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:

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 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

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 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 (Lenmeldy)) 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.

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:

 Novel mechanism of action or approach may allow successful treatment of patients for whom other available treatments have failed.

 Successful treatment may reduce the potential for disease and standard treatment-related morbidity and mortality and improve quality of life.

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 (Lenmeldy). 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 (Lenmeldy) requires inpatient hospitalization. Atidarsagene autotemcel (Lenmeldy) 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

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

 Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

 Studies with duplicative or overlapping populations were excluded.

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 MLD: Children with expected disease onset ≤30 months of age and an ARSA genotype consistent with late infantile MLD. Pre-symptomatic status was defined as the absence of neurological signs and symptoms of MLD.

 Pre-symptomatic early juvenile MLD: Children with expected disease onset >30 months and <7 years of age and an ARSA genotype consistent with early juvenile MLD. Pre-symptomatic 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 early juvenile MLD: Children with disease onset >30 months and <7 years of age and an ARSA genotype consistent with early juvenile MLD. Early symptomatic status was defined as walking independently (Gross Motor Classification [GMFC]-MLD level 0 with ataxia or GMFC-MLD level 1) and IQ ≥ 85. Note that the original protocol defined early symptomatic early juvenile MLD as IQ ≥70 and the ability to take ≥10 steps independently. However, a post-hoc analysis of treatment failures done during the evaluation process by the European Medicines Agency suggested that treatment was not effective below certain thresholds of cognitive and motor function. Thus, the protocol was amended to include only MLD patients with IQ ≥85 and GMFC-MLD level ≤1.

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 (Lenmeldy) 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 (Lenmeldy) 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 (Lenmeldy). 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 (Lenmeldy) 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 (Lenmeldy) 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 (Lenmeldy). 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 (Lenmeldy) 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 (Lenmeldy) 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 (Lenmeldy) clinical development program was anti- ARSA antibodies in 6 participants. No evidence of malignancy, clonal expansion, or insertional oncogenesis associated with Atidarsagene autotemcel (Lenmeldy) were observed. Additional risks of Atidarsagene autotemcel (Lenmeldy) 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 (Lenmeldy)

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

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,

Table 6. Summary of Results in the Pivotal Integrated Analysis

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.

The FDA approved Atidarsagene autotemcel (Lenmeldy) based on a pooled analysis of multiple single-arm studies. Results from single arm studies are susceptible to biases as there may be differences between the treated population and the control arm that are not accounted for, affecting the estimates of treatment differences. Additionally, data in the natural history cohort was sparser than in the trial patients – for example, only baseline ARSA levels were known and other outcomes such as GMFC scores and measures of cognitive function were not necessarily collected at the same timepoints in the natural history cohort as in the trial making direct comparisons difficult. However, given MLD’s rarity, using single-arm studies and an external natural history cohort as comparators is reasonable.

Treatment with Atidarsagene autotemcel (Lenmeldy) resulted in robust and large treatment effects among individuals with pre-symptomatic late-infantile MLD which guards it against potential biases noted above. However, the statistical evidence for treatment effects in the pre-symptomatic and early symptomatic early juvenile MLD patients was limited. This was due to small sample sizes and high heterogeneity of the disease trajectories in these populations as well as questionable comparability with the natural history cohort. Nevertheless, individual data evaluations suggested that Atidarsagene autotemcel (Lenmeldy) was clinically beneficial for individuals in terms of motor functions. Furthermore, although cognitive function endpoints were analyzed in a descriptive manner, the observed treatment effects on cognitive function appeared to be substantial for most individuals.

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.

The long-term durability of Atidarsagene autotemcel (Lenmeldy) remains uncertain. Patients are typically treated in infancy or early childhood, and follow-up in current studies spans from 2.4 to 11 years for late infantile

patients and 0.6 to 9.2 years for early juvenile MLD patients. While ARSA levels have not significantly declined over time in most patients, the optimal ARSA level required to prevent disease progression remains uncertain due to the lack of correlation between ARSA levels and clinical outcomes. ARSA activity levels increased in all groups to normal or supranormal levels after treatment. Data on 35 MLD patients with up to 11 years of follow-up show that none of the treated patients had PBMC ARSA activity level below the reference range during extended follow-up. Additionally, a few patients did have progression of disease and it is not clear whether those patients were treated too late in the disease course to prevent disability or whether there are other factors besides ARSA levels that affect disease progression, since all patients were fully engrafted after Atidarsagene autotemcel (Lenmeldy) treatment.

 The limited sample sizes of the studies also create uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and as such may not be observed in trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty still remains about risk of hematologic malignancy. While no cases of malignancy, clonal expansion, or insertional oncogenesis were reported in the trial participants, such risk cannot be ruled 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.Long-term follow-up (>15 years) is required to establish precision around side effects.

Table 7. Study Relevance Limitations

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

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 (Lenmeldy) 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 (Lenmeldy) 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 (Lenmeldy) 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 (Lenmeldy) 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.

REFERENCES

1.  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.

2.  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

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-

40. PMID 9096767

4.  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

5.  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

6.  van Rappard DF, Boelens JJ, Wolf NI. Metachromatic leukodystrophy: Disease spectrum and approaches for treatment. Best Pract Res Clin Endocrinol Metab. Mar 2015; 29(2): 261-73. PMID 25987178

7.  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

8.  Zafeiriou DI, Kontopoulos EE, Michelakakis HM, et al. Neurophysiology and MRI in late-infantile metachromatic leukodystrophy. Pediatr Neurol. Nov 1999; 21(5): 843-6. PMID 10593679

9.  Takakura H, Nakano C, Kasagi S, et al. Multimodality evoked potentials in progression of

metachromatic leukodystrophy. Brain Dev. 1985; 7(4): 424-30. PMID 4061780

10.  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

11. Shaimardanova AA, Chulpanova DS, Solovyeva VV, et al. Metachromatic Leukodystrophy: Diagnosis,

Modeling, and Treatment Approaches. Front Med (Lausanne). 2020; 7: 576221. PMID 33195324

12.  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

13.  van Rappard DF, de Vries ALC, Oostrom KJ, et al. Slowly Progressive Psychiatric Symptoms: Think Metachromatic Leukodystrophy. J Am Acad Child Adolesc Psychiatry. Feb 2018; 57(2): 74-76. PMID 29413149

14.  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

15.  Zlotogora J, Bach G, Barak Y, et al. Metachromatic leukodystrophy in the habbanite Jews: high frequency in a genetic isolate and screening for heterozygotes. Am J Hum Genet. Sep 1980; 32(5): 663-

9. PMID 6107044

16.  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

17.  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

18.  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

19.  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

20.  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

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

22.  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

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): 555-561. PMID 33214709

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

25.  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

26.  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

27.  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

28.  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

29.  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

30.  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

31.  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

32.  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 (Lenmeldy). Orphanet J Rare Dis. Aug 29 2023; 18(1): 248. PMID 37644601

33.  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

34.  Food and Drug Administration: Statistical Review for Atidarsagene autotemcel (Lenmeldy) (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.

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

36.  Prescribing label for Lenmeldy (Atidarsagene autotemcel (Lenmeldy)) 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.

37.  Institute for Clinical and Evidence Review: Atidarsagene autotemcel (Lenmeldy) 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.

38.  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

39.  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.