Spinraza Drug Information
Generic name: NUSINERSEN
Survival Motor Neuron-2-directed RNA Interaction [EPC] Antisense Oligonucleotide [EPC]
Uses of Spinraza
is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. SPINRAZA is a survival motor neuron-2 (SMN2)-directed antisense oligonucleotide indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients
Dosage & Administration of Spinraza
Administer a total of four loading doses as follows:
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Administer a total of two loading doses as follows:
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Side Effects of Spinraza
Clinical 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. SPINRAZA Low Dose Regimen (12 mg loading doses/12 mg maintenance doses) In clinical studies, 385 patients (47% male, 68% Caucasian, and 12% Asian) were treated with SPINRAZA Low Dose Regimen , including 353 exposed for at least 6 months, 314 exposed for at least 1 year, and 256 exposed for at least 5 years. Clinical Trial in Infantile-Onset SMA (Study 1) In Study 1, baseline disease characteristics were largely similar in the SPINRAZA-treated patients and sham-control patients except that SPINRAZA-treated patients at baseline had a higher percentage compared to sham-control patients of paradoxical breathing (89% vs 66%), pneumonia or respiratory symptoms (35% vs 22%), swallowing or feeding difficulties (51% vs 29%), and requirement for respiratory support (26% vs 15%). The most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were lower respiratory infection and constipation.
Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (18%) than in control patients (10%). Because patients in Study 1 were infants, adverse reactions that are verbally reported could not be assessed in this study. Table 2. Adverse Reactions that Occurred in at Least 5% of SPINRAZA Patients and Occurred at Least 5% More Frequently or At Least 2 Times as Frequently Than in Control Patients with Infantile-Onset SMA (Study 1) 1 Low Dose Regimen 2 Includes adenovirus infection, bronchiolitis, bronchitis, bronchitis viral, corona virus infection, Influenza, lower respiratory tract infection, lower respiratory tract infection viral, lung infection, parainfluenzae virus infection, pneumonia, pneumonia bacterial, pneumonia influenzal, pneumonia moraxella, pneumonia parainfluenzae viral, pneumonia pneumococcal, pneumonia pseudomonal, pneumonia respiratory syncytial viral, pneumonia viral, and respiratory syncytial virus bronchiolitis. Adverse Reactions SPINRAZA 12 mg 1 N = 80 % Sham-Procedure Control N = 41 % Lower respiratory infection 2 55 37 Constipation 35 22 Teething 18 7 Urinary tract infection 9 0 Upper respiratory tract congestion 8 2 Ear infection 6 2 Flatulence 5 2 Decreased weight 5 2 In an open-label clinical study in infants with symptomatic SMA, severe hyponatremia was reported in a patient treated with SPINRAZA requiring salt supplementation for 14 months.
Cases of rash were reported in patients treated with SPINRAZA. One patient, 8 months after starting SPINRAZA treatment, developed painless red macular lesions on the forearm, leg, and foot over an 8-week period. The lesions ulcerated and scabbed over within 4 weeks, and resolved over several months. A second patient developed red macular skin lesions on the cheek and hand ten months after the start of SPINRAZA treatment, which resolved over 3 months.
Both cases continued to receive SPINRAZA and had spontaneous resolution of the rash. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. It is unknown whether any effect of SPINRAZA on growth would be reversible with cessation of treatment.
