Description
Zolgensma (onasemnogene abeparvovec-xioi) is an adeno-associated virus vector-based gene therapy indicated for the treatment of pediatric patients with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.

Limitation of Use:

• The safety and effectiveness of repeat administration of Zolgensma has not been evaluated.
• The use of Zolgensma in patients with advanced SMA (e.g., complete paralysis of limbs, permanent ventilator dependence) has not been evaluated.

Policy
Onasemnogene abeparvovec-xioi may be considered medically necessary if all of the following conditions are met: 

1. Diagnosis of Type 1 or Type 2 SMA confirmed by genetic testing demonstrating bi-allelic mutations in the survival motor neuron 1 (SMN1) gene (examples below):
   1. Deletion of both copies of the SMN1 gene OR
   2. Compound heterozygous mutations of the SMN1 gene (defined below): 
      1. Pathogenic variant(s) in both copies of the SMN1 gene OR
      2. Pathogenic variant in one copy and deletion of the second copy of the SMN1 gene OR
   3. If applicable, diagnosis of SMA based on the results of SMA newborn screening
      1. Patient has 3 copies or less of Survival of Motor Neuron 2 (SMN2)
      2. Patient is less than or equal to 6 months of age
2. Patient is less than 24 months of age at the time of infusion of onasemnogene abeparvovec-xioi.
3. Patient does not have advanced SMA, is not depended on the use of non-invasive ventilation beyond use for naps and nighttime sleep (e.g., complete paralysis of limbs, permanent ventilator dependence).
4. Baseline anti-adeno-associated virus serotype 9 (AAV9) antibody titers < 1:50.
5. Prescribed by a neurologist with expertise in treating SMA.
6. Treatment with Spinraza or Evrysdi (nusinersen) must be discontinued prior to infusion of Zolgensma (onasemnogene abeparvovec).
7. Documentation confirms member has not received previous Zolgensma (onasemnogene abeparvovec) infusion(s)

Onasemnogene abeparvovec is considered INVESTIGATIONAL for all other indications.

Concurrent use of onasemnogene abeparvovec and nusinersen is considered INVESTIGATIONAL.

Rationale
Type 1 SMA
A phase 1, open-label, single site, dose-escalation study (CL-101) evaluated the safety and efficacy of a one-time IV administration of Zolgensma in 15 patients with type 1 SMA with 2 copies of survival motor neuron 2 (SMN2) 9 months of age or younger who developed symptoms of SMA prior to 6 months of age. Three of the patients received a low dose (6.7 × 10¹³ vg per kilogram of body weight), and 12 received a high dose (2.0 × 10¹⁴ vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. As of the data cutoff for the manuscript publication on Aug. 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP-INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone.^11,12,14

A follow-up presentation of the CL-101 study showed that all patients were alive and without the need for ventilation at 24 months. In the high dose cohort (cohort 2), all patients achieved at least one motor milestone, with 11 of 12 achieving motor milestones rarely seen in the type 1 SMA population. All 11 patients who achieved these milestones were 6 months of age or less at the time of gene therapy administration. The one patient not experiencing advanced motor milestone achievement was 8 months of age at the time of gene therapy administration. Patients treated with Zolgensma had a marked, early, and rapid improvement in CHOP-INTEND score, in contrast with untreated SMA type 1 patients, who experienced a 10.7-point drop in CHOP-INTEND scores from 6 – 12 months of age. At 24 months follow-up, patients had a mean CHOP-INTEND score increase of 25.4 points from baseline (n = 12). Eleven of 12 patients achieved and maintained a score > 40 points for a mean of 19.5 months. In contrast, one recent natural history study reported that SMA type 1 children neither achieve nor maintain CHOP-INTEND scores > 40 points after 6 months of age. As of April 2018, the oldest subject in cohort 2 was 46.2 months of age with 40.6 months of follow-up.

