Nusinersen (Spinraza)

Number: 0915

Policy

Note: REQUIRES PRECERTIFICATION.Footnotes 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.

Continued use of nusinersen is considered 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.

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 three 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.

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: 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 SMA or Kugelberg-Welander disease): 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: