Medical Policy

Policy Num:     05.003.003
Policy Name:   Gene Therapies for Metachromatic Leukodystrophy
Policy ID:         [05.003.003]  [Ac / B / M+ / P+]  [5.01.49]

Last Review:    July 16, 2024
Next Review:    July 20, 2025
 

Related Policies: None

Gene Therapies for Metachromatic Leukodystrophy
 

Population Reference No.  Populations Interventions Comparators Outcomes
                                               1 Individuals:
  • With pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy
 Interventions of interest are:
  • Atidarsagene autotemcel
 Comparators of interest are:
  • Standard of care
 Relevant outcomes include:
  • Overall survival
  • Disease-specific survival
  • Change in disease status
  • Functional outcomes
  • Quality of life
  • Treatment-related morbidity
  • Treatment-related mortality

Summary

Description

Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder. It arises due to biallelic pathogenic variants in the arylsulfatase A(ARSA) gene, which leads to a deficiency of the lysosomal ARSA enzyme. This enzyme plays a crucial role in metabolizing sulfatides, a major component of myelin membranes in both the central and peripheral nervous system. When ARSA is deficient, undegraded sulfatides accumulate within the central and peripheral nervous system causing microglial damage, progressive demyelination, neurodegeneration, and ultimately resulting in the loss of motor and cognitive functions, often leading to early death –especially in patients with symptom onset before the age of 7 years. MLD subtypes are primarily defined based on age of symptom onset. The late infantile subtype is defined by symptom onset before 30 months of age while early juvenile subtype is defined by symptom onset between 30 months and 7 years of age. In late juvenile subtype, symptom onset is between 7 years and 16 years of age. Symptom onset after 16 years of age is defined as adult onset. Late infantile and early juvenile are the most severe subtypes. Prior to the approval of atidarsagene autotemcel, there were no approved treatments for MLD in the US. Allogeneic hematopoietic stem cell transplantation has shown benefit in some patients with late-onset MLD who are pre-symptomatic or minimally symptomatic at the time of transplant, but it offers little or no benefit in patients with late infantile or early juvenile MLD. Atidarsagene autotemcel is an autologous hematopoietic stem cell (HSC)-based gene therapy which adds functional copies of the ARSA gene into patients’ HSCs through transduction of autologous CD34+ cells with Lenti-D lentiviral vector. The genetically repaired cells are infused back into the individual, where, once engrafted, they differentiate into multiple cell types, some of which migrate across the blood-brain barrier into the central nervous system and express the functional enzyme.

Summary of Evidence

For individuals with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy (MLD) who receive atidarsagene autotemcel, the evidence includes integrated efficacy analyses of several single arm studies compared with an external natural history cohort. The interventional studies enrolled 39 patients with late infantile and early juvenile MLD. All study participants were classified as having MLD on the basis of 2 known pathologic mutations in the ARSA gene, 2 null mutations for pre-symptomatic late infantile and at least 1 mutation encoding residual enzyme for pre-symptomatic or early symptomatic early juvenile MLD. Late infantile was defined as expected disease onset ≤30 months of age while early juvenile was defined as expected or actual disease onset >30 months and <7 years of age. Pre-symptomatic status was defined as the absence of neurological signs and symptoms of MLD or physical exam findings limited to abnormal reflexes and/or clonus. Early symptomatic status was defined as walking independently and IQ ≥85. In children with pre-symptomatic late infantile MLD (n=21), treatment with atidarsagene autotemcel demonstrated improvement in severe motor impairment-free survival (defined as the interval from birth to the first occurrence of loss of locomotion and loss of sitting without support or death), and in survival and cognitive function outcomes when compared to natural history cohort (n=28). In children with pre-symptomatic early juvenile MLD (n=7), the effectiveness of atidarsagene autotemcel was demonstrated by slowing of the progression of motor and cognitive disease manifestations compared to untreated children and matched sibling comparators. In children with early symptomatic early juvenile MLD (n=10), atidarsagene autotemcel effectiveness was demonstrated in a subject-level analysis which showed slowing of cognitive disease progression despite continued progression of motor disease in treated children, which is unexpected in untreated patients. The major risks of atidarsagene autotemcel treatment include thrombosis and thromboembolic events, encephalitis, serious infection, veno-occlusive disease, and delayed platelet engraftment. In the context of MLD, the associated risks are deemed acceptable due to the severity of the disease and the lack of effective standard treatments. Notable limitations include use of single arm studies with an external historical cohort which are susceptible to biases that may affect the estimates of treatment differences. Additionally, the sample size was limited with high heterogeneity of the disease trajectories in patients with pre-symptomatic or early symptomatic early juvenile MLD. There were also instances of missing data or inappropriate exclusions. Two patients with early symptomatic early juvenile died due to disease progression after treatment. These 2 patients were ultimately not included in the primary survival analysis due to not meeting the more stringent treatment entry criteria established after they were recruited into the study and based on post-hoc analysis of the data. Removal of these 2 patients creates greater uncertainty about the potential harms in the early symptomatic early juvenile MLD population. In addition, there are uncertainties about long-term durability and safety. While no cases of malignancy, clonal expansion, or insertional oncogenesis were reported in the trial participants, such risk cannot be ruled out in the larger, real-world, population. There is a risk of oncogenesis with lentiviral vectors and, given that patients will be treated early on in life, this will be an important long-term harm to evaluate. While there is residual uncertainty around the estimates of some of the clinical outcomes, the observed magnitude of the benefit indicates that atidarsagene autotemcel will frequently be successful in treating patients with late infantile or early juvenile MLD especially when given in pre-symptomatic phase. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this evidence review is to determine if use of atidarsagene autotemcel in children with pre-symptomatic late infantile, pre-symptomatic early juvenile or early symptomatic early juvenile metachromatic leukodystrophy improves the net health outcome.

