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Atidarsagene autotemcel (Lenmeldy)
08.02.24

Policy

 MEDICALLY NECESSARY

 

Misspelled WordAtidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) is considered medically necessary and, therefore, covered as a one-time administration for the treatment of metachromatic Misspelled Wordleukodystrophy (MLD) in individuals young​Misspelled Worder than 18 years of age when ALL of the following criteria are met:

  • Individual has a confirmed diagnosis of MLD (also known as arylsulfatase A deficiency [ARSA]) as evidenced by the following biochemical and molecular markers:​
    • ARSA enzyme activity below the normal range in peripheral blood mononuclear cells-leukocytes or fibroblasts OR increased urinary excretion of Misspelled Wordsulfatides; AND
    • Presence of Misspelled Wordbiallelic ARSA pathogenic or likely pathogenic variation(s) of known polymorphisms identified by gene sequencing and/or deletion/duplication assessment (Note: for individuals with novel mutations, a 24-hour urine collection must show elevated Misspelled Wordsulfatide levels)
      • ​For the initial ​individual within a family with one of the below clinical classifications (i.e., a potential Misspelled Wordproband), both of the following are present:
        1. ​​ARSA enzyme activity in leukocytes below reference values; AND
        2. ​​Urinary Misspelled Wordsulfatide levels above reference values; AND
  • Individual has confirmed clinical classification of pre-symptomatic late infantile (PSLI), Misspelled Wordpresymptomatic, early juvenile (PSEJ) or early symptomatic early juvenile (ESEJ) MLD disease​ based on phenotypes including age and presence of applicable signs and symptoms (see Guidelines Section)
  • The biologic is used as single-agent therapy (Note: not inclusive of Misspelled Wordbusulfan-conditioning regimen); AND
  • Individual has not received a prior allogeneic stem cell transplant (or has, but is without evidence of residual donor cells present), and is a candidate for autologous stem cell transplantation (e.g., adequate renal and hepatic function); AND
  • Individual has not received other gene therapy for MLD; AND
  • Individual is negative for hepatitis B virus (HBV), hepatitis C virus (HCV), human T-Misspelled Wordlymphotropic virus 1 and 2 (HTLV-1/HTLV-2), human immunodeficiency virus 1 and 2 (HIV-1/HIV-2), and mycoplasma infection before collection of cells for manufacturing.

NOTE: Misspelled WordEvio has been selected by the Company to administer clinical outcomes monitoring for individuals receiving certain high-cost drug therapies. Misspelled WordAtidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) is included in the portfolio of high-cost drug/biologic therapies for which Misspelled WordEvio will be tracking clinical outcomes. If an individual meets all medical policy criteria, the requesting physician and/or individual being treated must agree to providing clinical outcomes data and information via Misspelled WordEvio's secure web portal as requested. ​


EXPERIMENTAL/INVESTIGATIONAL


All other uses for Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy), including but not limited to when the above criteria are not met, for all other indications, and repeat treatment with it, are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

 

REQUIRED DOCUMENTATION


The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.


The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.​

Guidelines

In addition to the criteria listed in the Policy section above, the following conditions are necessary for coverage of Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy):

  • Individual risk factors for thrombosis as well as Misspelled Wordveno-occlusive disease have been evaluated prior to administration.
  • Individual will not be administered vaccinations during the 6 weeks preceding the start of Misspelled Wordmyeloablative conditioning, and until hematological recovery following treatment (Note: w​​here feasible, administer childhood vaccinations prior to Misspelled Wordmyeloablative conditioning); AND
  • Prophylaxis for infection will be followed according to standard institutional guidelines; AND
  • Individual will be monitored for hematological malignancies periodically after treatment; AND
  • Individuals will not receive prophylactic HIV anti-retroviral therapy for at least one-month preceding mobilization (Note: anti-Misspelled Wordretrovirals may interfere with​ manufacturing); AND
  • Individual will have mobilization of stem cells using granulocyte-colony stimulating factor (GCSF with or without Misspelled Wordplerixafor).
PROBAND

The first individual in a family to be identified as possibly having a genetic disorder or condition.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy)​ is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met. 

