Nusinersen (Spinraza)

Number: 0915

Policy

Note: REQUIRES PRECERTIFICATIONFootnotes for Precertification of nusinersen^*

Aetna considers nusinersen (Spinraza) medically necessary for persons with spinal muscular atrophy (SMA) who meet all of the following criteria:

1. Member has SMA types I, II or III; and
2. There is genetic documentation of 5q SMA homozygous gene mutation, homozygous gene deletion, or compound heterozygote; and
3. The member is 15 years of age or younger at initiation of treatment; and
4. The medication is prescribed by or in consultation with a physician who specializes in treatment of spinal muscular atrophy.

Aetna considers continued use of nusinersen medically necessary for members who have responded to therapy, as demonstrated by maintenance or improvement in motor milestones.

Aetna considers nusinersen experimental and investigational for all other indications.

Aetna considers intrathecal administration with ultrasound or other imaging guidance medically necessary for nusinersen.

Aetna considers the following procedures medically necessary for administration of nusinersen in persons with scoliosis or spinal fusion with instrumentation that interferes with lumbar access:

• Cervical puncture with ultrasound guidance
• Subcutaneous intrathecal catheter system for repeated dosing of nusinersen
• Transforaminal lumbar puncture with cone-beam computed tomography.

The medically necessary dosage of nusinersen is 12 mg (5 ml) per administration. Four loading doses of nusinersen are considered medically necessary for initiation of treatment; the first 3 loading doses are administered at 14-day intervals, and the 4th loading dose is administered 30 days after the 3rd dose.  A maintenance dose is considered medically necessary once every 4 months thereafter. 

Footnotes^* Precertification of nusinersen is required of all Aetna participating providers and members in applicable plan designs.  For precertification of nusinersen, call (866) 503-0857, or fax (866) 267-3277. 

Background

Spinal muscular atrophy (SMA) is characterized by loss of motor neurons in the spinal cord and lower brain stem, resulting in severe and progressive muscular atrophy and weakness (Biogen, 2016). Ultimately, individuals with the most severe type of SMA can become paralyzed and have difficulty performing the basic functions of life, like breathing and swallowing. 

Due to a loss of, or defect in, the SMN1 gene, people with SMA do not produce enough survival motor neuron (SMN) protein, which is critical for the maintenance of motor neurons (Biogen, 2016). The severity of SMA correlates with the amount of SMN protein. People with Type 1 SMA, the most severe life-threatening form, produce very little SMN protein and do not achieve the ability to sit without support or live beyond two years without respiratory support. People with Type 2 and Type 3 SMA produce greater amounts of SMN protein and have less severe, but still life-altering forms of SMA. 

The U.S. Food and Drug Administration (FDA) approved nusinersen (Spinraza) for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients (Biogen, 2016). Nusinersen is an antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Nusinersen alters the splicing of SMN2 pre-mRNA in order to increase production of full-length SMN protein. 

The FDA approval of nusinersen was based on positive results from multiple clinical studies involving approximately 170 patients (Biogen, 2016). The data package included the interim analysis of ENDEAR, a Phase 3 controlled study evaluating nusinersen in infantile-onset, as well as open-label data in pre-symptomatic and symptomatic patients with, or likely to develop, Types 1, 2 and 3 SMA. 

The efficacy of nusinersen was demonstrated in a multicenter, randomized, double-blind, sham-procedure controlled (ENDEAR) 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) (Biogen, 2016). Patients were randomized 2:1 to receive either nusinersen or sham injection. 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, 44% were male and 56% were female. Age at first treatment ranged from 30 to 262 days (median 181). Eighty-seven (87%) of subjects were Caucasian, 2% were Black, and 4% were Asian. Length of treatment ranged from 6 to 442 days (median 261 days). Baseline demographics were balanced between the nusinersen and control groups with the exception of age at first treatment (median age 175 vs. 206 days, respectively). The nusinersen and control groups were balanced with respect to gestational age, birth weight, disease duration, and SMN2 copy number (2 copies in 98% of subjects in boths groups). Median disease duration was 14 weeks. There was some imbalance in age at symptom onset with 88% of subjects in the nusinersen 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) (Biogen, 2016). 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 a motor milestone response in the nusinersen group compared to the sham-control group (40% versus 0%; p<0.0001). 

