Onasemnogene Abeparvovec (Zolgensma and Itvisma)
Number: 0953
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses abeparvovec (Zolgensma and Itvisma) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.
Note: Requires Precertification:
Precertification of onasemnogene abeparvovec (Zolgensma or Itvisma) is required of all Aetna participating providers and members in applicable plan designs. For precertification of onasemnogene abeparvovec (Zolgensma or Itvisma), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.
Note: Unless member's health plan has elected not to require, gene and cellular therapies must be administered at an Aetna Institutes® Gene Based, Cellular and Other Innovative Therapy (GCIT®) Network. For onasemnogene abeparvovec (Zolgensma or Itvisma), see Aetna Institutes® GCIT Designated Networks.
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Prescriber Specialties
This medication must be prescribed by or in consultation with a physician who specializes in treatment of spinal muscular atrophy. -
Criteria for Initial Approval
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Onasemnogene abeparvovec-xioi (Zolgensma)
Aetna considers onasemnogene abeparvovec-xioi (Zolgensma) medically necessary for the treatment of spinal muscular atrophy (SMA) when all of the following criteria are met:
- 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
- Member experienced onset of disease before 6 months of age; and
- Member is less than 2 years of age; and
- 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
- 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
- Member does not have an active infectious process (e.g., viral, bacterial, or febrile illness) prior to treatment; and
- Member does not have a serious concomitant illness (e.g., severe liver or kidney disease, symptomatic cardiomyopathy); and
- Member’s vaccination status will be up to date prior to Zolgensma administration; and
- Liver function, platelet count, troponin I, and creatinine levels have been assessed at baseline and will be monitored after Zolgensma administration as clinically appropriate; and
- If the member is on nusinersen (Spinraza) or risdiplam (Evrysdi), it will be discontinued prior to administration of the requested drug (see Pharmacy CPB for Evrysdi criteria); and
- Member has not received Zolgensma, Itvisma, or other gene therapy previously.
Aetna considers Zolgensma as experimental, investigational, or unproven for all other indications.
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Onasemnogene abeparvovec-brve (Itvisma)
Aetna considers onasemnogene abeparvovec-brve (Itvisma) medically necessary for the treatment of spinal muscular atrophy (SMA) when all of the following criteria are met:
- Member has a genetically confirmed diagnosis of SMA, with documentation of bi-allelic pathogenic variants in the survival motor neuron 1 (SMN1) gene (deletions or point mutations); and
- Member has 3 or fewer copies of SMN2 gene; and
- Member’s onset of clinical signs and symptoms of disease occurred at 6 months of age or older; and
- Member is 2 to less than 18 years of age at the time of treatment administration; and
- Member does not require invasive ventilation, awake noninvasive ventilation for greater than 6 hours during a 24-hour period, noninvasive ventilation for greater than 12 hours during a 24-hour period or require tracheostomy; and
- Member does not have contraindication(s) to lumbar puncture procedure (e.g., increased intracranial pressure, any impediment to cerebrospinal fluid access, administration of any intrathecal therapy); and
- 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
- Member does not have an active infectious process (e.g. viral, bacterial, or febrile illness) prior to treatment; and
- Member does not have a serious concomitant illness (e.g., severe liver or kidney disease, symptomatic cardiomyopathy); and
- Member does not have a history of allergy or hypersensitivity to treatment regimen (e.g., glucocorticoids) or it's excipients; and
- Liver function, platelet count, troponin I, creatinine, neurologic evaluation, and Hammersmith Functional Motor Scale-Expanded (HFMSE) assessment will be assessed at baseline and will be monitored after Itvisma administration as clinically appropriate; and
- Member’s vaccination status will be up to date prior to Itvisma administration; and
- If the member is on nusinersen (Spinraza) or risdiplam (Evrysdi), it will be discontinued prior to administration of the requested drug; and
- Member has not received Itvisma, Zolgensma, or other gene therapy previously.
Aetna considers Itvisma as experimental, investigational, or unproven for all other indications.
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Continuation of Therapy
Aetna considers repeat administration of onasemnogene abeparvovec experimental, investigational, or unproven because the safety and effectiveness of this approach has not been established.
See also CPB 0915 - Nusinersen (Spinraza).
Dosage and Administration
Zolgensma
Zolgensma is a suspension for intravenous (IV) infusion, supplied in single-use vials. It is provided in a kit containing 2 to 14 vials, with two possible fill volumes: either 5.5 mL or 8.3 mL. All vials have a nominal concentration of 2.0 × 1013 vector genomes (vg) per mL, and each vial contains an extractable volume of no less than either 5.5 mL or 8.3 mL. Zolgensma is intended for single-dose intravenous infusion only.