A pivotal, Phase 3, multicenter, open-label trial (STRIVE) is currently underway evaluating the safety and efficacy of a one-time intravenous administration of Zolgensma in patients less than 6 months of age with type 1 SMA based on genetic confirmation of a bi-allelic mutation of the SMN1 gene with 1 or 2 copies of the SMN2 gene who are not dependent on invasive or non-invasive ventilatory support for greater than 6 hours a day. Enrollment in the study is complete, with 22 patients with 2 copies of SMN2 receiving Zolgensma. The patient population and baseline characteristics closely match those studied in the CL-101 study. The mean baseline age was 3.7 months with a range of 0.5 – 5.9 months. The mean baseline CHOP-INTEND score was 32 (range 17 – 52). Early results of the first 6 patients enrolled in the STR1VE study suggest a rapid increase in CHOP-INTEND scores at 1 and 3 months post-Zolgensma administration, similar to what has been described in the CL-101 trial.^8,10

Pre-Symptomatic Patients Likely To Develop Type 1 SMA
A phase 3, multicenter, open-label trial (SPR1NT) is currently underway evaluating the safety and efficacy of a one-time intravenous administration of Zolgensma in patients less than 6 weeks of age with SMA based on a genetic confirmation of a bi-allelic mutation of the SMN1 gene with 2 or 3 copies of the SMN2 who have yet to develop symptoms, who have a baseline compound muscle action potential (CMAP) > 2 mV at baseline. Enrollment is underway, with planned enrollment of at least 15 patients each in cohorts with 2 and 3 copies of SMN2 respectively. Patients are to receive a one-time intravenous administration of Zolgensma at a dose on 1.1 x 10¹⁴ vg per kg. As of August 2018, 3 patients have received Zolgensma in the trial, with positive results reported in the one patient with data available. ^9,15

Prediction of SMA Phenotype Based on SMN2 Copy Number
As stated above, current literature indicates that the number of copies of the SMN2 gene a patient has is the best predictor of clinical phenotype; however, the correlation is not absolute. A recent publication assessed the correlation of SMN2 copy number to SMA phenotype in 3,459 patients worldwide from reports published after 1999. Analysis of the North American cohort showed similar findings. Seventy-three percent of patients of patients with 2 copies were diagnosed with Type I SMA, accounting for 79% of all Type I SMA cases. Patients with 3 copies of SMN2 were the most numerous in the entire cohort, accounting for approximately half of the cases. Fifteen percent of patients with 3 copies of SMN2 were diagnosed with Type I SMA. Approximately 15% of patients in the worldwide cohort had 4 copies of SMN2. Patients with 4 copies of SMN2 were highly unlikely to be diagnosed with Type I SMA, as greater than 99% of cases were diagnosed with Type II or Type III SMA. Patients with 4 copies of SMN2 accounted for 0.2% of all cases diagnosed with type I SMA.^6,19

Type 2 SMA
A phase 1, multicenter, open-label, dose-escalation trial (STRONG) is currently underway evaluating the safety and efficacy of a one-time intrathecal administration of onasemnogene abeparvovec in patients with SMA based on a genetic confirmation of a bi-allelic mutation of the SMN1 gene with 3 copies of SMN2, who are able to sit but cannot stand or walk at the time of study entry. These patients would be classically considered patients with likely type 2 SMA. Patients will receive onasemnogene abeparvovec in a dose comparison safety study of two potential therapeutic doses (3 patients at each dose). Patients will be stratified in two groups: those < 24 months of age at time of dosing and those ≥ 24 months and < 60 months of age at time of dosing. Fifteen patients < 24 months will be enrolled and twelve patients ≥ 24 < 60 months will be enrolled. The first cohort will enroll 3 patients (cohort 1) < 24 months of age who will receive intrathecal administration of 6.0 x 10¹³ vg of onasemnogene abeparvovec (Dose A). After review of the data from cohort 1 by the Data Safety Monitoring Board (DSMB), a determination will be made to advance to Dose B, in which 3 patients from cohort 2 will receive 1.2 x 10¹⁴ vg of onasemnogene abeparvovec intrathecally. This trial is currently ongoing, with no data reported publically as of October 2018.¹⁶

Professional Societies
In the 2018 Cure SMA Working Group treatment algorithm, the working group stresses the need for early intervention through newborn screening to maximize the benefit of treatment. This treatment algorithm was published prior to the approval of onasemnogene abeparvovec. The group recommends the development of dependable and validated screening techniques to enable treatment of presymptomatic patients who may be more responsive to treatment than those already experiencing symptoms. For patients with SMA Types II or III with three or fewer copies of the SMN2 gene, the group recommends immediate treatment with a disease modifying therapy and referral to both a neuromuscular specialist and a geneticist; for those with only one copy of SMN2 who are symptomatic at birth, the group states that the attending physician should determine whether the patient and family would benefit from treatment. Lastly, patients with four copies of SMN2 should be screened periodically for symptoms and referred to a geneticist to determine the exact number of SMN2 copies, but the working group recommends against immediate treatment with a disease modifying therapy.¹⁸

U.S. Food and Drug Administration (FDA)
Zolgensma (onasemnogene abeparvovec-xioi) is an adeno-associated virus vector-based gene therapy indicated for the treatment of pediatric patients less than 2 years of age with SMA with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.