POLICY statements

Atidarsagene autotemcel

Atidarsagene autotemcel is considered medically necessary for individuals if they meet criteria 1 through 5:

  1. Confirmed diagnosis of metachromatic leukodystrophy (MLD) by gene sequencing and/or deletion/duplication assessment identifies biallelic ARSA pathogenic or likely pathogenic variants.

  2. If a proband individual, has all of the following:

    1. ARSA enzyme activity in leukocytes below reference values

    2. Urinary sulfatide levels above reference values.

  3. Confirmed diagnosis of one of the following subtypes of MLD (see Policy Guidelines):

    1. Pre-symptomatic late infantile

    2. Pre-symptomatic early juvenile

    3. Early symptomatic early juvenile.

  4. Meet the institutional requirements for a stem cell transplant procedure where the individual is expected to receive gene therapy. The requirements may include:

    1. Adequate performance status score (e.g., Karnofsky performance status, Lansky performance status)

    2. Absence of advanced liver disease

    3. Adequate estimate glomerular filtration rate (eGFR)

    4. Adequate diffusing capacity of the lungs for carbon monoxide (DLCO)

    5. Adequate ventricular ejection fraction (LVEF)

    6. Absence of clinically significant active infection(s).

  5. Have not received a previous allogenic hematopoietic stem cell transplant or gene therapy.

Atidarsagene autotemcel is considered investigational when the above criteria are not met.

Atidarsagene autotemcel is considered investigational for all other indications.

Repeat treatment with atidarsagene autotemcel is considered investigational.

POLICY GUIDELINES

Recommended Dose

Metachromatic Leukodystrophy Subtype Minimum Recommended Dose (CD34+ cells/kg) Maximum Recommended Dose (CD34+ cells/kg)
Pre-symptomatic late infantile 4.2 × 106 30 × 106
Pre-symptomatic early juvenile 9 × 106 30 × 106
Early symptomatic early juvenile 6.6 × 106 30 × 106

Dosing Limits

1 injection per lifetime

Other Considerations

The FDA approved label includes a normal range for ARSA enzyme activity to be 31 to 198 nmol/mg/h. Elevated urinary sulfatide levels may differ among laboratory testing facilities.

In the clinical trials of atidarsagene autotemcel, children were classified as having pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy based on the following:

Metachromatic Leukodystrophy Subtype Disease Classification
Pre-symptomatic late infantile
  • Expected disease onset ≤30 months of age
  • ARSA genotype consistent with late infantile
  • Absence of neurological signs and symptoms
Pre-symptomatic early juvenile
  • Expected disease onset >30 months and <7 years of age
  • ARSA genotype consistent with early juvenile
  • Absence of neurological signs and symptoms or physical exam findings limited to abnormal reflexes and/or clonus
Early symptomatic early juvenile
  • Disease onset >30 months and <7 years of age
  • ARSA genotype consistent with early juvenile
  • Walking independently (GMFC-MLD Level 0 with ataxia or GMFC-MLD Level 1) and IQ ≥ 85
GMFC: Gross Motor Classification; MLD: metachromatic leukodystrophy
Atidarsagene autotemcel is a lentiviral vector gene therapy which has a potential risk of lentiviral vector-mediated insertional oncogenesis post-treatment. In clinical trials for atidarsagene autotemcel, no cases of insertional oncogenesis have been reported. Individuals treated with atidarsagene autotemcel may develop hematological malignancies and should be monitored lifelong. Individuals should be monitored with a complete blood count (with differential) annually and integration site analysis as warranted for at least 15 years post-treatment.

Coding

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration‒approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

Metachromatic Leukodystrophy

Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal disease that causes progressive demyelination of the central and peripheral nervous system. It is caused by deficient activity of the lysosomal enzyme arylsulfatase A (ARSA). The ARSA gene, located on chromosome 22q13.3-qter, encodes this enzyme. In almost all cases, biallelic pathogenic variants in the ARSA gene lead to MLD. A rare variant form of MLD is caused by a deficiency of sphingolipid activator protein SAP-B (saposin B), which is responsible for the degradation of sulfatides by ARSA. This form is caused by mutations in the prosaposin gene (PSAP gene). 1,

Numerous pathogenic variants of the ARSA gene have been documented. Among individuals of European descent, 2 specific alleles (A and I) contribute to roughly 50% of cases.2,3, However, different populations have different allele distributions.4, The 2 most common pathogenic variants are described below:

The ARSA enzyme is responsible for the breakdown of sulfatides, one of the most common sphingolipids in the myelin sheath. Due to the deficient activity of ARSA enzyme, breakdown of sulfatides is impeded and they accumulate within the central and peripheral nervous system. This accumulation impairs the function and integrity of myelin sheaths, leading to demyelination. Sulfatides can also accumulates in other organs, including the kidneys, testes, and gallbladder. MLD can be classified based on the age of onset and clinical features of the disease. All forms of the disease involve a progressive deterioration of neurodevelopment and neurocognitive function. MLD is categorized based on the age of onset and is summarized in Table 1. Mean survival varies based on subtype, with late infantile MLD children surviving around 8 years and those with early juvenile MLD 10 to 20 years.5,6,