The recommended dosage of Zolgensma is 1.1 × 1014 vg per kg of body weight. Zolgensma is administered as an IV infusion over 60 minutes.
The safety and effectiveness of repeat administration of Zolgensma have not been evaluated.
See Full Prescribing Information for complete dosage and administration recommendations.
Source: Novartis Gene Therapies, 2025b
Itvisma
Itvisma is a suspension for intrathecal injection, supplied in single-dose vials. Each single-dose vial contains 1.2 × 1014 vg of onasemnogene abeparvovec in 3 mL of suspension. Itvisma has a nominal concentration of 4 ×1013 vg/mL, and each vial contains an extractable volume of not less than 3 mL. Itvisma is intended for single-dose intrathecal injection only.
The recommended dosage of Itvisma is 1.2 × 1014 vector genomes (vg) as an intrathecal bolus injection over approximately 1 to 2 minutes.
See Full Prescribing Information for complete dosage and administration recommendations.
Source: Novartis Gene Therapies, 2025a
Background
U.S. Food and Drug Administration (FDA)-Approved Indications
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Zolgensma is indicated for the treatment of pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron (SMN1) gene. Limitations of use:
- The safety and effectiveness of repeat administrations 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.
- Itvisma is indicated for the treatment of spinal muscular atrophy (SMA) in adults and pediatric patients 2 years of age and older with confirmed mutation in survival motor neuron 1 (SMN1) gene
Onasemnogene abeparvovec is a recombinant adeno-associated virus vector-based (AAV9-based) gene therapy designed to deliver a copy of the gene encoding the human SMN protein for treatment of spinal muscular atrophy (SMA). SMA is caused by a bi-allelic mutation in the SMN1 gene, which results in insufficient SMN protein expression. Onasemnogene abeparvovec is marketed under the names Zolgensma and Itvisma, both developed by Novartis Gene Therapies, Inc. While Zolgensma and Itvisma contain the same active ingredient, their primary differences lie in the FDA-approved age range for patients and the method of administration.
Zolgensma (onasemnogene abeparvovec-xioi) carries a boxed warning for serious liver injury and acute liver failure, with reports of fatal outcomes associated with these conditions and elevated aminotransferases. Patients with preexisting liver impairment or acute hepatic viral infections are at heightened risk for these adverse effects. Prior to infusion, it is crucial to assess liver function through clinical examination and laboratory testing, including hepatic aminotransferases (AST and ALT), total bilirubin, albumin, prothrombin time, PTT, and INR. Specifically, patients with ALT, AST, or total bilirubin levels exceeding two times the upper limit of normal (ULN), except due to neonatal jaundice, have not been included in clinical trials, warranting careful consideration of the risks and benefits of Zolgensma therapy for these individuals. All patients should receive systemic corticosteroids before and after the infusion to mitigate the risk of aminotransferase elevations, and adjustments to the corticosteroid regimen may be necessary in cases of immune-mediated hepatotoxicity. Continuous monitoring of liver function is recommended for at least three months following the infusion and as clinically indicated, with weekly assessments during the first month and biweekly monitoring for an additional month if the patient remains stable. The label advises close observation of patients with worsening liver function tests or signs of acute illness, with further testing of albumin, PTT, and INR if hepatic injury is suspected. While asymptomatic aminotransferase elevations have been frequently reported, there have also been instances of acute serious liver injury and liver failure, some resulting in death, necessitating prompt consultation with a pediatric gastroenterologist or hepatologist if acute liver injury or failure is suspected.
The Zolgensma label includes additional warnings and precautions related to systemic immune response, thrombocytopenia, thrombotic microangiopathy, elevated troponin-I levels, and infusion-related reactions. There is a theoretical risk of tumorigenicity due to the potential integration of AAV vector DNA into the genome. Furthermore, the use of Zolgensma in premature neonates before they reach full-term gestational age is not recommended, as concomitant treatment with corticosteroids may negatively impact neurological development. Therefore, it is advised to delay the infusion until the patient has reached full-term gestational age.
The most common adverse reactions, occurring in 5% or more of patients who received Zolgensma, include elevated aminotransferases and vomiting.