Clinical Trial in Later-Onset SMA (Study 2) In Study 2, baseline disease characteristics were largely similar in the SPINRAZA-treated patients and sham-control patients except for the proportion of SPINRAZA-treated patients who had ever achieved the ability to stand without support (13% vs 29%) or walk with support (24% vs 33%). The most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were pyrexia, headache, vomiting, and back pain. Table 3. Adverse Reactions that Occurred in at Least 5% of SPINRAZA Patients and Occurred at Least 5% More Frequently or At Least 2 Times as Frequently Than in Control Patients with Later-Onset SMA (Study 2) 1 Low Dose Regimen Adverse Reactions SPINRAZA 12 mg 1 N=84 % Sham - Procedure Control N=42 % Pyrexia 43 36 Headache 29 7 Vomiting 29 12 Back pain 25 0 Epistaxis 7 0 Fall 5 0 Respiratory tract congestion 5 2 Seasonal allergy 5 2 Post-lumbar puncture syndrome has also been observed after administration of SPINRAZA. SPINRAZA High Dose Regimen (50 mg loading doses/28 mg maintenance doses) The safety of SPINRAZA High Dose Regimen was studied in 2 clinical trials in symptomatic patients with SMA (approximately 14 days to 65 years of age at first dose). In clinical studies, 128 patients (50% male, 63% Caucasian, and 22% Asian) were treated with SPINRAZA High Dose Regimen, including 113 exposed for at least 6 months, 95 exposed for at least 1 year, and 67 exposed for at least 2 years. Clinical Trial in Infantile-Onset SMA (Study 4) The most common adverse reactions that occurred in at least 10% of SPINRAZA treated patients and occurred at least 5% more frequently than in historic-matched sham-control patients from Study 1 were pneumonia, COVID-19, pneumonia aspiration, and malnutrition in patients with infantile-onset SMA. COVID-19 was not discovered at the time of Study 1. Table 4: Adverse Reactions that Occurred in at least 5% of SPINRAZA High Dose Regimen Patients and Occurred at Least 5% More Frequently or At Least 2 Times as Frequently Than Matched Sham Control in Patients with Infantile Onset SMA (Study 4) SPINRAZA High Dose Regimen (Study 4) (N=50) % Matched Sham Control (Study 1) (N=20) % Pneumonia 20 5 COVID-19 16 0 Pneumonia aspiration 14 5 Malnutrition 10 0 Procedural pain 6 0 Myocardial necrosis marker increased 6 0 Anemia 6 0
Postmarketing 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.
Warnings & Cautions for Spinraza
Thrombocytopenia and Coagulation Abnormalities 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 , 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 Renal toxicity, including potentially fatal glomerulonephritis, has been observed after
administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney . 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.
Pregnancy Safety for Spinraza
Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of SPINRAZA in pregnant women. When nusinersen was administered by subcutaneous injection to mice throughout pregnancy and lactation, developmental toxicity (long-term neurobehavioral impairment) was observed at all doses tested (see Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Data Animal Data When nusinersen (0, 3, 10, or 25 mg/kg) was administered subcutaneously to male and female mice every other day prior to and during mating and continuing in females throughout organogenesis, no adverse effects on embryofetal development were observed. Subcutaneous administration of nusinersen (0, 6, 12.6, or 25 mg/kg) to pregnant rabbits every other day throughout organogenesis produced no evidence of embryofetal developmental toxicity. When nusinersen (1.4, 5.8, or 17.2 mg/kg) was administered to pregnant female mice by subcutaneous injection every other day throughout organogenesis and continuing once every six days throughout the lactation period, adverse neurobehavioral effects (alterations in locomotor activity, learning and memory deficits) were observed when offspring were tested after weaning or as adults.
A no-effect level for neurobehavioral impairment was not established.
Pediatric Use of Spinraza
Pediatric Use The safety and effectiveness of SPINRAZA in pediatric patients from newborn to 17 years have been established. Juvenile Animal Toxicity Data In intrathecal toxicity studies in juvenile monkeys, administration of nusinersen (0, 0.3, 1, or 3 mg/dose for 14 weeks and 0, 0.3, 1, or 4 mg/dose for 53 weeks) resulted in brain histopathology (neuronal vacuolation and necrosis/cellular debris in the hippocampus) at the mid and high doses and acute, transient deficits in lower spinal reflexes at the high dose in each study. In addition, possible neurobehavioral deficits were observed on a learning and memory test at the high dose in the 53-week monkey study.
In a combined 6 and 13 week toxicity study in juvenile monkeys, intrathecal administration of nusinersen at higher doses (0, 5, 10, or 15 mg/dose) resulted in additional acute, transient effects, including limited use of limbs at the mid and high dose and uncoordinated movement at the high dose. The no-effect dose for neurohistopathology in monkeys (0.3 mg/dose) is approximately equivalent to and lower than the recommended clinical maintenance doses of 12 and 28 mg, respectively, when calculated on annual dose basis and corrected for species differences in CSF volume.
