Atidarsagene Autotemcel (Lenmeldy)

Number: 1058

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses atidarsagene autotemcel (Lenmeldy) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of atidarsagene autotemcel (Lenmeldy) is required of all Aetna participating providers and members in applicable plan designs. For precertification of atidarsagene autotemcel (Lenmeldy), contact National Medical Excellence (NME) at 877-212-8811.  

Note: Unless member's health plan has elected not to require, gene and cellular therapies must be administered at an Aetna Institutes^® Gene Based, Cellular and Other Innovative Therapy (GCIT^®) Network. For atidarsagene autotemcel (Lenmeldy), see Aetna Institutes® GCIT Designated Centers. 

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a physician who specializes in the treatment of metachromatic leukodystrophy (MLD). 

2. Criteria for Initial Approval

   Aetna considers a one-time administration of atidarsagene autotemcel (Lenmeldy) medically necessary for the treatment of metachromatic leukodystrophy (MLD) when all of the following criteria are met:

   1. Member must have one of the following:
      
      1. Pre-symptomatic late infantile (PSLI); or
      2. Pre-symptomatic early juvenile (PSEJ); or
      3. Early symptomatic early juvenile (ESEJ); and

   2. The diagnosis was confirmed by all of the following:

      1.  Biochemical testing documenting ARSA activity is below the normal range for the laboratory performing the test; and
      2.  The presence of two disease-causing ARSA alleles, either known or novel mutations, identified on genetic testing; and
      3.  If novel mutations are identified, a 24-hour urine collection showing elevated sulfatide levels; and

   3. Member has not received Lenmeldy or any other gene therapy previously; and
   4. Member does not have evidence of residual cells of donor origin if the member has received a prior allogeneic hematopoietic stem cell transplant (allo-HSCT).

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Related Policies 

   1. CPB 0202 - Magnetic Resonance Spectroscopy (MRS)
   2. CPB 0871 - Hematopoietic Cell Transplantation for Inherited Metabolic Disorders and Genetic Diseases

Dosage and Administration

Atidarsagene autotemcel is available as Lenmeldy, a single-dose cell suspension for autologous use and administered as a one-time intravenous infusion. Lenmeldy is composed of one to eight infusion bags which contain 2 to 11.8 x 10⁶ cells/mL (1.8 to 11.8 x 10⁶ CD34+ cells/mL) suspended in cryopreservation solution. Mobilization, apheresis, and myeloablative conditioning are required prior to Lenmeldy infusion.

• Children are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34+ cells for Lenmeldy manufacturing.
• Dosing of Lenmeldy is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight.
• The minimum recommended dose is based on the MLD disease subtype.
• Myeloablative conditioning must be administered before infusion of Lenmeldy.

For additional information, refer to the Full Prescribing Information for Lenmeldy.

Source: Orchard Therapeutics, 2024

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
38204	Management of recipient hematopoietic progenitor cell donor search and cell acquisition
38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogeneic
38206	autologous
81405	Molecular pathology procedure, Level 6 full gene sequence ARSA (arylsulfatase A) (eg, arylsulfatase A deficiency)
84392	Sulfate, urine
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96366	each additional hour (list in addition to code for primary procedure)
HCPCS codes covered if selection criteria are met:
Atidarsagene autotemcel (Lenmeldy) –no specific code
ICD-10 codes covered if selection criteria are met:
E75.25	Metachromatic leukodystrophy

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Lenmeldy is indicated for the treatment of children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ) or early symptomatic early juvenile (ESEJ) metachromatic leukodystrophy (MLD). 

Atidarsagene autotemcel, branded as Lenmeldy (Orchard Therapeutics North America), is a cell-based gene therapy consisting of autologous CD34+ cells, containing hematopoietic stem cells (HSCs), transduced with a lentiviral vector (LVV) encoding the human arylsulfatase A (ARSA) gene, suspended in cryopreservation solution. Lenmeldy works by correcting the underlying genetic cause of metachromatic leukodystrophy (MLD) by inserting one or more functional copies of the human ARSA gene ex vivo into the genome of the patient’s own HSCs using a LVV, as a gene delivery vehicle. The genetically modified cells are then transplanted back into the patient via a one-time, single-dose intravenous infusion. The transduced CD34+ HSCs engraft (attach and multiply) within the bone marrow, enabling the body to make the ARSA enzyme, which is needed to break down the harmful buildup of sulfatides in the cells that are responsible for the progression of demyelination of the central and peripheral nervous system in patients with MLD.