Table 1. Clinical Classification of Metachromatic Leukodystrophy
Classification Onset Clinical features
Late Infantile form 6 months to 4 years of age
  • Most common and most severe form
  • Infants and toddlers may present with developmental delay or regression of motor skills due to peripheral neuropathy even before any evidence of brain magnetic resonance imaging changes. In some cases, the first symptoms may be apparent after a febrile illness or anesthesia.1, Symptoms may then abate for weeks before continuing to progress. Other early signs can include gait difficulties, seizures, ataxia, hypotonia, extensor plantar responses, and optic atrophy.7,8,
  • Deep tendon reflexes are sometimes reduced or absent, reflecting the peripheral neuropathy. Sensory potentials are affected earlier and more severely than are motor responses.9,
  • The prognosis is worse than later-onset forms of metachromatic leukodystrophy; progression to death typically occurs within 5 to 6 years, although some patients survive into the second decade of life.1,
Early Juvenile 4 to 6 years of age
  • Heterogeneous in presentation. Some children present between 4 and 6 years of age (early juvenile) while others may presents between 6 and 16 years of age (late juvenile).7,10,
  • Children may present with intellectual impairment, behavioral difficulties, gait disturbance, ataxia, upper motor neuron signs, and a peripheral neuropathy; seizures may also occur.
  • Progression is slower compared with the late infantile form, and these children may survive until early adulthood.
Late Juvenile 6 to 16 years of age
Adult form Beyond 16 years of age
  • Least common form, is usually heralded by dementia and behavioral difficulties, and a substantial minority present with neuropathy, psychosis, schizophrenia, or seizures.7,11, Optic atrophy has also been reported.12,
  • A late-onset or adult-onset phenotype limited to psychiatric disease with minimal or no motor findings is well described but often remains undiagnosed for many years; the course is static or very slowly progressive.13, Affected patients may survive for 20 to 30 years after onset.11,

Epidemiology

The prevalence of MLD ranges from 1 in 40,000 to 1 in 100,000 in the northern European and North American populations.14,However, a higher prevalence has been found in certain groups, including Habbanite Jews in Israel, Arabs living in Israel, and Navajo Indians in the United States 15,16,17, Incidence is estimated to be 1/40,000 births in the United States. There is no sexual and racial predilection.

Diagnosis

Leukodystrophies are generally suspected in pediatric patients with difficulties in meeting appropriate development milestones when previously able to do so. Peripheral neuropathy can present prior to dysarthria and other CNS manifestations.18, A decline in gross and fine motor skills at any age should be evaluated for MLD. Diagnosis can be challenging for the late infantile form, as the brain MRI may be normal initially and the early presenting symptoms of hyporeflexia and developmental delay are relatively nonspecific. In a patient with progressive neurologic dysfunction and/or leukodystrophy, the diagnosis of MLD due to ARSA deficiency is established when all of the following criteria are met:

Elevated urinary sulfatides are present in all types of MLD, including MLD due to sphingolipid activator protein B (Sap-B) deficiency.1,19,20, Both enzyme assay and sulfatide substrate measurement are essential parts of the biochemical diagnosis. They complement gene sequencing, especially in the case of a proband. For siblings of an index case, gene sequencing alone is sufficient. Additionally, assessing both enzyme activity and sulfatides aids in distinguishing ARSA pseudodeficiency from MLD. ARSA pseudodeficiency refers to individuals who have non-disease-causing pseudodeficiency alleles in the ARSA gene which results in low ARSA enzyme activity levels approximating those of patients with MLD. Thus, the diagnosis of MLD should not be based only on the activity of ARSA; screening for pseudodeficiency alleles is important when low, but not absent, levels of ARSA are detected.21, ARSA pseudodeficiency is present in approximately 1 percent of the general population.

Delays in diagnosis and misdiagnosis are common in children without a diagnosed sibling, with a the time from first symptom to diagnosis of 4 months to 1 year with late infantile MLD and up to seven years for children with juvenile MLD. 22,

Availability of newborn screening for MLD is limited and is not yet recommended in the United States by the federal Recommended Uniform Screening Panel.23,. Newborn screening for MLD, based on detection of elevated blood sulfatide levels, is occurring in Germany and in New York.24,

Treatment

Allogeneic hematopoietic stem cell transplant (HSCT) has been used for years but has yielded mixed results.25, Engraftment typically requires myeloablative conditioning, often with high doses of busulfan, which can cross the blood-brain barrier and cause neurologic decline. Despite significant advancements in allogeneic transplantation, this therapeutic approach continues to be a topic of controversy for several reasons. Firstly, systematic outcome data are scarce and challenging to generalize due to variations in eligibility criteria and transplantation protocols across different studies. Secondly, relying on outcome data from older patient cohorts may not accurately predict current results given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient human leukocyte antigen typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors. Lastly, and different types of MLDs have shown varying responses.

Allogeneic HSCT has been found to be ineffective for late infantile or early juvenile forms and is not recommended for this population.25, Allogeneic HSCT may provide some benefit in late-onset MLD who are pre-symptomatic or minimally symptomatic at the time of transplant.Solders M, Martin DA, Andersson C, et al. Hematopo.... 49(8): 1046-51. PMID 24797185]27,28,29,30,31, In a 2023 systematic review, disease progression at 10 years involving decreased motor function or loss of language occurred in 8 of 20 patients (40 percent) with juvenile onset who received HSCT compared with 28 of 41 patients (68%) with juvenile onset who did not receive HSCT.32, In a single-center cohort report with 16 evaluable long-term (10-year) MLD survivors who received HSCT, the investigators concluded that the aggregate motor and language function was favorable compared with the natural history.27,

Regulatory Status

On March 18, 2024, Lenmeldy (atidarsagene autotemcel) was approved by the Food and Drug Administration (FDA) for the treatment of children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy.

