106 Form

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Medical Policy
Gene Therapies for Metachromatic Leukodystrophy Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History

Policy Number: 106 BCBSA Reference Number: 5.01.49 NCD/LCD: N/A Related Policies
Prior Authorization Request Form for Lenmeldy (atidarsagene autotemcel), #109 Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

Atidarsagene autotemcel (Lenmeldy) Atidarsagene autotemcel is considered MEDICALLY NECESSARY treatment of metachromatic leukodystrophy when ALL of the following criteria are met:

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: a. ARSA enzyme activity in leukocytes below reference values b. Urinary sulfatide levels above reference values.
3. Confirmed diagnosis of one of the following subtypes of MLD (see Policy Guidelines): a. Pre-symptomatic late infantile b. Pre-symptomatic early juvenile c. 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: a. Adequate performance status score (e.g., Karnofsky performance status, Lansky performance status) b. Absence of advanced liver disease c. Adequate estimate glomerular filtration rate (eGFR) d. Adequate diffusing capacity of the lungs for carbon monoxide (DLCO) e. Adequate ventricular ejection fraction (LVEF) f. Absence of clinically significant active infection(s).
5. Have not received a previous allogenic hematopoietic stem cell transplant or gene therapy.

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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.

Prior Authorization Information
Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient

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• For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

Outpatient Commercial Managed Care (HMO and POS) Prior authorization is required. Commercial PPO and Indemnity Prior authorization is required. Medicare HMO BlueSM Prior authorization is required. Medicare PPO BlueSM Prior authorization is required.

Requesting Prior Authorization Using Authorization Manager Providers will need to use Authorization Manager to submit initial authorization requests for services. Authorization Manager, available 24/7, is the quickest way to review authorization requirements, request authorizations, submit clinical documentation, check existing case status, and view/print the decision letter. For commercial members, the requests must meet medical policy guidelines.

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Complete Prior Authorization Request Form for Lenmeldy (atidarsagene autotemcel) (109) using Authorization Manager.

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CPT Codes / HCPCS Codes / ICD Codes
Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable. HCPCS Codes HCPCS codes:

Code Description C9399 Unclassified drugs or biologicals J3391 Injection, atidarsagene autotemcel, per treatment J3490 Unclassified drugs J3590 Unclassified biologics ICD-10 Diagnosis Codes ICD-10-CM diagnosis codes: Code Description E75.25 Metachromatic leukodystrophy

Description Background Metachromatic Leukodystrophy (MLD)

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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: • 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 allele are associated with late infantile onset forms. Compound heterozygotes (with the other allele unknown) also have a late infantile onset.1, • Homozygosity for the A allele (p.P426L) is the most common of hypomorphic 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 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. Late Juvenile 6 to 16 years of age

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Progression is slower compared with the late infantile form, and these children may survive until early adulthood. 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: • Genetic test identifies biallelic 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. • Sulfatide measurement reveals elevated levels in urine.

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

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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,

Summary 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

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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.

Policy History Date Action 1/15/2026 Association annual review: policy updated with literature review through April 13, 2025; no references added. Policy statements unchanged. 7/2025 Clarified coding information. 5/2025 Policy summary and background clarified. Policy statements unchanged. 12/2024 New medical policy describing medically necessary and investigational indications. 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. Effective 12/1/2024. Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines References

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3. 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

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3. 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-
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21. 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
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23. 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-
24. PMID 33214709
25. MLD newborn screening. Available at https://mldnewbornscreening.org/. Accessed May 5, 2024.
26. Wang RY, Bodamer OA, Watson MS, et al. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. May 2011; 13(5): 457-84. PMID 21502868
27. Solders M, Martin DA, Andersson C, et al. Hematopoietic SCT: a useful treatment for late metachromatic leukodystrophy. Bone Marrow Transplant. Aug 2014; 49(8): 1046-51. PMID 24797185
28. 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
29. 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
30. 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
31. van Rappard DF, Boelens JJ, van Egmond ME, et al. Efficacy of hematopoietic cell transplantation in metachromatic leukodystrophy: the Dutch experience. Blood. Jun 16 2016; 127(24): 3098-101. PMID 27118454
32. 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
33. 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. Aug 29 2023; 18(1): 248. PMID 37644601
34. 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
35. 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.
36. 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, 2025.
37. 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, 2025.
38. 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-ReportFor-Publication10302023.pdf. Accessed on May 12, 2025.
39. 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
40. Sessa M, Lorioli L, Fumagalli F, et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet. Jul 30 2016; 388(10043): 476-87. PMID 27289174
41. National Institute for Health and Care Excellence: Atidarsagene autotemcel for treating metachromatic leukodystrophy (Highly specialized technologies guidance). Published: 28 March
42. Available at www.nice.org.uk/guidance/hst18. Accessed on May 12, 2025.