Onasemnogene abeparvovec-xioi (Zolgensma®)




    Purpose

    The purpose of this communication is to provide advance notice regarding coverage of Onasemnogene abeparvovec-xioi (Zolgensma®).


    Background

    SPINAL MUSCULAR ATROPHY (SMA)

    SMA is a rare autosomal recessive genetic disorder caused by homozygous deletions or pathogenic variants in the SMN1 gene located on chromosome 5. This gene produces the “survival of motor neuron” protein (SMN1), which is essential for motor neuron functioning. In this inherited disorder, as a consequence of absent or low levels of SMN1 protein, the motor neurons in spinal cord degenerate, resulting in atrophy of the voluntary muscles of the limbs and trunk. In 95% of SMA cases, there is a homozygous deletion of exon 7 in the SMN1 gene. The remaining 5% of cases are compound heterozygotes for SMN1 exon 7 deletions and small intragenic variants. Due to absent or low levels of the SMN1 protein, motor neurons in the spinal cord degenerate, resulting in atrophy of the voluntary muscles of the limbs and trunk affecting the ability to crawl, walk, sit up, and control the head. In more severe cases, feeding, swallowing, and breathing are affected as well. The exact role of the SMN protein in motor neurons has not been completely elucidated, and levels of the SMN protein required for optimal functioning are unknown.

    Onasemnogene Abeparvovec-Xioi (Zolgensma®)

    Onasemnogene abeparvovec-xioi was approved by FDA on May 24, 2019 for the treatment of pediatric individuals less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. Onasemnogene abeparvovec-xioi is intended as a one-time gene replacement therapy designed to deliver a functional copy of the SMN1 gene to motor neuron cells of individuals with SMA. Because motor neurons are nondividing cells, it is postulated that once the SMN1 gene is incorporated in the cells, it would be retained over time and potentially allow for long-term, sustained SMN protein expression.

    Onasemnogene abeparvovec-xioi is intended as a one-time gene replacement therapy designed to deliver a functional copy of the SMN1 gene to motor neuron cells of individuals with SMA. Because motor neurons are nondividing cells, it is postulated that once the SMN1 gene is incorporated into the cells, it would be retained over time and potentially allow for long-term, sustained SMN protein expression.

    Infantile-Onset or SMA Type I

    For individuals who have SMA type I (infantile-onset) who receive onasemnogene abeparvovec-xioi, the evidence includes a prospective cohort of 15 individuals followed for 2 years. Relevant outcomes are overall survival, change in disease status, functional outcomes, quality of life, and treatment-related mortality and morbidity. In this single phase 1 study of symptomatic infants with 2 copies of SMN2 gene, 12 of 15 infants received the proposed therapeutic dose while 3 received the minimally effective dose. At the end of the 2-year follow-up, all 15 infants survived and none of the 12 individuals who received the proposed therapeutic dose required permanent ventilation. All 12 individuals also achieved at least 1 motor milestone, with 92% of those achieving scores greater than 40 on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (a score >40 is a favorable outcome). The FDA approval was based on a pooled analysis of 21 individuals from the pivotal phase I and ongoing confirmatory phase III STRIVE-US trial. The observed treatment effect on survival, event-free survival and achievement of motor functions is beyond what is typical based on the known natural history of individuals with SMA type I with two copies of SMN2.The available published data support a clinically meaningful durable treatment effect through 2 years. However, there is limited data to assess the long-term durability of treatment effect as well as safety related to adverse events that are rare or have delayed onset. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

    Presymptomatic Individuals with a Diagnosis of SMA and Less Than 3 Copies of SMN2

    For individuals who are presymptomatic with a genetic diagnosis of SMA and less than 3 copies of SMN2 who receive onasemnogene abeparvovec-xioi, the evidence includes a prospective cohort with a planned enrollment of 44 individuals and a planned follow-up of 18 to 24 months. Relevant outcomes are overall survival, change in disease status, functional outcomes, quality of life, and treatment-related mortality and morbidity. The single prospective cohort study (SPRINT) is currently ongoing. As of March 2019, 18 individuals have been treated. The median follow-up after treatment was 2.9 months (range 0.4 to 8.7). All 18 children were alive and “event free.” Among 8 individuals with two copies of SMN2, all reportedly achieved age-appropriate motor milestones including 4 who could sit without support and 1 who could stand with assistance. Data was much more limited for individuals with 3 copies of SMN2. The evidence is insufficient to determine the effects of technology on health outcomes for individuals with 3 or more copies of SMN2.

    SMA Type II

    For individuals with SMA type II who receive intrathecal onasemnogene abeparvovec-xioi, the evidence includes a single prospective cohort study with a planned enrollment of 27 individuals who are up to 60 months old. Relevant outcomes are overall survival, change in disease status, functional outcomes, quality of life, and treatment-related mortality and morbidity. The single prospective cohort study (STRONG) evaluating use of intrathecal onasemnogene abeparvovec-xioi administration in individuals with age of symptom onset up to 60 months is currently ongoing. The evidence is insufficient to determine the effects of technology on health outcomes.