Itvisma (onasemnogene abeparvovec-brve) carries a boxed warning for acute serious liver injury and elevated aminotransferases, with hepatotoxicity manifesting as increased ALT and/or AST levels. Patients with preexisting hepatic impairment or acute hepatic viral infections may be at a higher risk for liver injury. To mitigate potential elevations in aminotransferases, systemic corticosteroids should be administered before and after the Itvisma injection. In cases of immune-mediated hepatotoxicity, adjustments to the corticosteroid regimen may be necessary, including extending the duration, increasing the dose, or prolonging the tapering process. Prior to the injection, liver function must be assessed through clinical examination and laboratory testing, and monitoring should continue for at least three months post-administration, as well as at other clinically indicated times. AST, ALT, and total bilirubin levels should be monitored weekly for the month following the Itvisma administration and during the corticosteroid taper. If the patient is clinically stable with no significant findings at the end of the taper, liver function should be monitored biweekly for an additional month. Tapering of systemic corticosteroids should not begin until AST and ALT levels are below two times the upper limit of normal (ULN). Patients should be closely monitored for worsening liver function test results or signs of acute illness, such as vomiting or deterioration in health, and further testing (including albumin, prothrombin time, partial thromboplastin time (PTT), and international normalized ratio (INR)) is recommended if hepatic injury is suspected. Prompt consultation with a gastroenterologist or hepatologist may be necessary.
Other warnings and precautions for Itvisma include the risk of thrombocytopenia, peripheral sensory neuropathy, thrombotic microangiopathy (TMA), and elevated cardiac troponin I levels. Transient decreases in platelet counts may occur within the first week following Itvisma administration, necessitating regular monitoring of platelet counts before the injection and at least weekly for the first month, or until they return to baseline. Peripheral sensory neuropathy has been reported, with symptoms such as numbness, tingling, prickling, or pain in the arms, hands, legs, and/or feet typically appearing around three weeks post-injection. Patients and caregivers should be informed about these symptoms and advised to notify their physician promptly if they occur. TMA, characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, may also arise with Itvisma administration, particularly in the context of concurrent immune system activation (e.g., infections, vaccinations). It is crucial to monitor for signs and symptoms of TMA, such as hypertension, easy bruising, seizures, or decreased urine output, and to conduct further diagnostic evaluations for hemolytic anemia and renal dysfunction if these occur alongside thrombocytopenia. Immediate consultation with a hematologist and/or nephrologist is recommended if clinical signs or laboratory findings consistent with TMA are observed. Additionally, increases in cardiac troponin I levels have been noted after Itvisma administration without clinical consequences, but cardiac toxicity was observed in animal studies, warranting consideration of cardiac evaluation post-administration and consultation with a cardiologist as needed. There is also a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome.
The most common adverse reactions that occurred in at least 10% of patients who received Itvisma were upper respiratory tract infection, upper gastrointestinal symptoms, pyrexia, and headache.
Spinal Muscular Atrophy
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.
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. Patients experienced the 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 the absence of the c.859G>C modification in exon 7 of the 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 the achievement of developmental motor milestones, such as sitting without support. Survival was defined as the 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.
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).
- pulmonary interventions;
- nutritional interventions;
- swallow function;
- hospitalization rates; and
- 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.
On November 24, 2025, the U.S. FDA approved Itvisma (onasemnogene abeparvovec-brve) for the treatment of SMA in adult and pediatric patients 2 years of age and older with confirmed mutation in the survival motor neuron 1 (SMN1) gene. Approval is supported by "substantial evidence" of effectiveness from a well-controlled Phase 3 study, along with confirmatory data on the product's mechanism of action and efficacy findings from Zolgensma, which shares the same active ingredient but is administered intravenously to younger patients. The applicant successfully justified the expansion of the indication to include adult patients with SMA, although it is important to note that warnings and precautions are warranted due to the heightened risk of adverse events, such as hepatotoxicity and cardiotoxicity, in adults with preexisting chronic conditions. Itvisma contains the same active ingredient as Zolgensma but is formulated at a different concentration for direct administration into the central nervous system through a single intrathecal injection, regardless of patient weight. This approach enables targeted delivery to motor neurons with a lower vector dose, resulting in a rapid onset of action that addresses the genetic root cause of SMA by restoring SMN protein production and halting disease progression. The FDA review team leveraged safety data from Zolgensma, finding that most side effects of Itvisma are consistent with those associated with Zolgensma. Consequently, the hepatotoxicity boxed warning from the Zolgensma label has been retained in the Itvisma label with appropriate modifications, supported by clinical data demonstrating hepatotoxicity in Itvisma studies (FDA, 2025).
Proud et al. (2025) conducted the STEER trial (NCT05089656), a 52-week, phase 3, multicenter, randomized, sham-controlled, double-blind study that evaluated intrathecal onasemnogene abeparvovec (OAV101 IT), a one-time gene transfer therapy, in patients with spinal muscular atrophy (SMA). The study included treatment-naive participants aged 2 to less than 18 years who were able to sit but had never walked independently. The primary efficacy endpoint was the change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score. A total of 126 patients were enrolled, with 75 receiving OAV101 IT and 51 undergoing a sham procedure. The primary endpoint was achieved, showing that patients treated with OAV101 IT had a significant increase in HFMSE score compared to the sham group (least squares mean difference of 1.88, 95% confidence interval: 0.51-3.25; P = 0.0074). The overall incidence of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESI) was comparable between the two groups. Increases in transaminases were infrequent, mostly low grade, and transient. Two participants in the OAV101 IT group and one in the sham group experienced sensory symptoms. Overall, the one-time administration of OAV101 IT resulted in a statistically significant improvement in motor function compared to the sham control, with acceptable safety findings reflected in similar rates of AEs, SAEs, and AESI across both groups.