Limitation of Use

• The safety and effectiveness of repeat administration of Zolgensma have not been evaluated.
• The use of Zolgensma in patients with advanced SMA (e.g., complete paralysis of limbs, permanent ventilator dependence) has not been evaluated.

References

1. Zolgensma [package insert].  January 2019.
2. Markowitz JA, Singh P, Darras BT. Spinal Muscular Atrophy: A Clinical and Research Update. Pediatric Neurology 46 (2012) 1-12.
3. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical  laboratory analysis of >72,400 specimens. Eur J Hum Genet 2012;20:27-32.
4. Prior TW, Snyder PJ, Rink BD, et al. Newborn and carrier screening for spinal muscular atrophy. Am J Med Genet  A. 2010 Jul;152A(7):1608-16.
5. Lunn MR, Wang CH. Spinal  muscular atrophy. Lancet. 2008 Jun 21;371(9630):2120-33.
6. Calucho M, Bernal M, Alias L, et al. Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscular disorders. 2018; 28:208-15.
7. Mendell JR, Al-Zaidy S, Shell R, et al. AVXS-101 Phase 1 gene-replacement therapy clinical trial in SMA type 1: 24-month event-free survival and achievement of developmental milestones. Poster presented at: The 23rd International  Annual Congress of the World Muscle Society, Mendoza, Argentina, October 2 –6, 2018.
8. Day JW, Feltner DE, Ogrinc F, et al. AVXS-101, gene-replacement therapy for spinal muscular atrophy type 1 (SMA1): Pivotal study (STR1VE) update. Poster presented at: The 23rd International Annual Congress of the World Muscle Society, Mendoza, Argentina, October 2–6, 2018.
9. Schultz M, Swoboda KJ, Wells C, et al. AVXS-101 gene-replacement therapy (GRT) clinical trial in presymptomatic spinal muscular atrophy (SMA): Phase 3 study design and initial baseline demographics. Poster presented at: The 23rd International  Annual Congress of the World Muscle Society, Mendoza, Argentina, October 2–6, 2018.
10. Day JW, Feltner DE,Ogrinc F, et al. Initial Data from AVXS-101 pivotal phase 3 study (STR1VE) appears to demonstrate a similar safety and early rapid motor function response as the phase 1 study. Poster presented at: The 70th Annual American Academy of Neurology Meeting, Los Angeles, CA, April 21 -27, 2018.
11. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377:1713-22
12. Protocol for: Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl  J Med 2017;377:1713-22. DOI: 10.1056/NEJMoa1706198
13. Glascock J, Sampson J, Haidet-Phillips A, et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. Journal of Neuromuscular Diseases. 2018;5:145-158.
14. Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1 (STR1VE) Clinicaltrials.gov website https://clinicaltrials.gov/ct2/show/NCT03306277?term=AVXS-101&rank=5 Accessed October 19, 2018.
15. Pre-Symptomatic Study of Intravenous AVXS-101 in Spinal Muscular Atrophy (SMA) for Patients With Multiple Copies of SMN2 (SPR1NT). Clinicaltrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03505099?term=AVXS-101&rank=1 Accessed October 19, 2018.
16. Study of Intrathecal Administration of AVXS-101 for Spinal Muscular Atrophy (STRONG). Clinicaltrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03381729?term=AVXS-101&rank=3  Accessed October 19, 2018.
17. Tse V, Moller-Tank S, Asokan A. Strategies to circumvent humoral immunity to adeno-associated viral vectors. Exper Opin Biol Ther.  2015;15(6):845-55.
18. Glascock J SJ, Haidet-Phillips A, et al. Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening.  Journal of Neuromuscular Diseases. 2018;5(2):145–158.
19. Appendix: Supplementary material for Calucho M, Bernal M, Alias L, et al. Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscular disorders. 2018; 28:208-15. https://doi.org/10.1016/j.nmd.2018.01.003.

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