RATIONALE

This evidence review was created in March 2024 with a search of the PubMed database. The most recent literature update was performed through March 19, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Metachromatic Leukodystrophy

Clinical Context and Therapy Purpose

The purpose of gene therapies in individuals with MLD is to provide a treatment option that is an improvement on existing therapies. Potential benefits of this one-time therapy may include the following:

The following PICO was used to select literature to inform this review.

Populations

The relevant populations of interest are children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile MLD.

Interventions

The therapy being considered is atidarsagene autotemcel. In this gene therapy protocol, hematopoietic stem cells are mobilized using granulocyte colony-stimulating factor (G-CSF) with or without plerixafor followed by apheresis to obtain a CD34+ cell-enriched population. These cells are then transduced ex vivo by lentiviral vector encoding the human arylsulfatase A (ARSA) gene. Individuals receive myeloablative conditioning with busulfan to deplete endogenous hematopoietic stem cells and lymphodepletion with cyclophosphamide, enabling therapeutic repopulation of the individual bone marrow with hematopoietic stem cells containing the transgene. Treatment with atidarsagene autotemcel requires inpatient hospitalization. Atidarsagene autotemcel aims to correct the underlying genetic cause of MLD. When the genetically repaired cells are infused back into the individual, where, once engrafted, they differentiate into multiple cell types, some of which migrate across the blood-brain barrier into the central nervous system and express the functional enzyme.

Comparators

The following strategies are currently being used to make decisions about allogenic stem hematopoietic stem cell transplantation and multidisciplinary supportive care to improve quality of life, maximize function, and reduce complications.

Outcomes

The general outcomes of interest are overall survival, disease-specific survival, change in disease status, functional outcomes, quality of life, treatment-related morbidity, and treatment-related mortality (Table 2). Follow-up at 15 years is of interest to monitor outcomes.

Table 2. Health Outcome Measures Relevant to Metachromatic Leukodystrophy
Outcome Measure (Units) Description and Administration Thresholds for Improvement/Decline or Clinically Meaningful Difference (if known)
Cognitive function Neuropsychological tests (Bayley Scale of Infant Development, Wechsler Preschool and Primary Scale of Intelligence, Wechsler Intelligence Scale for Children, or Wechsler Adult Intelligence Scale) according to the child’s age and/or ability. According to the child’s age and/or ability. When assessed within the appropriate age ranges, a standard score can be derived, allowing comparison of a child’s cognitive ability with the normative population. In trials, cognitive function was defined using the following:
  • Normal cognitive function, standard score ≥85;
  • Mild cognitive impairment, standard score ≥70 and <85;
  • Moderate cognitive impairment, score >55 and <70;
  • Severe cognitive impairment, score ≤55.
Motor function Gross motor function classification (GMFC-MLD)

Levels of GMFC-MLD33,

  • 0=Walking without support with quality of performance normal for age.
  • 1=Walking without support but with reduced quality of performance (i.e., instability when standing or walking).
  • 2= Walking with support. Walking without support not possible (fewer than 5 steps).
  • 3= Sitting without support and locomotion such as crawling or rolling. Walking with or without support not possible.
  • 4= Sitting without support but no locomotion or sitting without support not possible, but locomotion such as crawling or rolling possible.
  • 5= No locomotion nor sitting without support, but head control is possible.
  • 6= Loss of any locomotion as well as loss of any head and trunk control.
  

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

Review of Evidence

The clinical development program is summarized in Table 3. The FDA approval was based on the integrated efficacy analyses of the comparisons between 2 groups of pooled data. The pooled treated group included data from 39 individuals (n=18 from study 201222, n=10 from study 205756 and n=9 from a European Union expanded access program). The protocols for these studies did not differ substantially in their study design, eligibility criteria, and assessment schedule, thus supporting a pooled analysis. Differences across protocols stemmed from differences in myeloablative conditioning regimens, source of the CD34+ cells for transduction (bone marrow versus mobilized peripheral blood) and formulation of the drug product (fresh versus cryopreserved); these differences did not lead to differences in clinical outcomes. Two children with advanced disease were excluded from the efficacy analysis yielding a final sample of 37. The untreated natural history group consisted of 49 individuals (n=43 from study 204949 and 6 untreated siblings of individuals enrolled in study 205756). Natural history data was collected retrospectively through chart review and parental interviews and through prospective in-person assessments of the child.34,35,36,

Pivotal Study

Study characteristics, baseline patient characteristics, and results are summarized in Tables 3 to 6, respectively. In the trials, subgroups of MLD were classified as follows:

Pre-symptomatic Late Infantile

In this subgroup, there were 20 treated patients and 28 untreated patients from natural history cohort. None of the 17 children treated with atidarsagene autotemcel who were followed until 5 years of age progressed to severe motor impairment, while 100% of the 28 children in the natural history cohort did. Efficacy of atidarsagene autotemcel was also seen on survival, where 100% of the 14 treated children who were followed until 6 years of age were alive, compared to only 58% of the 24 untreated children in the natural history cohort. Detailed results are summarized in Table 6.