The inclusion criteria for the STEER trial required patients to have a confirmed diagnosis of 5q spinal muscular atrophy (SMA) during the screening period, be treatment-naive to all SMN-targeting therapies (such as risdiplam and nusinersen), be 2 to less than 18 years of age at Screening Visit 1, and exhibit the onset of clinical signs and symptoms at or after 6 months of age. Additionally, candidates had to complete a Hammersmith Functional Motor Scale - Expanded (HFMSE) assessment during screening, be able to sit independently, and have never walked independently. The exclusion criteria included having an elevated anti-adeno-associated virus serotype 9 (AAV9) antibody titer (greater than 1:50 or a validated elevated result) at screening, experiencing any infectious process or febrile illness within 30 days prior to OAV101 treatment or sham procedure, contraindications for lumbar puncture procedure, and having hepatic dysfunction indicated by alanine aminotransferase (ALT), total bilirubin, gamma-glutamyl transferase (GGT), or glutamate dehydrogenase (GLDH) levels exceeding the upper limit of normal. Patients who required invasive ventilation, awake noninvasive ventilation for more than 6 hours in a 24-hour period, noninvasive ventilation for over 12 hours in a 24-hour period, or those needing a tracheostomy were also excluded. Furthermore, any complications at screening that could interfere with motor efficacy assessments, such as severe contractures or a Cobb angle greater than 40 degrees while sitting, recent surgery for scoliosis or hip fixation within the past 12 months, or planned surgery within the next 64 weeks, as well as clinically significant sensory abnormalities noted during the neurological examination at screening, disqualified potential participants.
Combination Therapy with Nusinersen and Onasemnogene Abeparvovec-xioi
Mirea et al. (2021) stated that SMA is a neuromuscular progressive disease, characterized by decreased amounts of survival motor neuron (SMN) protein, due to an autosomal recessive genetic defect. Despite recent research, there is still no cure. Nusinersen, an antisense oligonucleotide acting on the SMN2 gene, is intrathecally administered all life long, while onasemnogene abeparvovec-xioi, a gene therapy, is administered intravenously only once. Both therapies have proven efficacy, with best outcomes obtained when administered pre-symptomatically. In recent years, disease-modifying therapies such as nusinersen and onasemnogene abeparvovec-xioi have changed the natural history of SMA. These researchers discussed findings of 7 SMA type I patients who received both therapies. They compared their motor function trajectories, ventilation hours and cough assist sessions to a control group of patients who received 1 therapy, in order to examine if combined therapy may be more effective than a single intervention alone. Patients who received both therapies, compared to the monotherapy cohort, had the same motor function trajectory. Moreover, it was observed that the evolution of motor function was better in the 6 months following the 1st therapy than in the first 6 months after adding the 2nd treatment. The authors concluded that the findings of this study suggested that the addition of gene therapy after nusinersen did not appear to provide supplementary benefits for motor function or respiratory status; however, early treatment resulted in better outcomes.
References
The above policy is based on the following references:
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- Farrar MA, Park SB, Vucic S, et al. Emerging therapies and challenges in spinal muscular atrophy. Ann Neurol. 2017;81(3):355-368.
- 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.
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- Novartis Gene Therapies, Inc. Itvisma (onasemnogene abeparvovec-brve) suspension, for intrathecal injection. Prescribing Information. Bannockburn, IL: Novartis Gene Therapies; November 2025a.
- Novartis Gene Therapies, Inc. Zolgensma (onasemnogene abeparvovec-xioi) suspension, for intravenous infusion. Prescribing Information. Bannockburn, IL: Novartis Gene Therapies; revised February 2025b.
- Novartis Pharmaceuticals. Efficacy and safety of intrathecal OAV101 (AVXS-101) in pediatric patients with type 2 spinal muscular atrophy (SMA) (STEER). ClinicalTrials.gov Identifier: NCT05089656. Bethesda, MD: National Library of Medicine; updated December 8, 2025.
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- Yang D, Ruan Y, Chen Y, et al. Safety and efficacy of gene therapy with onasemnogene abeparvovec in the treatment of spinal muscular atrophy: A systematic review and meta-analysis. J Paediatr Child Health. 2023;59(3):431-438.