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS​

On March 18, 2024, Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) was approved by the US Food and Drug Administration (FDA) for the treatment of children with Misspelled Wordpresymptomatic late infantile, Misspelled Wordpresymptomatic early juvenile, or early symptomatic early juvenile metachromatic Misspelled Wordleukodystrophy.

 

RECOMMENDED DOSES


​Metachromatic Misspelled WordLeukodystrophy SubtypeMinimum Recommended Dose (CD34+ cells/kg)Maximum Recommended Dose (CD34+ cells/kg)
Misspelled WordPresymptomatic late infantile
4.2 × 10630 × 106
Misspelled WordPresymptomatic early juvenile
9 × 10630 × 106
Early symptomatic early juvenile6.6 × 10630 × 106

 

Dosing Limits


One injection per lifetime.


Other Considerations


The FDA-approved label includes a normal range for arylsulfatase A deficiency (ARSA) enzyme activity to be 31 to 198 Misspelled Wordnmol/mg/h. Elevated urinary Misspelled Wordsulfatide levels may differ among laboratory testing facilities.


In the clinical trials of Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy), children were classified as having Misspelled Wordpresymptomatic late infantile, Misspelled Wordpresymptomatic early juvenile, or early symptomatic early juvenile metachromatic Misspelled Wordleukodystrophy based on the following:


Metachromatic Misspelled WordLeukody​Misspelled Wordstrophy SubtypeDisease Classification
Misspelled WordPresymptomatic late infantile
  • Expected disease onset ≤30 months of age
  • ARSA genotype consistent with late infantile
  • Absence of neurological signs and symptoms
Misspelled WordPresymptomatic 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

Abbreviations: GMFC, Gross Motor Function Classification; MLD, metachromatic Misspelled Wordleukodystrophy.


Misspelled WordAtidarsagene Misspelled Wordautotemcel is a Misspelled Wordlentiviral vector gene therapy that has a potential risk of Misspelled Wordlentiviral vector–​mediated insertional Misspelled Wordoncogenesis post-treatment. In clinical trials for Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy), no cases of insertional Misspelled Wordoncogenesis​ have been reported. Individuals treated with Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) may develop hematological malignancies and should received lifelong monitoring. 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.

Description

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, Misspelled Wordbiallelic 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 (Misspelled Wordsaposin B), which is responsible for the degradation of Misspelled Wordsulfatides by ARSA. This form is caused by mutations in the Misspelled Wordprosaposin gene (PSAP gene).

 

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

 

  • Homozygosity for the I allele (c.459+1G>A) is the most common of the null alleles (also called "0" alleles), which are pathogenic variants that completely abolish enzyme activity; other common null alleles are c.1210+1G>A and p.Asp257His. These alleles are associated with late infantile onset forms. Compound heterozygotes (with the other allele unknown) also have a late infantile onset. 
  • Homozygosity for the A allele (p.P426L) is the most common of Misspelled Wordhypomorphic alleles (also called "R" for residual] alleles), which are pathogenic variants that cause reduced but not absent enzyme activity. It is associated with the juvenile- or adult-onset forms; compound heterozygotes have later onset of disease. 
  • Presence of both I and A alleles is associated with juvenile onset. 

The ARSA enzyme is responsible for the breakdown of Misspelled Wordsulfatides, one of the most common sphingolipids in the myelin sheath. Due to the Misspelled WorddeficieMisspelled Wordnt activity of ARSA enzyme, breakdown of Misspelled Wordsulfatides 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. Misspelled WordSulfatides can also accumulate 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 below. 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.


