The efficacy of Spinraza was demonstrated in a double-blind, sham-procedure controlled clinical trial in symptomatic infantile-onset SMA patients and was supported by open-label clinical trials conducted in presymptomatic and symptomatic SMA patients. The study was done 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 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 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 (2 copies in 98% of subjects in both groups). 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) an 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 Spinraza group compared to the sham-control group.

The efficacy of nusinersen in patients with SMA Types II and III was demonstrated in a longitudinal analysis across two open-label studies (Study CS2 and Study CS12). The analysis included 28 patients who received their first dose in Study CS2 and then transferred to the extension phase, CS12. A sustained improvement in HFMSE was seen in patients with SMA Type II, with a mean improvement from baseline of 12.3 (SD 5.46, N = 6), and with a mean total score of 35.3 (SD 12.58) after 1,050 days of treatment. No plateau was observed in HFMSE was observed. This is in comparison with the decline typically observed in patients with later-onset SMA over time. Patients with SMA Type III demonstrated a mean improvement from baseline HFMSE score of 1.6 (SD 3.91, N = 7), with a mean total score of 53.0 (SD 9.22) after 1,050 days. In patients with SMA Type II, the ULM test was conducted, with mean improvement of 4.6 (SD 3.53, N = 6), with a mean total score of 16.8 (SD 1.41) observed after 1,050 days. The 6-Minute Walk Test (6MWT) was conducted for ambulatory patients only. In these patients, a mean improvement of 96.7 meters (SD 42.36, N = 6), with a mean 6MWT distance of 278.2 (SD 157.58), was observed after 1,050 days. Two previously non-independent ambulatory patients (Type III) achieved independent walking, and one non-ambulatory patient (Type II) achieved independent walking.

The most common side effects that occurred were lower respiratory infection, upper respiratory infection and constipation.

Policy:
[(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)

The requirements of the Horizon BCBSNJ Nusinersen (Spinraza) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable)].

I. Spinraza (nusinersen) is medically necessary for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients when all of the following criteria are met:

a. Member has a confirmed genetic diagnosis of SMA types I, II or III (documentation of medical records required) AND
I. Member has SMA type 1 OR

II. If member has SMA type II or III onset of clinical signs and symptoms at ≥ 6 months (180 days)

b. Genetic documentation of 5q SMA homozygous gene deletion, homozygous mutation or compound heterozygote (documentation of medical records required) AND

c. Member retains meaningful voluntary motor function such as (ability to manipulate objects using upper extremities, walk, etc) AND

d. Documentation of baseline and prior to each dose, platelet count, coagulation laboratory testing and quantitative spot urine protein testing will be obtained (documentation of medical records required) AND


[INFORMATIONAL NOTE: Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides.]

e. Baseline documentation of at least one of the following (documentation of medical records required):
I. Member’s weight in those who are without gastrostomy tube OR

II. Motor function/milestones, as shown in the Hammersmith Infant Neurologic Exam (HINE) Hammersmith Functional Motor Scale Expanded (HFMSE), 6-minute walk test (6MWT), upper limb nodule (ULM), CHOP-INTENT OR

[INFORMATIONAL NOTE: The HINE Exam 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) an 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; 6MWT an objective evaluation of functional exercise capacity that measures the maximum distance a person can walk in 6 minutes over a 25-meter linear course; ULM is an outcome measure specifically developed to assess upper limb functional abilities in patients with SMA, including young children and patients with severe contractures in the lower limbs, in whom the possibility to detect functional changes, such as rolling or long sitting, is limited; CHOP-INTEND measures motor function via 16 different items, which capture neck, trunk, proximal and distal limb strength. Scored from 0 (least function) to 4 (most function) for each of the 16 items]