Pre-symptomatic Early Juvenile

In this subgroup, there were 7 treated patients and 21 untreated patients from natural history cohort. Children were between 11 and 67 months (median 31 months) of age at the time of treatment with atidarsagene autotemcel. Of the 7 treated children, 1 (14%) child died at age 2.1 years from a cerebral infarction. Of the remaining 6, there were insufficient data in 3 children who were too young at last follow-up to evaluate efficacy of atidarsagene autotemcel as symptom onset may not begin until 7 years of age. Because of the small sample size and large heterogeneity in this population as well as questionable comparability with the natural history cohort, the FDA statistical reviewer concluded that the pre-specified comparative analyses of the efficacy endpoints would not provide meaningful information. Therefore, the efficacy was evaluated descriptively, rather than being evaluated via confirmatory statistical hypothesis testing.34,

Data from 3 children is summarized in Table 6. Two had evaluable motor and cognitive outcomes while one had evaluable motor outcomes, but while showing stable normal cognitive function, was neither old enough nor had sibling data for cognitive events to be evaluable. Three children retained independent ambulation (GMFC-MLD ≤ Level 1) at last follow-up at ages 8.3, 11.0 and 13.6 years. Additionally, all 3 children retained cognitive functioning in the “broadly average” range (performance and language standard scores ≥85). Based on the published natural history of early juvenile MLD, untreated early juvenile MLD patients would be expected to lose independent ambulation (GMFC-MLD ≥ Level 2) and experience impairment in cognitive functioning at those ages.33,5, Three other children were still under 7 years of age at time of last follow-up, and as early juvenile MLD may be asymptomatic until 7 years of age, it is premature to detect clinical outcomes that deviate from the natural history in these children. It is unknown whether atidarsagene autotemcel impacts survival in pre-symptomatic MLD as the duration of follow-up was limited; untreated children with early juvenile MLD may not progress to death until adulthood.

Early-symptomatic Early Juvenile

In this subgroup, there were 10 treated patients. Two children (20%) died from MLD disease progression 8 and 15 months after treatment with atidarsagene autotemcel. In the final analysis, data from 7 treated children were included. The same 21 untreated early juvenile subjects from natural history cohort used in the analyses for pre-symptomatic early juvenile subgroup was used in the analyses for early-symptomatic early juvenile subgroup. Children developed symptom onset prior to treatment between 29 and 83 months of age (median 62 months) and were treated with atidarsagene autotemcel between 31 and 140 months (median 70 months). All treated children experienced motor disease progression after treatment that did not appear slowed when compared to the natural history children. However, clinical benefit of atidarsagene autotemcel was observed in the slowing of cognitive disease progression in the treated children. Four children (40%) retained normal performance standard scores (≥85) and 3 of these children retained normal language standard scores (≥85) between the ages of 13 and 16 years. Preservation of cognitive functioning in these 4 children occurred despite progression of motor disease. This is unexpected in the natural history of early juvenile MLD where cognitive and motor functioning are expected to decline in parallel, with significant cognitive impairment expected by adolescence.33,

Safety

Safety data includes data from 39 study participants treated in clinical trials.34,35, The median (range) years of follow-up was 6.8 years (0.6-12.2). Three deaths were reported in the clinical development program. Two deaths in study 201222 were attributed to rapid progression of underlying disease that eventually led to severe dysphagia. The study participant died at 8- and 15-months post-gene therapy. One death in the expanded access program occurred at approximately 14 months post-gene therapy due to left hemisphere cerebral ischemic stroke. These events were not considered to be related to gene therapy by the investigators. The only treatment-related adverse event in the atidarsagene autotemcel clinical development program was anti-ARSA antibodies in 6 participants. No evidence of malignancy, clonal expansion, or insertional oncogenesis associated with atidarsagene autotemcel were observed. Additional risks of atidarsagene autotemcel observed in the clinical trial include serious infections (occurred in 39% of all children, including 2 events of sepsis), veno-occlusive disease (occurred in 8% of children, with no events meeting Hy’s law criteria), and delayed platelet engraftment (platelet engraftment after day 60 occurred in 10% of all children). Other adverse reactions were related to myeloablative conditioning or underlying disease. Finally, six patients developed anti-ARSA antibodies. Although these antibodies resolved in all patients, some patients were treated with rituximab therapy. It is also not clear what the potential long-term impact of anti-ARSA antibodies may be, and whether they may impact long-term response.37,