Clinical Studies of Spinraza
Infantile-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 ( 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. Table 5. Motor Milestone Response and CHOP-INTEND Results of the Final Analysis of Patients with Infantile-Onset SMA (Study 1) 1 Low Dose Regimen 2 At the final analysis, CHOP-INTEND and motor milestone analyses were conducted using the Efficacy Set (SPINRAZA n=73; Sham-control n=37). 3 Assessed at the later of Day 183, Day 302, and Day 394 Study Visit 4 According to HINE section 2: ≥2 point increase in ability to kick, OR ≥1 point increase in the motor milestones of head control, rolling, sitting, crawling, standing or walking, AND improvement in more categories of motor milestones than worsening), defined as a responder for this primary analysis. 5 Not statistically controlled for multiple comparisons Endpoint SPINRAZA - treated Patients 1 (n=73) Sham-control Patients (n=37) Motor function Motor milestones 2 Proportion achieving pre-defined motor milestone responder criteria (HINE section 2) 3, 4 37 (51%) P<0.0001 0 (0%) CHOP-INTEND 2 Proportion achieving a 4-point improvement Proportion achieving a 4-point worsening 5 52 (71%) p<0.0001 2 (3%) 1 (3%) 17 (46%) Table 6. Survival Results of Patients with Infantile-Onset SMA (Study 1) 1 Low Dose Regimen 2 At the final analysis, event-free survival and overall survival were assessed using the Intent to Treat population (ITT SPINRAZA n=80; Sham-control n=41). 3 Based on log-rank test stratified by disease duration Endpoint SPINRAZA-treated Patients 1 (n=80) Sham-control Patients (n=41) Survival Event-free survival 2 Number of patients who died or received permanent ventilation Hazard ratio (95% CI) p-value 3 31 (39%) 28 (68%) 0.53 (0.32 -0.89) p=0.005 Overall survival 2 Number of patients who died Hazard Ratio (95% CI) p-value 3 13 (16%) 16 (39%) 0.37 (0.18 – 0.77) p=0.004 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). Table 7. Motor Milestone Response and CHOP-INTEND Results of the Final Analysis of Patients with Infantile-Onset SMA (Study 4) 1 High Dose Regimen 2 ANCOVA and Multiple Imputation applied 3 Least Square Mean difference 4 Fisher Exact Test Efficacy Parameter SPINRAZA 1 (n = 50) Matched Sham from Study 1 (n = 20) Differences between arms (95% CI) CHOP-INTEND LS mean (95% CI) for ranked score of change from baseline to Day 183 LS mean change (95% CI) from baseline to Day 183 2,3 42.9 15.1 16.9 -11.1 (-15.9, -6.2) 26.06 p<0.0001 3 26.2 2 HINE-2 Responder Proportion achieving motor milestone responder criteria at Day 183 29 (58%) 0 (0%) 58% 4 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.
Figure 1 Figure 2
Later-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 ( Table 8 ). Table 8. HFMSE Results in Patients with Later-Onset SMA (Study 2) 1 Low Dose Regimen 2 Assessed using the Intent to Treat population who received at least one dose of SPINRAZA or at least one sham procedure (SPINRAZA n=84; Sham-control n=42); data for patients without a Month 15 visit were imputed using the multiple imputation method 3 Least squares mean 4 Negative value indicates worsening, positive value indicates improvement. 5 Based on logistic regression with treatment effect and adjustment for each subject's age at screening and HFMSE score at baseline Endpoint SPINRAZA-treated Patients 1 (n=84) Sham-control Patients (n=42) HFMSE score Change from baseline in total HFMSE score at 15 months,2,3, 4 Proportion of patients who achieved at least a 3-point improvement from baseline to Month 15 2 3.9 (95% CI: 3.0, 4.9) p=0.0000001 56.8% (95% CI: 45.6, 68.1) p=0.0006 5 -1.0 (95% CI: -2.5, 0.5) 26.3% (95% CI: 12.4, 40.2) Figure 3. Mean Change from Baseline in HFMSE Score Over Time in the Intent to Treat Set 1, 2 (Study 2) 1 Data for patients without a Month 15 visit were imputed using the multiple imputation method 2 Error 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. Figure 3
Presymptomatic
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 . 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).
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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