CLINICAL CLASSIFICATION OF METACHROMATIC LEUKODYSTROPHY

​

Classification​OnsetClinical features
Late Infantile form6 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 (MRI) changes. In some cases, the first symptoms may be apparent after a febrile illness or anesthesia. Symptoms may then abate for weeks before continuing to progress. Other early signs can include gait difficulties, seizures, ataxia, Misspelled Wordhypotonia, extensor plantar responses, and optic atrophy.
  • Deep tendon reflexes are sometimes reduced or absent, reflecting peripheral neuropathy. Sensory potentials are affected earlier and more severely than are motor responses.
  • The prognosis is worse than later-onset forms of metachromatic leukodystrophy; progression to death typically occurs within 5 to 6 years, although some individuals survive into the second decade of life.
Early Juvenile4 to 6 years of age
  • Heterogeneous in presentation. Some children present between 4 and 6 years of age (early juvenile), while others may present between 6 and 16 years of age (late juvenile).
  • Children may present with intellectual impairment, behavioral difficulties, gait disturbance, ataxia, upper motor neuron signs, and peripheral neuropathy; seizures may also occur.
  • Progression is slower compared with the late infantile form, and these children may survive until early adulthood.
Late Juvenile6 to 16 years of age
Adult formBeyond 16 years of age
  • This least common form is usually heralded by dementia and behavioral difficulties, and a substantial minority present with neuropathy, psychosis, schizophrenia, or seizures. Optic atrophy has also been reported.
  • 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. Affected patients may survive for 20 to 30 years after onset.​


 EPIDEMIOLOGY


The prevalence of MLD ranges from one in 40,000 to one in 100,000 in Northern European and North American populations. However, a higher prevalence has been found in certain groups, including Misspelled WordHabbani Jews in Israel, Arabs living in Israel, and Navajo people in the United States. Incidence is estimated to be one in 40,000 births in the United States. There is no sexual or racial predilection.


DIAGNOSIS

 

Misspelled WordLeukodystrophies are generally suspected in pediatric individuals who have difficulties in meeting appropriate development milestones when previously able to do so. Peripheral neuropathy can present prior to dysarthria and other central nervous system manifestations. 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 Misspelled Wordhyporeflexia and developmental delay are relatively nonspecific. In an individual 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:

 

  • Genetic test identifies Misspelled Wordbiallelic ARSA pathogenic variants. 
  • Enzyme assay confirms deficient ARSA enzyme activity in leukocytes. (In individuals with MLD, ARSA activity levels typically range from undetectable to less than 10 percent of normal values.) 
  • Misspelled WordSulfatide measurement reveals elevated levels in urine. 

Elevated urinary Misspelled Wordsulfatides are present in all types of MLD, including MLD due to sphingolipid activator protein B (Sap-B) deficiency. Both enzyme assay and Misspelled Wordsulfatide substrate measurement are essential parts of the biochemical diagnosis. They complement gene sequencing, especially in the case of a Misspelled Wordproband. For siblings of an index case, gene sequencing alone is sufficient. Additionally, assessment of​ both enzyme activity and Misspelled Wordsulfatides helps to distinguish ARSA Misspelled Wordpseudodeficiency from MLD. ARSA Misspelled Wordpseudodeficiency refers to individuals who have non-disease-causing Misspelled Wordpseudodeficiency alleles in the ARSA gene, which results in low ARSA enzyme activity levels approximating those of individuals with MLD.


Thus, the diagnosis of MLD should not be based only on the activity of ARSA; screening for Misspelled Wordpseudodeficiency alleles is important when low, but not absent, levels of ARSA are detected. ARSA Misspelled Wordpseudodeficiency is present in approximately 1 percent of the general population.

 

Delays in diagnosis and misdiagnosis are common in children without a diagnosed sibling, with the time from first symptom to diagnosis of 4 months to 1 year, with late infantile MLD and up to 7 years for children with juvenile MLD.

 

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

 

TREATMENT


There is no cure for MLD. Treatment has included symptomatic supportive care to address neurocognitive and neuropsychiatric disturbances, seizures, Misspelled Worddystonias, spasticity, feeding problems, and constipation. Allogeneic hematopoietic stem cell transplantation (HSCT) has been used as a treatment for MLD. Allogeneic HSCT may halt or prevent disease progression of CNS manifestations in individuals with pre- or early symptomatology(Misspelled Wordies), and has been considered the standard of care for eligible individuals with no or early MLD disease involvement. However, HSCT appears to treat CNS manifestations of MLD but not peripheral neuropathy. Long-term follow-up from a 2016 case-control study in 24 transplanted patients suggest continued progression of the peripheral neuropathy. Furthermore, in a 2023 systematic review by Armstrong et al., 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 percent) with juvenile onset who did not receive HSCT. This systematic review identified eight studies (total n=172) that evaluated HSCT for individuals with MLD and reported survival outcomes. After approximately 5 years of follow-up, overall survival rates ranged from 57% to 74%. When examined by disease subtype, survival rates at 5 to 6 years after HSCT ranged from 50% to 60% in individuals with late-infantile MLD, and from 59% to 82% in individuals with juvenile MLD.

 

A consensus guideline for the monitoring and management of MLD in the United States was released in April 2024. In early-onset MLD, including late infantile and early juvenile subtypes, gene therapy (Misspelled WordLenmeldy) should be considered for Misspelled Wordpresymptomatic individuals where available. In late-onset MLD, including late juvenile and adult subtypes, HSCT (allogeneic) should be considered for individuals with no or minimal disease involvement.​


PEER-REVIEWED EVIDENCE

 

For individuals with Misspelled Wordpresymptomatic late infantile, Misspelled Wordpresymptomatic early juvenile, or early symptomatic early juvenile MLD who receive Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy), the evidence includes integrated efficacy analyses of several single-arm studies compared with an external natural history cohort. The interventional studies enrolled 39 individuals with late infantile and early juvenile MLD. All study participants were classified as having MLD on the basis of two known pathologic mutations in the ARSA gene, two null mutations for Misspelled Wordpresymptomatic late infantile and at least one mutation encoding residual enzyme for Misspelled Wordpresymptomatic or early symptomatic early juvenile MLD. Late infantile was defined as expected disease onset at 30 months of age or older, while early juvenile was defined as expected or actual disease onset greater than 30 months and less than 7 years of age. Misspelled WordPresymptomatic status was defined as the absence of neurological signs and symptoms of MLD or physical examination findings limited to abnormal reflexes and/or clonus. Early symptomatic status was defined as walking independently and IQ  greater than or equal to 85. In children with Misspelled Wordpresymptomatic late infantile MLD (n=21), treatment with Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) 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 Misspelled Wordpresymptomatic early juvenile MLD (n=7), the effectiveness of Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) 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), Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) effectiveness was demonstrated in a subject-level analysis that showed slowing of cognitive disease progression despite continued progression of motor disease in treated children, which is unexpected in untreated individuals. 


The major risks of Misspelled Wordatidarsagene Misspelled Wordautotemcel treatment include thrombosis and thromboembolic events, encephalitis, serious infection, Misspelled Wordveno-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 that 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 individuals with Misspelled Wordpresymptomatic or early symptomatic early juvenile MLD. There were also instances of missing data or inappropriate exclusions. Two individuals with early symptomatic early juvenile died due to disease progression after treatment. These two individuals 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 two individuals 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 Misspelled Wordoncogenesis were reported in the trial participants, such risk cannot be ruled out in the larger, real-world, population. There is a risk of Misspelled Wordoncogenesis with Misspelled Wordlentiviral vectors and, given that individuals will be treated early on in life, this will be an important long-term harm to evaluate. Although there is residual uncertainty around the estimates of some of the clinical outcomes, the observed magnitude of the benefit indicates that Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) will frequently be successful in treating individuals with late infantile or early juvenile MLD especially when given in the Misspelled Wordpresymptomatic phase. 


PRACTICE GUIDELINES AND POSITION STATEMENTS


AMERICAN COLLEGE OF MEDICAL GENETICS AND GENOMICS

In 2011, the ACMG workgroup published consensus-based guidelines for the diagnostic confirmation and management of individuals identified by newborn screening, family-based testing after Misspelled Wordproband 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.


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


  • For late infantile MLD, no approved specific therapy exists at all and treatment efforts are restricted to palliative and/or supportive measures, including the prevention or delay of secondary complications.
  • Early HSCT at a Misspelled Wordpresymptomatic stage is completely ineffective and is not recommended.
  • Because of the less rapid disease progression, HSCT has been established for several years as the only specific therapeutic option for juvenile and adult forms of MLD.

 

INSTITUTE FOR CLINICAL AND ECONOMIC REVIEW

On October 30, 2023, the Institute for Clinical and Economic Review published a final report on Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) for MLD with the following conclusions:


  • For children with Misspelled Wordpresymptomatic late infantile and Misspelled Wordpresymptomatic early juvenile MLD, there is a high certainty that treatment with Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) has substantial net health benefit (“A") versus standard of care.
  • For children with early-symptomatic early juvenile MLD, there is moderate certainty of a small or substantial net health benefit with high certainty of at least a small net health benefit (“B+") versus standard of care.

