compared to untreated SMA infants.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of SPINRAZA or of other nusinersen products.

The immunogenic response to nusinersen in patients who received SPINRAZA Low Dose Regimen was evaluated in 367 patients with post-baseline plasma samples for anti-drug antibodies (ADAs). Thirty eight patients (10%) developed treatment-emergent ADAs, of which 16 were transient and 22 were considered to be persistent. Persistent was defined as having one positive test followed by another one more than 100 days after the first positive test. In addition, “persistent” is also defined as having one or more positive samples and no sample more than 100 days after the first positive sample. Transient was defined as having one or more positive results and not confirmed to be persistent.

The immunogenic response to nusinersen in patients who received SPINRAZA High Dose Regimen was evaluated in 117 patients with post-baseline plasma samples for ADAs. Eleven patients (9%) developed treatment-emergent ADAs, of which 5 were transient and 6 were persistent.

There are insufficient data to evaluate an effect of ADAs on clinical response, adverse events, or the pharmacokinetic profile of nusinersen.

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 (Table 5). Fifty-one percent of patients in the SPINRAZA group achieved the definition of a motor milestone responder compared to 0% of patients in the sham-control group. Figure 1 is a descriptive display of the distribution of net change from baseline in the total motor milestone score for Section 2 of the HINE for patients in the final efficacy set who did not die or withdraw from the study.

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 (Table 6). A 47% reduction in the risk of death or permanent ventilation was observed in the SPINRAZA group (p=0.005) (Figure 2). Median time to death or permanent ventilation was not reached in SPINRAZA group and was 22.6 weeks in the sham-control group. A statistically significant 63% reduction in the risk of death was also observed (p=0.004).

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 Table 5.

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 (Table 7).

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.

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 (Table 8).

Figure 3. Mean Change from Baseline in HFMSE Score Over Time in the Intent to Treat Set^{1, 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) [see Dosage and Administration (2.1)].

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.

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 [see Dosage and Administration (2.1)]. Patients were assessed with the World Health Organization (WHO) motor milestones, a set of 6 milestones in motor development that would be expected to be attained by 24 months of age in healthy children. An interim analysis was performed after all patients had received SPINRAZA for at least 14 months (median 25 months, range 14 to 34 months). Patients ranged in age from 14 to 34 months (median age of 26 months) at the time of the analysis. At the time of the interim analysis (data cutoff May 2018), all patients receiving SPINRAZA before the onset of SMA symptoms survived without requiring permanent ventilation, and beyond what would be expected based on their SMN2 copy number. All 25 patients (100%) had achieved the WHO motor milestone of sitting without support, and 22 patients (88%) had achieved the milestone of walking with assistance. Of the 22 patients who were older than the age expected to have achieved the ability to walk independently (as defined by the 95th percentile of the WHO expected age of achievement), 17 (77%) achieved the milestone of walking alone (i.e., walking independently).

SPINRAZA injection is a sterile, clear and colorless, preservative-free solution in single-dose glass vials supplied as one vial per carton in the following strengths:

• 12 mg/5 mL (2.4 mg/mL) (NDC 64406-058-01)
• 28 mg/5 mL (5.6 mg/mL) (NDC 64406-036-01)
• 50 mg/5 mL (10 mg/mL) (NDC 64406-037-01)

Store in a refrigerator between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze.

SPINRAZA should be protected from light and kept in the original carton until time of use.

If no refrigeration is available, SPINRAZA may be stored in its original carton, protected from light at or below 30^oC (86^oF) for up to 14 days.

Prior to administration, unopened vials of SPINRAZA can be removed from and returned to the refrigerator, if necessary. If removed from the original carton, the total combined time out of refrigeration should not exceed 30 hours at a temperature that does not exceed 25^oC (77^oF).

Thrombocytopenia and Coagulation Abnormalities

Inform patients and caregivers that SPINRAZA could increase the risk of bleeding. Inform patients and caregivers of the importance of obtaining blood laboratory testing at baseline and prior to each dose to monitor for signs of increased potential for bleeding. Instruct patients and caregivers to seek medical attention if unexpected bleeding occurs [see Warnings and Precautions (5.1)].

Renal Toxicity

Inform patients and caregivers that SPINRAZA could cause renal toxicity. Inform patients and caregivers of the importance of obtaining urine testing at baseline and prior to each dose to monitor for signs of potential renal toxicity [see Warnings and Precautions (5.2)].

60110-01

Manufactured for:
Biogen
Cambridge, MA 02142
SPINRAZA is a registered trademark of Biogen.
© Biogen 2016-2026