Table 3. Summary of the Clinical Development Program for Atidarsagene Autotemcel
Study NCT No Phase Study Population Status Study Dates Design Sample Size Follow-Up
Study 201222 NCT01560182 1/2 Individuals with early-onset MLD (late infantile to early juvenile) Started on April 9, 2010, at Ospedale San Raffaele, in Milan, Italy. Completed and published.38,39, 2010-2018 Single arm, single center 20a 24 months
Study 205756 NCT03392987 1/2 Individuals with early-onset MLD (late infantile to early juvenile) Started on January 25, 2018, at the Ospedale San Raffaele Telethon Institute for Gene Therapy, in Milan, Italy. As of November 2022. 2018-ongoing Single arm, single center 10 24 months
EAP Not available - Individuals with early-onset MLD (late infantile to early juvenile) Dates for enrollment not available. Study conducted at the Ospedale San Raffaele Telethon Institute for Gene Therapy, in Milan, Italy. Not available Single arm, single center 9 Unknown
Study 204949 NHx Not available Natural history Individuals with early-onset MLD who did not receive any treatments for MLD apart from supportive care Dates for enrollment not available. Study conducted at the Ospedale San Raffaele Telethon Institute for Gene Therapy, in Milan, Italy. Not available Observational, single arm, single center 43 Unknown
MLD: metachromatic leukodystrophy.
a The study included 20 patients, but analysis was conducted on 29 patients: 20 from the study and 9 from an expanded access program.
Table 4. Summary of Key Nonrandomized Trial
Study Study Type Country Dates Participants Treatment Follow-Up
NCT01560182 Single-arm, prospective Italy 2010-2018 Inclusion criterion
  • Age ≤7 years
  • Pre-symptomatica with late infantile variantb or pre-symptomatic or early symptomaticc with early juvenile variantd
Exclusion criterion
  • HIV virus, hepatitis C and/or hepatitis B virus positive
  • Neoplastic disease
  • Cytogenetic alteration typical of myelodysplastic syndrome or acute myeloid leukemia
  • End-organ dysfunction or other severe disease
  • Allogenic hematopoietic stem cell transplant in past 6 months or evidence of residual cells of donor origin
Co-primary endpoints:
  • >10% improvement in total GMFC score in treated patients compared with natural history cohort patients at year 2 post treatment
  • Increase in residual ARSA activity in peripheral blood mononuclear cells from baseline to year 2 post treatment compared with pretreatment values
Secondary endpoints:
  • Safety
 Atidarsagene autotemcel by IV infusion (fresh formulation) 2-20 x 106 CD34+ cells/kg (n=20) Primary follow-up completed 24 months post gene therapy, with additional follow-up visits to be conducted over a period of 8 years post gene therapy
NCT03392987 Single-arm, prospective Italy 2018-ongoing Inclusion criterion
  • Children ≤6 years of age
  • Diagnosis of MLD confirmed by evaluation of ARSA activity and identification of 2 ARSA alleles with mutations that cause disease.
  • Early-onset MLD, demonstrated by either an older sibling with MLD whose onset of symptoms was at ≤6 years of age or approval by the Orchard medical monitor if the child has an early-onset variant of MLD that was detected pre-symptomatically in a patient without an older sibling with MLD.f
Primary endpoint
  • Change in gross motor function measure score at 24 months post gene therapy
 Atidarsagene autotemcel by IV infusion (cryopreserved formulation): (3-30 × 106 CD34+ cells/kg) (n=10) Primary follow-up completed 24 months post gene therapy, with additional follow-up visits to be conducted over a period of 8 years post gene therapy
Integrated analysis Pooled data from NCT01560182 (n=18), NCT0339298737 (n=10), and an European Union Expanded Access Program (n=9) Italy Information not available Primary endpoint
  • Severe motor impairment-free survival defined as the time interval from birth to the first occurrence of loss of locomotion and loss of sitting without support (GMFC-MLD level ≥5) or death.

Secondary endpoints

  • Proportion of individuals who had experienced severe motor impairment or death by year 2 post-treatment evaluated in a subset of matched subjects. Similar analyses for year 5 post-treatment were also performed in a descriptive manner.
  • Overall survival defined as the time interval between birth and death from any cause.

Additional outcomes

  • Descriptive results on motor function progression to lower severity levels of GMFC-MLD and cognitive function, in terms of performance and language standard scores, were considered as other important measures for efficacy.
 - Median follow-up 6.8 years (0.6, 12.2) for safety analysis
ARSA: arylsulfatase A; GMFC: Gross Motor Classification; MLD: metachromatic leukodystrophy
a Pre-symptomatic: No disease-related neurological impairment with or without signs of disease revealed by instrumentational evaluation
b Late infantile: 2 of 3 criteria met (age at onset of symptoms in older sibling ≤30 months, 2 null [0] mutant arylsulfatase A [ARSA] allele[s], peripheral neuropathy at electroneurographic study)
c Early symptomatic: 2 criteria met (intelligence quotient [IQ] ≥70 and ability to walk independently for ≥10 steps)
d Early juvenile: 2 of 3 criteria met (age at onset of symptoms in subject or older sibling between 30 months and 6 years, 1 null [0] and 1 residual [R] mutant ARSA allele[s], peripheral neuropathy at electroneurographic study)
e As of the 2018 data cut
f Classification of disease was based on age of diagnosis and genotype; LI: Symptom onset at ≤30 months of age and genotype typically 0/0; EJ: symptom onset >30 months and ≤6 years of age and genotype typically 0/R. Patients may be classified as intermediate LI/EJ if the case cannot be characterized unambiguously. 
Table 5. Summary of Baseline Demographics and Disease Characteristics in the Pivotal Integrated Analysis36,
Characteristic Pre-symptomatic late infantile (N=20) Pre-symptomatic early juvenile (N=7) Pre-symptomatic early juvenile (N=10)
Median age at treatment, months (range) 12 (8, 19) 31 (11, 67) 70 (31, 140)
Male, n (%) 13 (65) 6 (86) 6 (60)
Race, n (%)      
White/Caucasian 18 (90) 6 (86) 10 (100)
Asian 2 (10) 0 0
Black or African American 0 1 (14) 0
Ethnicity – Hispanic or Latino, n (%) 1 (5) 0 0
Table 6. Summary of Results in the Pivotal Integrated Analysis
Outcomes Treated Natural History
Pre-symptomatic late infantile34,36, N=20 N=28
Severe motor impairment or death, n/N (%) 1/20 (5) 28/28 (100)
Kaplan Meir estimate for event-free survival up to 5 years of age 100% 0%
Survival at 6 years of age, n/N (%) 14/14 (100%) 14/24 (58%)
Severe motor impairment or death by 2 years post-treatment, n/N (%) 0/20 (0) 15/25 (60%)
Severe motor impairment or death by 5 years post-treatment, n/N (%) 2/13 (15%) 26/26 (100%)
Cognitive functiona 19/20 >55 through to the last follow-up. At the last assessment, 2 of these individuals were below the threshold for moderate impairment (< 70), with all others maintaining ≥ 70 and most maintaining normal scores (≥ 85) All had severe cognitive performance and language impairment (≤55).
Pre-symptomatic early juvenile34,36, N=7 N=21
Motor function 3 of 7 children had evaluable motor outcomes:b
  • Child 1 treated at 4.1 years of age retained normal gait (GMFC-MLD Level 0) at age 11.9 years.
  • Child 2 treated at 3.6 years of age retained normal gait (GMFC-MLD Level 0) at age 7.3 years.
  • Child 3 treated at 5.6 years of age retained normal gait (GMFC-MLD Level 0) until age 12.8 years and still had independent ambulation (GMFC-MLD Level 1) at 13.6 years of age.
  • Matched sibling comparator of child 1 lost all motor function (GMFC-MLD Level 6) by age 6 years.
  • Matched sibling comparator of child 2 developed impaired gait (GMFC-MLD Level 1) at age 5 years.
  • Comparator data not available for child 3.
Cognitive function 2 of 7 children had evaluable cognitive outcomes:b
  • One child treated at 4.1 years of age retained stable normal cognitive function (performance and language standard scoresc of 130 and 122, respectively) at age 11.9 years.
  • One child treated at 5.6 years of age retained stable normal performance standard scorec (116 at 11.4 years). While language standard score remained normal (86 at 11.4 years), it declined from 102 at baseline.
 Not available
Early-symptomatic early juvenile34,36, N=10 N=21d
Severe motor impairment or death at year 2, n/N (%) 2/10 (20%) 2/15 (13%)
Severe motor impairment or death at year 5, n/N (%) 2/8 (25%) 11/12 (92%)
Died, n/N (%) 2/10 (20%) 3/21 (14%)
Normal performance standard scores (≥85) between the ages of 13 and 16 years, n/N (%) 4/10 (40%) Motor functioning is expected to decline by adolescence
Normal language standard scores (≥85) between the ages of 13 and 16 years, , n/N (%) 3/10 (30%) Cognitive functioning is expected to decline by adolescence
GMFC: Gross Motor Classification; MLD: metachromatic leukodystrophy.
a Cognitive function was defined using the following: normal cognitive function, standard score ≥ 85; mild cognitive impairment, standard score ≥ 70 and < 85; moderate cognitive impairment, score >55 and < 70; severe cognitive impairment, score ≤ 55
b As per the FDA statistical review, because of the small sample size and large heterogeneity in this population as well as questionable comparability with the natural history early juvenile MELD patients, the pre-specified comparative analyses of the efficacy endpoints would not provide meaningful information. Therefore, the efficacy was evaluated descriptively based on clinical knowledge and expectation of similar subjects in the literature, rather than being evaluated via confirmatory statistical hypothesis testing.
c Standard scores were derived, allowing comparison of a child’s cognitive ability with the normative population.
d The same 21 untreated early juvenile patients from natural history cohort used in the analyses for pre-symptomatic early juvenile was used in the analyses for early-symptomatic early juvenile patients. 