This cell-based gene therapy process requires the patient to undergo CD34+ HSC mobilization (where stem cells are stimulated out of the bone marrow space) followed by apheresis (the procedure used to collect stem cells from the blood) to isolate the CD34+ cells needed for Lenmeldy manufacturing. The autologous stem cells are then genetically modified ex vivo (outside the body) with a recombinant replication-incompetent self-inactivating human immunodeficiency virus-1 (HIV-1) - based LVV that has been modified to carry the ARSA complementary deoxyribonucleic acid (cDNA) sequence under the human phosphoglycerate kinase (PGK) promoter. Prior to the Lenmeldy infusion, the patient must undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the newly modified stem cells in Lenmeldy, as part of a hematopoietic stem cell transplant (HSCT) procedure. In clinical trials of Lenmeldy, busulfan was used for myeloablative conditioning. 

After infusion with Lenmeldy, patients should be monitored for neutrophil counts and risk of delayed platelet engraftment until engraftment has been achieved. 

Although there are no known contraindications, Lenmeldy carries warnings and precautions for thrombosis and thromboembolic events, encephalitis, serious infection after myeloablative conditioning, veno-occlusive disease, delayed platelet engraftment, risk of neutrophil engraftment failure, risk of insertional oncogenesis, and risk of hypersensitivity reactions. 

A child with pre-symptomatic early juvenile (PSEJ) MLD died after experiencing a left hemisphere cerebral infarction secondary to a thrombotic event in a large blood vessel approximately one year after treatment with Lenmeldy. Prior to the cerebral infarction, the child’s D-dimer was elevated (82 nmol/L, normal range: 1.5 - 4.2). Additional clinical findings included a minor elevation of liver enzymes. The etiology of the cerebral infarction was unclear but attribution to Lenmeldy could not be ruled out.

A child with early symptomatic early juvenile (ESEJ) MLD developed a serious event of encephalitis after treatment with Lenmeldy. The etiology of this event is unclear but attribution to Lenmeldy could not be ruled out. Treatment with Lenmeldy may trigger a relapsing-remitting pattern of disease progression. 

In the period between start of conditioning and within one year after Lenmeldy treatment, severe Grade 3 infections occurred in 39% of all children (21% bacterial, 5% viral, 5% bacterial and viral or bacterial and fungal, and 8% unspecified). The most common Grade 3 infections were device related infections (18%) (including two events of sepsis), respiratory tract infections (including 1 Grade 3 event of pneumonia) (8%), and gastroenteritis/enteritis (8%). 

Three children (8%) treated in clinical trials developed veno-occlusive disease (VOD), with one Grade 4 serious adverse event (SAE) and two Grade 3 adverse events (AEs). None of these three events met Hy’s Law criteria. Hy's law is a rule of thumb that a patient is at high risk of a fatal drug-induced liver injury (DILI) if given a medication that causes hepatocellular injury with jaundice. 

In clinical trials, 4 (10%) children had delayed platelet engraftment after day 60 (range day 67-109), with 3 children requiring platelet transfusions until engraftment occurred. All children treated with Lenmeldy received transfusion support with platelets according to best clinical practice.

Although there is a potential risk of neutrophil engraftment failure after Lenmeldy treatment, there were no cases reported in clinical trials. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) greater than or equal to 500 cells/microliter obtained on different days by Day 60 after infusion of Lenmeldy.

There is a potential risk of LVV-mediated insertional oncogenesis after treatment with Lenmeldy. In clinical trials, no cases of insertional oncogenesis have been reported. Children treated with Lenmeldy may develop hematologic malignancies and should be monitored lifelong. 