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

On March 28, 2022, the National Institute for Health and Care Excellence (NICE) published a highly specialized technologies guidance report on Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) for treating MLD. The guidance report makes the following recommendations:


Misspelled WordAtidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) is recommended, within its marketing authorization, as an option for treating metachromatic leukodystrophy​ with mutations in the ARSA gene:


  • For children who have late infantile or early juvenile types, with no clinical signs or symptoms.
  • For children who have the early juvenile type, with early clinical signs or symptoms, and who can still walk independently and have no cognitive decline.

It is recommended only if the company provides Misspelled Wordatidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) according to the commercial arrangement.


Misspelled WordAtidarsagene Misspelled Wordautotemcel (Misspelled WordLenmeldy) should be delivered in a highly specialized service by a specialist multidisciplinary team.

References

Armstrong N, Olaye A, Noake C, et al. A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel. Orphanet J Rare Dis. 2023;18(1): 248. 


Barth ML, Ward C, Harris A, et al. Frequency of arylsulphatase A pseudodeficiency associated mutations in a healthy population. J Med Genet. 1994; 31(9): 667-71. PMID 7815433.


Berger J, Löschl B, Bernheimer H, et al. Occurrence, distribution, and phenotype of arylsulfatase A mutations in patients with metachromatic leukodystrophy. Am J Med Genet. Mar 31 1997; 69(3): 335-40. PMID 9096767.


Beschle J, Döring M, Kehrer C, et al. Early clinical course after hematopoietic stem cell transplantation in children with juvenile metachromatic leukodystrophy. Mol Cell Pediatr. Sep 03 2020; 7(1): 12. PMID 32910272.


Boucher AA, Miller W, Shanley R, et al. Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report. Orphanet J Rare Dis. Aug 07 2015; 10: 94. PMID 26245762.


Chen X, Gill D, Shaw P, et al. Outcome of Early Juvenile Onset Metachromatic Leukodystrophy After Unrelated Cord Blood Transplantation: A Case Series and Review of the Literature. J Child Neurol. Mar 2016; 31(3): 338-44. PMID 26187619.


Food and Drug Administration: Statistical Review for Atidarsagene Autotemcel (Approval History, Letters, Reviews, and Related Documents - Lenmeldy). Available at https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/lenmeldy. Accessed on May 12, 2024.


Food and Drug Administration: Summary Basis for Regulatory Action for Atidarsagene Autotemcel. Available at https://www.fda.gov/media/177578/download?attachment. Accessed on May 12, 2024.


Fumagalli F, Calbi V, Natali Sora MG, et al. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access. Lancet. Jan 22 2022; 399(10322): 372-383. PMID 35065785.


Fumagalli F, Zambon AA, Rancoita PMV, et al. Metachromatic leukodystrophy: A single-center longitudinal study of 45 patients. J Inherit Metab Dis. Sep 2021; 44(5): 1151-1164. PMID 33855715.


Gomez-Ospina N. Arylsulfatase A Deficiency. 2006 May 30 [updated 2024 Feb 8]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 19932024. PMID: 20301309.


Groeschel S, Kühl JS, Bley AE, et al. Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Juvenile Metachromatic Leukodystrophy Compared With Nontransplanted Control Patients. JAMA Neurol. Sep 01 2016; 73(9): 1133-40. PMID 27400410.


Harrington M, Whalley D, Twiss J, et al. Insights into the natural history of metachromatic leukodystrophy from interviews with caregivers. Orphanet J Rare Dis. Apr 29 2019; 14(1): 89. PMID 31036045.


Heinisch U, Zlotogora J, Kafert S, et al. Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area. Am J Hum Genet. Jan 1995; 56(1): 51-7. PMID 7825603.


Henseler M, Klein A, Reber M, et al. Analysis of a splice-site mutation in the sap-precursor gene of a patient with metachromatic leukodystrophy. Am J Hum Genet. Jan 1996; 58(1): 65-74. PMID 8554069.