The results of the controlled trial in infantile-onset SMA patients were supported by open-label uncontrolled trials conducted in symptomatic SMA patients who ranged in age from 30 days to 15 years at the time of first dose, and in presymptomatic patients, who ranged in age from 8 days to 42 days at the time of first dose (Biogen, 2016). The patients in these studies had or were likely to develop Type 1, 2, or 3 SMA. Some patients achieved milestones such as ability to sit unassisted, stand, or walk when they would otherwise be unexpected to do so, maintained milestones at ages when they would be expected to be lost, and survived to ages unexpected considering the number of SMN2 gene copies of patients enrolled in the studies.  

Nusinersen is supplied as a 12 mg/5 mL (2.4 mg/mL) solution in a single-dose vial. Nusinersen is administered via intrathecal injection. The recommended dosage is 12 mg (5 mL) per administration. 

Initiate nusinersen treatment with 4 loading doses. The first three loading doses should be administered at 14-day intervals. The 4th loading dose should be administered 30 days after the 3rd dose. A maintenance dose should be administered once every 4 months thereafter. 

If a loading dose is delayed or missed, administer nusinersen as soon as possible, with at least 14-days between doses and continue dosing as prescribed. If a maintenance dose is delayed or missed, administer nusinersen as soon as possible and continue dosing every 4 months.

The most common adverse reactions reported for nusinersen were upper respiratory infection, lower respiratory infection and constipation (Biogen, 2016). Serious adverse reactions of atelectasis were more frequent in nusinersen-treated patients. Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides.

Cervical Puncture with Ultrasound Guidance for Administration of Nusinersen

Veerapandiyan and associates (2018) noted that SMA is a neuromuscular disorder characterized by profound muscle weakness, atrophy, and paralysis due to degeneration of the anterior horn cells.  Nusinersen, the 1st FDA-approved treatment for SMA, is administered intrathecally via lumbar puncture; however, many patients with SMA have scoliosis or solid spinal fusion with hardware that makes lumbar access impossible.  Studies in primates have demonstrated better spinal cord tissue concentration with intrathecal injections than with intracerebral ventricular injections.  In a retrospective chart review, these researchers reported their experience in delivering intrathecal nusinersen through cervical puncture in patients with SMA with no lumbar access.  They used C1/C2 puncture as an alternative to administer nusinersen.  Intrathecal nusinersen via cervical puncture was given to 3 patients who had thoracic and lumbo-sacral spinal fusion: a 12-year-old girl with type 1 SMA, and 2 17-year old girls with type 2 SMA.  Cervical puncture was performed without deep sedation under fluoroscopic guidance using a 25-G or a 24-G Whitacre needle in the posterior aspect of C1 to C2 interspace and full dose of nusinersen (12 mg/5 ml) was injected after visualizing free cerebrospinal fluid (CSF) flow.  Patients completed their 4 loading doses and 1st maintenance dose of nusinersen, and 15 procedures were successful and well-tolerated.  The authors concluded that the findings of this report suggested that cervical puncture, when done by providers with experience in this technique, is a feasible alternative route to administer intrathecal nusinersen in patients with longstanding SMA and spine anatomy precluding lumbar access.  However, they stated that more case studies are needed to determine the safety of cervical puncture in patients with SMA.

In a retrospective study, Ortiz and co-workers (2019) examined the technical feasibility and complications of ultrasound (US)-guided cervical puncture for nusinersen administration.  These investigators reviewed 14 consecutive US-guided cervical punctures for nusinersen administration with local anesthesia; they reviewed technical success and complications.  All procedures were technically successful.  There were no major complications; however, there were 2 minor complications (including headaches) that resolved within 24 hours after the procedure.  The authors concluded that this case-series study described a successful novel method of US-guided cervical spine access for intrathecal administration of nusinersen, adding to the armamentarium of procedures for delivering nusinersen to adolescents with challenging lumbar spine access caused by scoliosis and spinal instrumentation. They stated that this technique has the advantages of real-time US guidance and potential avoidance of general anesthesia in children.