    Definitions

    Reliable Evidence

    Peer-reviewed reports of clinical studies that have been designed according to accepted scientific standards such that potential biases are minimized to the fullest extent, and generalizations may be made about safety and effectiveness of the technology outside of the research setting. Studies are to be published or accepted for publication, in medical or scientific journals that meet nationally recognized requirements for scientific manuscripts and that are generally recognized by the relevant medical community as authoritative. Furthermore, evidence-based guidelines from respected professional organizations and governmental entities may be considered Reliable Evidence if generally accepted by the relevant medical community.

    Experimental/Investigative Services
    A drug, biological product, device, medical treatment or procedure, or diagnostic test which meets any of the following criteria:
    • Is the subject of ongoing clinical trials;
    • Is the research, experimental study, or investigational arm of an ongoing clinical trial(s) or is otherwise under a systematic, intensive investigation to determine its maximum tolerated dose, its toxicity, its safety, its efficacy, or its efficacy as compared with a standard means of treatment or diagnosis;
    • Is not of proven benefit for the particular diagnosis or treatment of the Member's particular condition;
    • Is not generally recognized by the medical community, as clearly demonstrated by Reliable Evidence, as effective and appropriate for the diagnosis or treatment of the Member's particular condition; or
    • Is generally recognized, based on Reliable Evidence, by the medical community as a diagnostic or treatment intervention for which additional study regarding its safety and efficacy for the diagnosis or treatment of the Member's particular condition, is recommended.

    Any drug, biological product, device, medical treatment or procedure, or diagnostic procedure is not considered Experimental/Investigative if it meets all of the criteria listed below:
    • When required, the drug, biological product, device, medical treatment or procedure, or diagnostic test must have final approval from the appropriate governmental regulatory bodies (e.g., FDA).
    • Reliable Evidence demonstrates that the drug, biological product, device, medical treatment or procedure, or diagnostic test meets technical standards, is clinically valid, and has a definite positive effect on health outcomes.
    • Reliable Evidence demonstrates that the drug, biological product, device, medical treatment or procedure, or diagnostic test leads to measurable improvement in health outcomes (that is, the beneficial effects outweigh any harmful effects).
    • Reliable Evidence clearly demonstrates that the drug, biological product, device, medical treatment or procedure, or diagnostic test is at least as effective in improving health outcomes as established technology, or is usable in appropriate clinical contexts in which established technology is not employable.
    • Reliable Evidence clearly demonstrates that improvement in health outcomes, as defined in the previous bullet, is possible in standard conditions of medical practice, outside clinical investigatory settings.
    • Reliable Evidence shows that the prevailing opinion among experts regarding the drug, biological product, device, medical treatment or procedure, or diagnostic test is that studies or clinical trials have determined its maximum tolerated dose, its toxicity, its safety, its efficacy, or its efficacy as compared with a standard means of treatment for a particular diagnosis.


    Coverage Statement

    MEDICALLY NECESSARY

    Onasemnogene abeparvovec-xioi (Zolgensma®) is considered medically necessary and, therefore, covered as a single-dose intravenous infusion for pediatric individuals of less than two years of age, when all of the following criteria are met:
    • Diagnosis of spinal muscular atrophy (SMA) confirmed by genetic testing demonstrating bi-allelic mutations in the survival motor neuron 1 (SMN1) gene (examples below):
      • deletion of both copies of the SMN1 gene OR
      • compound heterozygous mutations of the SMN1 gene (defined below):
        • pathogenic variant(s) in both copies of the SMN1 gene
        • pathogenic variant(s) in one copy and deletion of the second copy of the SMN1 gene.
    • Documentation of a genetic test confirms no more than 2 copies of the SMN2 gene.
    • Individuals have Baseline anti-adeno-associated virus serotype 9 (AAV9) antibody titers < 1:50
    • Individual does not have advanced SMA (e.g., complete paralysis of limbs, permanent ventilator dependence).
    • The medication is prescribed by a neurologist, who specializes in treatment of spinal muscular atrophy.

    EXPERIMENTAL/INVESTIGATIONAL

    All other uses for onasemnogene abeparvovec-xioi (Zolgensma®), including those below, are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, and based upon Reliable Evidence, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics:
    • Repeat administration of Zolgensma®
    • Concurrent treatment with nusinersen (Spinraza®)
    • Ante-partum administration

    BLACK BOX WARNINGS

    Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.


    Coding

    The following codes represent Onasemnogene abeparvovec-xioi, (Zolgensma®):

    CPT Codes:

    C9399
    J3490
    J3590

    ICD-10 Diagnosis Code

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

    Issued on - 07/03/2019

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