Holve S, Hu D, McCandless SE. Metachromatic leukodystrophy in the Navajo: fallout of the American-Indian wars of the nineteenth century. Am J Med Genet. Jul 01 2001; 101(3): 203-8. PMID 11424134.


Hong X, Daiker J, Sadilek M, et al. Toward newborn screening of metachromatic leukodystrophy: results from analysis of over 27,000 newborn dried blood spots. Genet Med. Mar 2021; 23(3): 555-561. PMID 33214709.


Institute for Clinical and Evidence Review: Atidarsagene Autotemcel for Metachromatic Leukodystrophy. Final Evidence Report published October 30, 2023. Available at https://icer.org/wp-content/uploads/2023/10/MLD-Final-Evidence-Report_For-Publication_10302023.pdf. Accessed on May 12, 2024.


Kehrer C, Blumenstock G, Raabe C, et al. Development and reliability of a classification system for gross motor function in children with metachromatic leucodystrophy. Dev Med Child Neurol. Feb 2011; 53(2): 156-60. PMID 21087233.


Kuchar L, Ledvinová J, Hrebícek M, et al. Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations. Am J Med Genet A. Feb 15 2009; 149A(4): 613-21. PMID 19267410.


Ługowska A, Ponińska J, Krajewski P, et al. Population carrier rates of pathogenic ARSA gene mutations: is metachromatic leukodystrophy underdiagnosed?. PLoS One. 2011; 6(6): e20218. PMID 21695197.


MacFaul R, Cavanagh N, Lake BD, et al. Metachromatic leucodystrophy: review of 38 cases. Arch Dis Child. Mar 1982; 57(3): 168-75. PMID 7073297.


Mahdieh N, Sharifi A, Rabbani A, et al. Novel disease-causing variants in a cohort of Iranian patients with metachromatic leukodystrophy and in silico analysis of their pathogenicity. Clin Neurol Neurosurg. Feb 2021; 201: 106448. PMID 33385934.


Mahmood A, Berry J, Wenger DA, et al. Metachromatic leukodystrophy: a case of triplets with the late infantile variant and a systematic review of the literature. J Child Neurol. May 2010; 25(5): 572-80. PMID 20038527.


Martinez AC, Ferrer MT, Fueyo E, et al. Peripheral neuropathy detected on electrophysiological study as first manifestation of metachromatic leucodystrophy in infancy. J Neurol Neurosurg Psychiatry. Feb 1975; 38(2): 169-74. PMID 1151398.


MLD newborn screening. Available at https://mldnewbornscreening.org/. Accessed May 5, 2024.


National Institute for Health and Care Excellence: Atidarsagene autotemcel for treating metachromatic leukodystrophy (Highly specialized technologies guidance). Published: 28 March 2022. Available at www.nice.org.uk/guidance/hst18. Accessed on May 12, 2024.


Polten A, Fluharty AL, Fluharty CB, et al. Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med. Jan 03 1991; 324(1): 18-22. PMID 1670590.


Prescribing label for Lenmeldy (atidarsagene autotemcel) suspension for intravenous infusion. Available at https://www.orchard-tx.com/wp-content/uploads/2024/03/USPI_final_3-18-24.pdf. Accessed on May 12, 2024.


Quigley HA, Green WR. Clinical and ultrastructural ocular histopathologic studies of adult-onset metachromatic leukodystrophy. Am J Ophthalmol. Sep 1976; 82(3): 472-9. PMID 961798.


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Coding

CPT Procedure Code Number(s)
N/A​
ICD - 10 Procedure Code Number(s)
N/A​
ICD - 10 Diagnosis Code Number(s)
E75.25 Metachromatic leukodystrophy​
HCPCS Level II Code Number(s)
THE FOLLOWING CODES ARE USED TO REPRESENT ATIDARSAGENE AUTOTEMCEL (LENMELDY):​

C9399 Unclassified drugs or biologicals

J3590 Unclassified biologics​
Revenue Code Number(s)
N/A​

Coding and Billing Requirements

Policy History

Revisions From 08.02.24:
12/23/2024
New policy #08.02.24 was developed to communicate the Company's coverage position and criteria on ​​atidarsagene autotemcel (Lenmeldy)​. 

12/23/2024
12/23/2024
08.02.24
Medical Policy Bulletin
Commercial
No