The most common non-laboratory adverse reactions (incidence 10% or more) included febrile neutropenia (85%), stomatitis (77%), respiratory tract infections (54%), rash (33%), device related infections (31%), other viral infections (28%), pyrexia (21%), gastroenteritis (21%), and hepatomegaly (18%). The most common laboratory abnormalities included elevated D-dimer (67%), neutropenia (28%), and elevated liver enzymes (23%). 

Per the label, patients should not take anti-retroviral medications for at least one month prior to initiating medications for stem cell mobilization and for the expected duration of time needed for the elimination of the medications.

Children who have received Lenmeldy are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion resulting in a false-positive test for HIV. Therefore, children who have received Lenmeldy should not be screened for HIV infection using a PCR-based assay.

The safety and effectiveness of vaccination during or following Lenmeldy treatment have not been studied. Vaccination is not recommended during the 6 weeks preceding the start of myeloablative conditioning, and until hematological recovery following treatment. Where feasible, childhood vaccinations are administered prior to myeloablative conditioning for Lenmeldy.

There is no data on the effects of Lenmeldy on fertility. Further, there are no clinical data for use of Lenmeldy in pregnant women.

Lenmeldy has not been studied in children with renal or hepatic impairment. Children should be assessed for impairment to ensure HSC transplantation is appropriate. 

Metachromatic Leukodystrophy 

Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disease that leads to progressive demyelination of the central and peripheral nervous system, resulting in in loss of motor and cognitive function and early death. MLD is caused by a deficiency of the arylsulfatase A (ARSA) enzyme, as a consequence of mutations in the ARSA gene, which leads to a buildup of sulfatides in the cells. This buildup subsequently damages the myelin sheath that covers most nerve fibers of the central (CNS) and peripheral (PNS) nervous system, manifesting into clinical symptoms. MLD follows an autosomal recessive pattern of inheritance and is estimated to affect one in every 40,000 individuals in the United States. In some cases, MLD is due to the 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).

There are 3 major subtypes of MLD, which are distinguished based on the age of onset: late infantile, juvenile, and adult form. The most common subtype (approximately 50–60% of cases) is late infantile MLD, which is characterized by symptom onset at age less than or equal to 2.5 years and is generally associated with the most rapid and severe disease progression. Juvenile MLD is defined by symptom onset at age greater than 2.5 to less than 16 years. It typically represents 20–30% of cases. In addition, this subtype may be further subdivided into early-juvenile MLD (age at onset, greater than  2.5 to less than 6 years) and late-juvenile MLD (onset at age 6 to less than 16 years). Adult MLD (age at onset, 16 years and older) accounts for approximately 15–20% of cases (Chang et al, 2024).

Early signs of late infantile form includes regression of motor skills, gait difficulty, ataxia, hypotonia, extensor plantar responses, optic atrophy, and peripheral neuropathy. The juvenile form presents with gait disturbance, intellectual impairment, ataxia, upper motor neuron signs, and a peripheral neuropathy. Further, seizures may occur in this subtype. Dementia and behavioral difficulties are typically seen in the adult-onset form of MLD (Bronkowsky, 2024).

The diagnosis of MLD is "established by the identification of biallelic pathogenic variants in ARSA, together with deficient ARSA enzyme activity in leukocytes and elevated urinary excretion of sulfatides. The finding of normal ARSA activity associated with elevated urinary sulfatides suggests the possibility of sphingolipid activator protein B (Sap-B) deficiency and should prompt molecular analysis of the PSAP gene" (Bronkowsky, 2024).

There has been no cure for MLD. Treatment has included symptomatic supportive care to address neurocognitive and neuropsychiatric disturbances, seizures, dystonias, spasticity, feeding problems, and constipation. Allogeneic hematopoietic cell transplantation (HCT) may halt or prevent disease progression of CNS manifestations in pre- or early symptomatic patients, and has been considered the standard of care for eligible patients with no or early MLD disease involvement. However, HCT 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 HCT compared with 28 of 41 patients (68 percent) with juvenile onset who did not receive HCT. Ex vivo gene therapy with HCT has shown to be promising as a treatment option for MLD (Bonkowsky, 2024).