The purpose of the study limitations tables is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement. Multiple limitations were noted.

Table 7. Study Relevance Limitations

Study Populationa Interventionb Comparatorc Outcomesd Duration of Follow-upe
Integrated analysis34,36,     1. Not clearly defined;
5. Other (non-contemporaneous historical control, baseline characteristics not reported)		   1. Not sufficient duration for benefit
2. Not sufficient duration for harms
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.
Table 8. Study Design and Conduct Limitations
Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Integrated analysis34,36, 1. Participants not randomly allocated
2. Allocation not concealed
3. Allocation concealment unclear
4. Inadequate control for selection bias		 4. Participants or study staff not blinded
2. Outcome assessors not blinded
3. Outcome assessed by treating physician
4. Outcomes not assessed centrally		 4. Other (post-hoc sub-group analysis not pre-specified) 1. High loss to follow-up or missing data
2. Inadequate handling of missing data
5. Inappropriate exclusions
 		 1. Power calculations not reported
2. Power not calculated for primary outcome
3. Power not based on clinically important difference		  
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Section Summary: Metachromatic Leukodystrophy

Evidence includes integrated efficacy analyses of several single arm studies compared with an external natural history cohort. The interventional studies enrolled 39 patients with late infantile and early juvenile MLD. In children with pre-symptomatic late infantile MLD (n=21), treatment with atidarsagene autotemcel demonstrated improvement in severe motor impairment-free survival defined as the interval from birth to the first occurrence of loss of locomotion and loss of sitting without support or death, and in survival and cognitive function outcomes when compared to natural history cohort (n=28). In children with pre-symptomatic early juvenile MLD (n=7), the effectiveness of atidarsagene autotemcel was demonstrated by slowing of the progression of motor and cognitive disease manifestations compared to untreated children and matched sibling comparators. In children with early-symptomatic early juvenile MLD (n=10), atidarsagene autotemcel effectiveness was demonstrated in a subject-level analysis which showed slowing of cognitive disease progression despite continued progression of motor disease in treated children, which is unexpected in untreated patients. The major risks of atidarsagene autotemcel treatment include thrombosis and thromboembolic events, encephalitis, serious infection, veno-occlusive disease, and delayed platelet engraftment. In the context of MLD, the associated risks are deemed acceptable due to the severity of the disease and the lack of effective standard treatments. Notable limitations include use of single arm studies with an external historical cohort which are susceptible to biases that may affect the estimates of treatment differences. Additionally, the sample sizes were limited with high heterogeneity of the disease trajectories in patients with pre-symptomatic or early symptomatic early juvenile MLD. There were also instances of missing data or inappropriate exclusions. In addition, there are uncertainties about long-term durability and safety. While no cases of malignancy, clonal expansion, or insertional oncogenesis were reported in the trial participants, such risk cannot be ruled out in the larger, real-world, population. There is a risk of oncogenesis with lentiviral vectors and, given that patients will be treated early on in life, this will be an important long-term harm to evaluate.