III. Respiratory function test such as forced vital capacity OR

IV. Member has exacerbations requiring hospitalization and/or antibiotic therapy for respiratory infection within the prior year

f. Member does not require use of invasive ventilatory support (tracheotomy with positive pressure) or use of non-invasive ventilator support (BiPAP) for more than 16 hours per day as a result of advanced SMA disease AND

g. The prescriber is a specialist in the area of the patient’s diagnosis (e.g. pediatric neurologist) or has consulted with a specialist in the area of the patient’s diagnosis AND

h. Member will not be using the requested agent in combination with Evrysdi (risdiplam)

a. The recommended dosage 12mg (5ml) per administration via intrathecal (IT) route with 4 loading doses; the first three loading doses should be administered at 14-day intervals; the 4^th loading dose should be administered 30 days after the 3^rd dose; a maintenance dose should be administered once every 4 months thereafter.

a. Documentation of current and prior to each dose, platelet count, coagulation laboratory testing and quantitative spot urine protein testing (documentation of medical records required) AND

b. Member meets one or more of the following (documentation of medical records required):

· Member has improvement or stability in motor milestone according to the Hammersmith Infant Neurologic Exam (HINE), Hammersmith Functional Motor Scale Expanded (HFMSE), 6-minute walk test (6MWT), upper limb nodule (ULM), CHOP-INTENDT OR

· Members who are without gastrostomy tube has shown stable or improved weight since the last authorization OR

· Member has shown improvement or stability in respiratory function tests such as force vital capacity (FVC) OR

· Member has reduction in exacerbations requiring hospitalization and/or antibiotic therapy for respiratory infection within the prior year AND


[INFORMATIONAL NOTE: SPINRAZA is present in and excreted by the kidney, in a clinical study (mean treatment exposure 7 months), 17 of 51 (33%) SPINRAZA-treated patients had elevated urine protein, compared to 5 of 25 (20%) sham-control patients. In a group of later-onset SMA patients (mean treatment exposure 34 months), 36 of 52 (69%) had elevated urine protein. No elevations in serum creatinine or cystatin C were observed in these studies. 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]

c. Member does not require use of invasive ventilatory support (tracheotomy with positive pressure) or use of non-invasive ventilator support (BiPAP) for more than 16 hours per day as a result of advanced SMA disease AND

d. Absence of unacceptable toxicity from the drug (e.g., significant renal toxicity, thrombocytopenia, coagulation abnormalities)

e. Member will not be using the requested agent in combination with Evrysdi (risdiplam)

________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Nusinersen (Spinraza)
Spinraza (Nusinersen)
Spinal Muscular Atrophy (SMA), Nusinersen (Spinraza)
SMA (Spinal Muscular Atrophy), Nusinersen (Spinraza)

References:
1. Spinraza (nusinersen) Prescribing information. Biogen. Cambridge, MA. December 2017. Updated June 2019.

2. Wang CH, Finkel RS et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007 Aug;22(8): 1027-49

3. ClinicalTrials.gov. Accessed April 27, 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT02865109?term=nusinersen&rank=2

4. Finkel RS, Chiriboga CA et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen; a phase 2, open-label, dose-escalation study. Lancet. 2017 Dec 17;388 (10063):3017-3026.

5. Mercuri E, Finkel R et al. Efficacy and Safety of Nusinersen in Children with Later-Onset Spinal Muscular Atrophy (SMA): Results of the Phase 3 CHERISH Study.

6. Prior TW, Finanger E. Spinal muscular atrophy. GeneReviews.
www.ncbi.nlm.nih.gov/books/NBK1352/. Accessed May11, 2017.

7. (AMCP Dossier) Spinraza (nusinersen) for Spinal Muscular Atrophy. Version 2 Final. April 13, 2017

8. Hwu, W. De D, Bertini E, et al. Outcomes after 1-year in presymptomatic infants with genetically diagnosed spinal muscular atrophy (SMA) treated with nusinersen: interim results from the NURTURE study. Neuromuscular Disorders , October 2017Volume 27, Supplement 2, Page S212

9. Evrysdi (risdiplam) [package insert]. Genetech, Inc. South San Fransisco, CA. August 2020.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

J2326