On March 18, 2024, the FDA announced the approval of Lenmeldy (atidarsagene autotemcel) gene therapy for the treatment of children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ), or early symptomatic early juvenile (ESEJ) metachromatic leukodystrophy (MLD). FDA approval was based on the safety and efficacy data obtained from 37 children who received Lenmeldy, compared to natural history, in two single-arm, open-label clinical trials and a European Union (EU) expanded access program (EAP). In clinical trials of Lenmeldy, children were classified as having PSLI, PSEJ, or ESEJ MLD based on the following criteria:

• PSLI MLD: children with expected disease onset less than or equal to 30 months (2.5 years) of age and an ARSA genotype consistent with LI MLD. Pre-symptomatic status was defined as the absence of neurological signs and symptoms of MLD.
• PSEJ MLD: children with expected disease onset greater than 30 months (2.5 years) and less than 7 years of age and an ARSA genotype consistent with EJ MLD. 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.
• ESEJ MLD: children with disease onset greater than 30 months (2.5 years) and less than 7 years of age and an ARSA genotype consistent with EJ MLD. Early symptomatic status was defined as walking independently (gross motor function classification [GMFC]-MLD Level 0 with ataxia or GMFC-MLD Level 1) and IQ greater than or equal to 85.

For pre-symptomatic status, children were permitted to have abnormal reflexes or abnormalities on brain magnetic resonance imaging and/or nerve conduction tests not associated with functional impairment (e.g., no tremor, no peripheral ataxia). 

The primary efficacy endpoint was 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. The clinical trials enrolled 13 children with PSLI, 6 children with PSEJ and 9 children with ESEJ MLD. The EU EAP enrolled 7 children with PSLI, 1 child with PSEJ and 1 child with ESEJ MLD. All children had documented biochemical and molecular diagnosis of MLD based on ARSA activity below the normal range and identification of two disease-causing ARSA alleles. In the case of a novel ARSA variant(s), a 24-hour urine collection was required to show elevated sulfatide levels. The major efficacy outcomes in clinical trials were motor and neurocognitive function, as assessed by GMFC-MLD levels and standard scores on age-appropriate neurocognitive tests, respectively. All children underwent mobilization followed by apheresis, and received busulfan for myeloablative conditioning. 

For children with PSLI, the primary endpoint was 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 (GMFC-MLD Level greater than or equal to 5) or death. Seventeen children treated with Lenmeldy had been followed until at least the age of 5 years. At the age of 5 years, 100% of Lenmeldy treated children remained event-free compared with 0% of untreated LI children. Twelve out of 17 children who were at least 5 years of age at last follow-up retained independent ambulation (GMFC-MLD Level less than or equal to 1). Fourteen treated children and 24 natural history children had sufficient follow-up to determine survival at 6 years from birth. At this timepoint, all patients treated with Lenmeldy were alive, and 10 natural history children had died (42%).

For children with PSEJ, seven children were treated with Lenmeldy. One child died at age 2.1 years from a cerebral infarction. There were insufficient data in three children who were too young at last follow-up to evaluate efficacy of Lemeldy, as symptom onset may not begin until 7 years of age in EJ MLD. Two children had evaluable motor and cognitive outcomes. One child 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.

For children with ESEJ, four children had favorable cognitive outcomes after treatment in the setting of motor decline. Retention of cognitive functioning has not been reported in this phase of EJ MLD disease, as motor and cognitive functioning typically decline together in untreated children.

In summary, in children with MLD, treatment with Lenmeldy significantly reduced the risk of severe motor impairment or death compared with untreated children. All children with PSLI MLD who were treated with Lenmeldy were alive at 6 years of age, compared to only 58% of children in the natural history group. At 5 years of age, 71% of treated children were able to walk without assistance.  Eighty five percent of the children treated had normal language and performance IQ scores, which has not been reported in untreated children. In addition, children with PSEJ and ESEJ MLD showed slowing of motor and/or cognitive disease (FDA, 2024).

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References