For individuals with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy (MLD) who receive atidarsagene autotemcel, the evidence includes integrated efficacy analyses of several single arm studies compared with an external natural history cohort. The interventional studies enrolled 39 patients with late infantile and early juvenile MLD. All study participants were classified as having MLD on the basis of 2 known pathologic mutations in the ARSA gene, 2 null mutations for pre-symptomatic late infantile and at least 1 mutation encoding residual enzyme for pre-symptomatic or early symptomatic early juvenile MLD. Late infantile was defined as expected disease onset ≤30 months of age while early juvenile was defined as expected or actual disease onset >30 months and <7 years of age. Pre-symptomatic status was defined as the absence of neurological signs and symptoms of MLD or physical exam findings limited to abnormal reflexes and/or clonus. Early symptomatic status was defined as walking independently and IQ ≥85. In children with pre-symptomatic late infantile MLD (n=21), treatment with atidarsagene autotemcel demonstrated improvement in severe motor impairment-free survival (defined as the interval from birth to the first occurrence of loss of locomotion and loss of sitting without support or death), and in survival and cognitive function outcomes when compared to natural history cohort (n=28). In children with pre-symptomatic early juvenile MLD (n=7), the effectiveness of atidarsagene autotemcel was demonstrated by slowing of the progression of motor and cognitive disease manifestations compared to untreated children and matched sibling comparators. In children with early symptomatic early juvenile MLD (n=10), atidarsagene autotemcel effectiveness was demonstrated in a subject-level analysis which showed slowing of cognitive disease progression despite continued progression of motor disease in treated children, which is unexpected in untreated patients. The major risks of atidarsagene autotemcel treatment include thrombosis and thromboembolic events, encephalitis, serious infection, veno-occlusive disease, and delayed platelet engraftment. In the context of MLD, the associated risks are deemed acceptable due to the severity of the disease and the lack of effective standard treatments. Notable limitations include use of single arm studies with an external historical cohort which are susceptible to biases that may affect the estimates of treatment differences. Additionally, the sample size was limited with high heterogeneity of the disease trajectories in patients with pre-symptomatic or early symptomatic early juvenile MLD. There were also instances of missing data or inappropriate exclusions. Two patients with early symptomatic early juvenile died due to disease progression after treatment. These 2 patients were ultimately not included in the primary survival analysis due to not meeting the more stringent treatment entry criteria established after they were recruited into the study and based on post-hoc analysis of the data. Removal of these 2 patients creates greater uncertainty about the potential harms in the early symptomatic early juvenile MLD population. In addition, there are uncertainties about long-term durability and safety. While no cases of malignancy, clonal expansion, or insertional oncogenesis were reported in the trial participants, such risk cannot be ruled out in the larger, real-world, population. There is a risk of oncogenesis with lentiviral vectors and, given that patients will be treated early on in life, this will be an important long-term harm to evaluate. While there is residual uncertainty around the estimates of some of the clinical outcomes, the observed magnitude of the benefit indicates that atidarsagene autotemcel will frequently be successful in treating patients with late infantile or early juvenile MLD especially when given in pre-symptomatic phase. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population

Reference No. 1

Policy Statement

 [X] Medically Necessary [ ] Investigational

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Medical Genetics and Genomics

The ACMG work group published a consensus based guidelines in 2011 for the diagnostic confirmation and management of individuals identified by newborn screening, family-based testing after proband identification, or carrier testing in at-risk populations, and subsequent prenatal or postnatal testing of those who are pre-symptomatic for a lysosomal storage disease.25,

In the section for MLD (OMIM# 250100), the following observations were made regarding management of individuals with MLD:

Institute for Clinical and Economic Review

The Institute for Clinical and Economic Review published a final report on atidarsagene autotemcel for MLD on October 30, 2023.37, The Report concluded that

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence published a highly specialised technologies guidance report on atidarsagene autotemcel for treating MLD on March 28, 2022.40, The guidance report makes the following recommendations:

Atidarsagene autotemcel is recommended, within its marketing authorisation, as an option for treating metachromatic leukodystrophy with mutations in the ARSA gene:

It is recommended only if the company provides atidarsagene autotemcel according to the commercial arrangement.

Atidarsagene autotemcel should be delivered in a highly specialised service by a specialist multidisciplinary team.

U.S. Preventive Services Task Force Recommendations

Not applicable

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 9.

Table 9. Summary of Key Trials
NCT No. Trial Name Planned Enrollment Completion Date
Ongoing      
NCT04283227 OTL-200 in Patients With Late Juvenile Metachromatic Leukodystrophy (MLD) 6 Mar 2031
NCT03392987 A Safety and Efficacy Study of Cryopreserved OTL-200 for Treatment of Metachromatic Leukodystrophy 10 Apr 2028
NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

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Codes

Codes Number Description
HCPCS C9399 Unclassified drugs or biologicals (use for atidarsagene autotemcel)
  J3490 Unclassified drugs
  J3590 Unclassified biologics
ICD10 CM E75.25 Metachromatic leukodystrophy
ICD10 PCS No code  
Place of Service Inpatient/Outpatient  
Type of Service Gene Therapy

Policy History

Date Action Description
07/16/2024  New Policy  Policy created with literature review through March 19, 2024. Atidarsagene autotemcel is considered medically necessary for treatment of children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy who meet criteria.