Subcutaneous Intrathecal Catheter System for Repeated Dosing of Nusinersen

Strauss and associates (2018) stated that many patients with SMA who might benefit from intrathecal nusinersen therapy have scoliosis or spinal fusion that precludes safe drug delivery.  To circumvent spinal pathology, these researchers designed a novel subcutaneous intrathecal catheter (SIC) system by connecting an intrathecal catheter to an implantable infusion port.  Device safety and tolerability were tested in 10 SMA patients (age of 5.4 to 30.5 years; 80 % with 3 copies of SMN2); each received 3 sequential doses of nusinersen (n = 30 doses).  Pre-treatment disease burden was evaluated using the revised Hammersmith Scale, dynamometry, National Institutes of Health (NIH) pegboard, pulmonary function testing, electromyography (EMG), and 2 health-related quality of life (QOL) tools.  Device implantation took less than or equal to 2 hours and was well-tolerated.  All outpatient nusinersen doses were successfully administered via SIC within 20 minutes on the first attempt, and required no regional or systemic analgesia, cognitive distraction, US guidance, respiratory precautions, or sedation.  Cerebrospinal fluid withdrawn from the SIC had normal levels of glucose and protein; CSF white blood cells were slightly elevated in 2 (22 %) of 9 specimens (median of 1 cell/µL; range of 0 to 12 cells/µL) and red blood cells were detected in 7 (78 %) specimens (median of 4; range of 0 to 2,930 cells/µL).  The authors concluded that preliminary observations revealed the SIC to be relatively safe and well-tolerated in SMA patients with advanced disease and spinal fusion.  They stated that the SIC warrants further study and, if proven effective in larger trials of longer duration, could double the number of patients able to receive nusinersen worldwide while reducing administration costs 5- to 10-fold.

Transforaminal Lumbar Puncture with Cone-Beam Computed Tomography for Administration of Nusinersen

Weaver and colleagues (2018) stated that nusinersen, the only treatment approved by the FDA for SMA, is delivered intrathecally.  Many children with SMA have extensive spinal instrumentation and deformities, often precluding the use of standard approaches for gaining intrathecal access.  Furthermore the anatomical distortion that often occurs with roto-scoliosis could complicate the use of fluoroscopic guidance.  Compared to fluoroscopy, computed tomography (CT) affords superior guidance for complex needle placements.  This opens up alternatives to the posterior (interlaminar) technique, including transforaminal and caudal approaches.  In a retrospective review, these investigators described the early results of technical success, complications and radiation dose of intrathecal delivery of nusinersen using cone-beam CT guidance with 2-axis fluoroscopic navigational overlay.  A total of 15 consecutive nusinersen injections performed in 4 children with SMA and extensive spinal hardware precluding standard posterior lumbar puncture techniques.  These children were treated using transforaminal thecal access employing cone-beam CT with navigational overlay.  These researchers analyzed results including technical success, complications and total fluoroscopy time.  All procedures were technically successful.  No major complications and 1 minor complication were reported; the minor complication was a post-procedural neuropathic headache that was attributed to procedural positioning and was treated successfully with gabapentin.  The average procedural fluoroscopy time and air kerma were 1.9 mins and 55.8 mGy, respectively.  The authors concluded that cone-beam CT guidance with 2-axis navigational overlay is a safe, effective method for gaining transforaminal intrathecal access in children with spinal abnormalities and hardware precluding the use of standard techniques.  These preliminary findings need to be further investigated.

Nascene and associates (2018) noted that they had recently used a transforaminal approach in selected situations.  Between May 2016 and December 2017, a total of 26 transforaminal lumbar punctures were performed in 9 patients (25 CT-guided, 1 fluoroscopy-guided); 7 had SMA and were referred for intrathecal nusinersen administration.  In 2, CT myelography was performed via transforaminal lumbar puncture.  The lumbar posterior elements were completely fused in 8, and there was an overlying abscess in 1.  The L1 to L2 level was used in 2; the L2 to L3 level, in 10; the L3 to L4 level, in 12; and the L4 to L5 level, in 2 procedures.  Post-lumbar puncture headache was observed on 4 occasions, which resolved without blood patching; 1 patient felt heat and pain at the injection site that resolved spontaneously within hours; 1 patient had radicular pain that resolved with conservative treatment.  The authors concluded that transforaminal lumbar puncture may become an effective alternative to classic interlaminar lumbar puncture or cervical puncture.

Appendix

Types of spinal muscular atrophy

SMA Type 1 (also called infantile onset SMA or Werdnig-Hoffmann disease): SMA symptoms are present at birth or by the age of 6 months

SMA Type 2: Onset of SMA symptoms between the ages of 7 and 18 months and before the child can stand or walk independently.

SMA Type 3: (also called Kugelberg-Welander disease): Onset of SMA symptoms after 18 months, and children can stand and walk independently, although they may require aids.

SMA Type 4 (also called adult-onset form of proximal spinal muscular atrophy): Onset of SMA symptoms in adulthood, and people are able to walk during their adult years.

Source: Muscular Dystrophy Association, 2016.

The above policy is based on the following references: