Onasemnogene abeparvovec-xioi (Zolgensma)

Number: 0953



Precertification of Zolgensma (onasemnogene abeparvovec-xioi)) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of Zolgensma (onasemnogene abeparvovec-xioi), call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

Note: Site of Care Utilization Management Policy applies.  For information on site of service for Zolgensma, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

Aetna considers onasemnogene abeparvovec-xioi (Zolgensma) medically necessary for children less than 2 years of age with spinal muscular atrophy (SMA) who meet all of the following criteria:

  1. Member has a genetically confirmed diagnosis of SMA, with documentation of bi-allelic mutations in the survival motor neuron 1 (SMN1) gene (deletions or point mutations); and

  2. Member does not have advanced SMA, including but not limited to any of the following:

    • Complete paralysis of limbs; or
    • Invasive ventilatory support (tracheostomy); or
    • Respiratory assistance for 16 or more hours per day (including non-invasive respiratory support) continuously for 14 or more days in the absence of acute reversible illness (excluding perioperative ventilation); and
  3. The member has an anti-adeno-associated virus 9 (AAV9) antibody titer less than or equal to 1:50 as determined by Enzyme- linked Immunosorbent Assay (ELISA) binding immunoassay; and

  4. The medication is prescribed by or in consultation with a physician who specializes in treatment of spinal muscular atrophyand

  5. If the member is on nusinersen (Spinraza) or risdiplam (Evrysdi), it will be discontinued prior to administration of onasemnogene abeparvovec-xioi (see Pharmacy CPB for Evrysdi criteria).

Aetna considers repeat administration of onasemnogene abeparvovec-xioi experimental and investigational because the effectiveness of this approach has not been established.

See also CPB 0915 - Nusinersen (Spinraza).

Dosing Recommendations

Zolgensma is for single-dose intravenous infusion only. The recommended dosage of Zolgensma is 1.1 × 1014 vector genomes (vg) per kg of body weight. Administer Zolgensma as an intravenous infusion over 60 minutes.

See prescribing information for complete dosage and administration recomendations. 

Source: AveXis 2019.


Spinal muscular atrophy (SMA) is an autosomal recessive hereditary disease characterized by neurodegeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem, resulting in progressive muscle weakness and atrophy. The incidence of spinal muscular atrophy ranges from 4 to 10 per 100,000 live births, and the carrier frequency of disease-causing survival motor neuron 1 (SMN1) gene mutations ranges from 1/90 to 1/47. SMA can be classified into five subtypes (0-4) based on age of onset of symptoms and motor milestone achievement. SMA type 0 is the most severe subtype. It designates a prenatal onset of SMA and was traditionally classified as SMA type 1. Mothers of affected patients with SMN 0 may recognize a decrease or loss of fetal movement in late pregnancy and at birth. Infants have severe weakness and hypotonia, often with areflexia, facial diplegia, and congenital heart defects. No motor milestones are achieved, and death occurs from respiratory failure by age six months. SMA type 1 (SMA1) phenotype is the most common and accounts for 60% of SMA patients. Without a functional survival motor neuron 1(SMN1) gene, infants with SMA Type 1 rapidly lose the motor neurons responsible for muscle functions such as breathing, swallowing, speaking and walking. Left untreated, a baby's muscles become progressively weaker eventually leading to paralysis or death, in most cases by his or her second birthday. SMA type 2 and SMA type 3 have a later onset and a less severe course. SMA type 4 (adult onset) is the least severe type (Bodamer 2019; Farrar 2017).

The most common forms of SMA are caused by a deficient or missing survival motor neuron 1 (SMN1) gene on chromosome 5q (i.e., 5q SMAs); however, there are several rare non-5q spinal muscular atrophies. The most common mutation of the SMN1 gene is a deletion of exon 7. Approximately 94 percent of patients with clinically typical SMA carry homozygous deletions of exon 7. SMN protein appears to play a role in mRNA synthesis in motor neurons and may inhibit apoptosis. The differences in SMN protein activity and phenotypic expression appear to be related in part to a modifying gene, called SMN2. The SMN1 and SMN2 genes are more than 99 percent identical and lie within an inverted duplication on chromosome 5q13.2. Thus, loss of the SMN1 protein is partially compensated by SMN2 protein synthesis. Disease severity in SMA generally correlates inversely with SMN2 gene copy number, which varies from 0 to 8 in the normal population, and to a lesser degree with the level of SMN protein. The presence of three or more copies of SMN2 is associated with a milder phenotype. Typically, individually with SMA types 2, 3, and 4 have more copies SMN 2 gene (i.e., less severe SMA, later onset, and longer life expectancy) (Bodamer 2019; Farrar 2017).

In 2007, an International Conference on the Standard of Care for SMA published a consensus statement on SMA standard of care that has been widely used throughout the world (Wang 2007). The 12 core committee members worked with more than 60 spinal muscular atrophy experts in the field through conference calls, e-mail communications, a Delphi survey, and 2 in-person meetings to achieve consensus on 5 care areas: diagnostic/new interventions, pulmonary, gastrointestinal/nutrition, orthopedics/rehabilitation, and palliative care. Consensus was achieved on several topics related to common medical problems in spinal muscular atrophy, diagnostic strategies, and recommendations for assessment and monitoring, and therapeutic interventions in each care area. A consensus statement was drafted to address the 5 care areas according to 3 functional levels of the patients: non-sitter, sitter, and walker. The committee also identified several medical practices lacking consensus and warranting further investigation. It is the authors' intention that this document be used as a guideline, not as a practice standard for their care. A practice standard for spinal muscular atrophy is urgently needed to help with the multidisciplinary care of these patients.

In 2016 the European Neuro Muscular Centre (ENMC) International workshop brought together twenty-six experts from nine countries and patient representatives to update the 2007 Consensus Statement for Standard of Care in Spinal Muscular Atrophy. Following the ENMC workshop, the multidisciplinary committee provided a two-part update of the topics that were covered in the previous 2007 recommendations (Mercuri 2018; Finkel 2018).  The ENMC experts agreed many aspects of care for infants and children with SMA have dramatically improved since the 2007 publication mostly, with respect to orthopedic management, nutrition and respiratory support. In part 1, the experts provide an update on the diagnosis, rehabilitation, orthopedic and spinal management; and nutritional, swallowing and gastrointestinal management (Mercuri 2018).

In Part 2 of these updated guidelines, the SMA care group discuss pulmonary management, acute care, other organ involvement, ethical issues, medications, and the impact of new treatments for SMA. The experts note that until recently no drug treatment had proved to be able to influence the disease course of SMA. A Cochrane review published in 2012 reported six randomized placebo-controlled trials on treatment for SMA using creatine, phenylbutyrate, gabapentin, thyrotropin-releasing hormone, hydroxyurea and combination therapy with valproate and acetyl-L-carnitine. None of these studies showed statistically significant effects on the outcome measures in participants with SMA types 2 and 3. Other possible therapeutic interventions include albuterol, a beta-adrenergic agonist, which showed promising functional improvements in open label studies. However, there is still a lack of evidence from randomized placebo-controlled trials for these drugs. Antibiotics or medications/supplements for bone health, such as vitamin D and calcium and bisphosphonate, or drugs for gastroesophageal reflux, were recommended with the exception of vitamin D, rarely used prophylactically, and mainly used if needed/deficient. Annual influenza and pneumococcal immunizations, as reported in the pulmonary section, were strongly recommended (Finkel 2018).

At the time of consensus completion, none of the drugs involved in clinical trial had completed the regulatory process and were commercially available. The consensus statement noted that olesoxime, a neuroprotective drug, has completed a phase 3 trial in patients with type 2 and 3 SMA, but the primary endpoint was not met. Secondary endpoints and sensitivity analyses indicate that olesoxime might maintain motor function in patients with SMA. Other approaches include small molecules aiming to increase SMN protein level or SMN1 gene replacement using viral vector, are also being used in clinical trials with promising preliminary results.

Subsequently, the U.S. Food and Drug Administration (FDA) approved nusinersen (Spinraza) for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients on December 23, 2016 (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. Due to nusinersen’s intrathecal administration, there is a required institutional infrastructure to provide administration and post-procedural monitoring in a reliable way.

On May 24, 2019, The U.S. Food and Drug Administration (FDA) approved Zolgensma (onasemnogene abeparvovec-xioi) the first gene therapy approved to treat children less than two years of age with spinal muscular atrophy (SMA), a leading genetic cause of infant mortality (FDA 2019). Whereas nusinersen works to increase proportion of SMN 2 gene mRNA transcripts that include exon 7, onasemnogene is an adeno-associated virus vector-based gene therapy that works to replace the deficient or absent SMN 1 gene. The vector delivers a fully functional copy of human SMN gene into the target motor neuron cells. A one-time intravenous administration of onasemnogene results in expression of the SMN protein in a child’s motor neurons, which improves muscle movement and function, and survival of a child with SMA. Dosing is determined based on the weight of the patient (AveXis 2019).

The FDA approval of onasemnogene in pediatric patients less than 2 years of age was evaluated in an open-label, single-arm clinical trial (ongoing STR1VE trial; n=21) and an open-label, single-arm, ascending-dose clinical trial (completed START trial; n=15) involving a total of 36 pediatric patients (AveXis 2019; Mendell 2017). Patients experienced onset of clinical symptoms consistent with SMA before 6 months of age. All patients had genetically confirmed bi-allelic SMN1 gene deletions, 2 copies of the SMN2 gene, and absence of the c.859G>C modification in exon 7 of SMN2 gene (which predicts a milder phenotype). All patients had baseline anti-AAV9 antibody titers of ≤ 1:50, measured by ELISA. In both trials, onasemnogene was delivered as a single-dose intravenous infusion. Efficacy was established based on survival, and achievement of developmental motor milestones such as sitting without support. Survival was defined as time from birth to either death or permanent ventilation. Permanent ventilation was defined as requiring invasive ventilation (tracheostomy), or respiratory assistance for 16 or more hours per day (including noninvasive ventilatory support) continuously for 14 or more days in the absence of an acute reversible illness, excluding perioperative ventilation. Efficacy was also supported by assessments of ventilator use, nutritional support and scores on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). CHOP-INTEND is an assessment of motor skills in patients with infantile-onset SMA (AveXis 2019).

The ongoing STR1VE clinical trial enrolled 21 patients (10 male and 11 female) with infantile-onset SMA. Before treatment with onasemnogene, none of the 21 patients required non-invasive ventilator (NIV) support, and all patients could exclusively feed orally (i.e., no need for non-oral nutrition). The mean CHOP-INTEND score at baseline was 31.0 (range 18 to 47). All the patients received 1.1 × 1014 vg/kg of onasemnogene. The mean age of the 21 patients at the time of treatment was 3.9 months (range 0.5 to 5.9 months). As of the March 2019 data cutoff, 19 patients were alive without permanent ventilation (i.e., event-free survival) and were continuing in the trial, while one patient died at age 7.8 months due to disease progression, and one patient withdrew from the study at age 11.9 months. The 19 surviving patients who were continuing in the trial ranged in age from 9.4 to 18.5 months. By the data cutoff, 13 of the 19 patients continuing in the trial reached 14 months of age without permanent ventilation, one of the study’s co-primary efficacy endpoints. In addition to survival, assessment of the other co-primary efficacy endpoint found that 10 of the 21 patients (47.6%) achieved the ability to sit without support for ≥ 30 seconds between 9.2 and 16.9 months of age (mean age was 12.1 months). Based on the natural history of the disease, patients who met the study entry criteria would not be expected to attain the ability to sit without support, and only approximately 25% of these patients would be expected to survive (i.e., being alive without permanent ventilation) beyond 14 months of age. In addition, 16 of the 19 patients had not required daily NIV use. Comparison of the results of the ongoing clinical trial to available natural history data of patients with infantile-onset SMA provides primary evidence of the effectiveness of onasemnogene (AveXis 2019).

The completed trial by Mendell et al (2017) was an open-label, dose-ranging study (START trial; NCT02122952) of 15 patients (6 males, 9 females) with infantile onset SMA who had homozygous SMN1 deletions of exon 7. Twelve patients were assigned to high-dose and three patients were assigned to low-dose onasemnogene intravenous infusion. The dosage received by patients in the low-dose cohort was approximately one-third of the dosage received by patients in the high-dose cohort. However, the precise dosages of onasemnogene received by patients in this completed clinical trial are unclear due to a change in the method of measuring onasemnogene concentration, and to decreases in the concentration of stored onasemnogene over time. The retrospectively-estimated dosage range in the high-dose cohort is approximately 1.1 × 1014 to 1.4 × 1014 vg/kg. At the time of treatment, the mean age of patients in the low-dose cohort was 6.3 months (range 5.9 to 7.2 months), and 3.4 months (range 0.9 to 7.9 months) in the high-dose cohort. The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, the authors compared scores on the CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the two cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts). By 24 months following onasemnogene infusion, one patient in the low-dose cohort met the endpoint of permanent ventilation; in the high-dose cohort, all 12 patients in the high-dose cohort were alive without permanent ventilation, 9 patients (75.0%) were able to sit without support for ≥ 30 seconds, and 2 patients (16.7%) were able to stand and walk without assistance. None of the patients in the low-dose cohort were able to sit without support, or to stand or walk. Comparison of the results of the low-dose cohort to the results of the high-dose cohort shows a dose-response relationship that supports the effectiveness of onasemnogene (AveXis 2019; Mendell 2017).

Al-Zaidy et al (2019; NCT02122952) stated Spinal Muscular Atrophy type 1 (SMA1) is a rare genetic neuromuscular disease where 75% of SMA1 patients die/require permanent-ventilation by 13.6 months. This phase 1 study assessed the health outcomes of SMA1 infants treated with AVXS-101 gene replacement therapy. Twelve genetically confirmed SMA1 infants with homozygous deletions of the SMN1 gene and two SMN2 gene copies received a one-time intravenous proposed therapeutic dose of AVXS-101 in an open label study conducted between December 2014 and 2017. Patients were followed for 2-years post-treatment for outcomes including
  1. pulmonary interventions;
  2. nutritional interventions;
  3. swallow function;
  4. hospitalization rates; and
  5. motor function.

All 12 patients completed the study. Seven infants did not require noninvasive ventilation (NIV) by study completion. Eleven patients had stable or improved swallow function, demonstrated by the ability to feed orally; 11 patients were able to speak. The mean proportion of time hospitalized was 4.4%; the mean unadjusted annualized hospitalization rate was 2.1 (range = 0, 7.6), with a mean length of stay/hospitalization of 6.7 (range = 3, 12.1) days. Eleven patients achieved full head control and sitting unassisted and two patients were walking independently. The authors concluded that AVXS-101 treatment in SMA1 was associated with reduced pulmonary and nutritional support requirements, improved motor function, and decreased hospitalization rate over the follow-up period. This contrasts with the natural history of progressive respiratory failure and reduced survival. The reduced healthcare utilization could potentially alleviate patient and caregiver burden, suggesting an overall improved quality of life following gene replacement therapy (Al-Zaidy 2019).

In clinical trials, the most common adverse reactions (incidence ≥ 5%) were elevated aminotransferases and vomiting. The prescribing information for onasemnogene contains a black box warning which states acute serious liver injury and elevated aminotransferases can occur with onasemnogene and patients with pre-existing liver impairment may be at higher risk. Prior to infusion, liver function of all patients should be assessed by clinical examination and laboratory testing (e.g., hepatic aminotransferases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], total bilirubin, and prothrombin time). Systemic corticosteroid should be administered to all patients before and after onasemnogene infusion and liver function should be monitored for at least 3 months after infusion. Other warnings with onasemnogene include thrombocytopenia and elevated Troponin-I. The prescribing information recommends monitoring platelet counts before onasemnogene infusion, and weekly for the first month and then every other week for the second and third month until platelet counts return to baseline. The prescribing information also recommends monitoring troponin-I before onasemnogene infusion, and weekly for the first month and then monthly for the second and third month until troponin-I level returns to baseline (AveXis 2019).

Ricci and colleagues (2019) stated that genetic neuromuscular diseases (NMDs) constitute a heterogeneous group of rare conditions, including some of the most disabling conditions in childhood.  Recently, advanced technologies have greatly expanded pre-clinical and clinical research, and specific therapies have been developed.  These investigators provided an overview of novel pharmacological approaches to the main NMDs, including Duchenne muscular dystrophy (DMD), SMA, X-linked myotubular myopathy, Pompe disease (PD), and myotonic dystrophy type 1, with attention to both achievements and unresolved therapeutic challenges.  They conducted a selected review of relevant publications in the last 5 years identified through PubMed and Scopus.  Additional information was derived from the website of clinicaltrials.gov and from the authors' direct knowledge of research activities.  For the first time, targeted therapies have received conditional regulatory approval and have been introduced into clinical care: enzyme replacement therapy for PD, gene expression modulation for DMD and SMA, and gene therapy for SMA.  The authors concluded that although not curative, these treatments can improve functioning and increase survival.  These researchers stated that issues still to be addressed include: early recognition, definition of new emerging phenotypes, development of more sensitive outcome measures, long-term risk-benefit estimates, high costs sustainability, and criteria for therapy initiation and discontinuation.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

Other CPT codes related to the CPB:

96365 - 96368 Intravenous infusion administration

HCPCS codes covered if selection criteria are met:

J3399 Injection, onasemnogene abeparvovec-xioi, per treatment, up to 5x10

Other HCPCS codes related to the CPB:

Risdiplam (Evrysdi) – no specific code

ICD-10 codes covered if selection criteria are met:

G12.0 Infantile spinal muscular atrophy, type I [Werdnig-Hoffman]

The above policy is based on the following references:

  1. Al-Zaidy S, Pickard AS, Kotha K, et al. Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy. Pediatr Pulmonol. 2019;54(2):179-185.
  2. AveXis, Inc. Zolgensma (onasemnogene abeparvovec-xioi) suspension for intravenous infusion. Prescribing Information. Bannockburn, IL: AveXis, Inc; 2019.
  3. Biogen. Spinraza (nusinersen) injection, for intrathecal use. Prescribing Information. Reference ID: 4332160. Cambridge, MA: Biogen; revised October 2018.
  4. Bodamer OA. Spinal muscular atrophy. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed February 2019.
  5. Farrar MA, Park SB, Vucic S, et al. Emerging therapies and challenges in spinal muscular atrophy. Ann Neurol. 2017;81(3):355-368.
  6. Finkel RS, Mercuri E, Meyer OH, et al; SMA Care group. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28(3):197-207.
  7. Lowes LP, Alfano LN, Arnold WD, et al. Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy. Pediatr Neurol. 2019;98:39-45.
  8. Malone DC, Dean R, Arjunji R, et al. Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients. J Mark Access Health Policy. 2019;7(1):1601484.
  9. 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.
  10. Mercuri E, Finkel RS, Muntoni F, et al; SMA Care Group. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103-115.
  11. Ricci F, Vacchetti M, Brusa C, et al. New pharmacotherapies for genetic neuromuscular disorders: opportunities and challenges. Expert Rev Clin Pharmacol. 2019;12(8):757-770.
  12. Saffari A, Weiler M, Hoffmann GF, Ziegler A. Gene therapies for neuromuscular diseases. Nervenarzt. 2019;90(8):809-816.
  13. Stevens D, Claborn MK, Gildon BL, et al. Onasemnogene abeparvovec-xioi: Gene therapy for spinal muscular atrophy. Ann Pharmacother. 2020 Mar 23 [Epub ahead of print].
  14. U.S. Food and Drug Administration (FDA). FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. FDA News Release. Silver Spring, MD: FDA; May 24, 2019.
  15. Wang CH, Finkel RS, Bertini ES, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007;22:1027-1049.