Atidarsagene Autotemcel (Monograph)

Brand name: Lenmeldy
Drug class: Gene Therapy

Introduction

Atidarsagene autotemcel is an autologous hematopoietic stem cell (HSC)-based gene therapy.

Uses for Atidarsagene Autotemcel

Atidarsagene autotemcel has the following uses:

Atidarsagene autotemcel 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 has been designated an orphan drug by FDA for the treatment of MLD.

MLD is a rare inherited condition caused by a deficiency of the arylsulfatase A (ARSA) enzyme, which results in the accumulation of fats (sulfatides) leading to the destruction of neurons and myelin surrounding the nerves in the brain and spinal cord.

Atidarsagene autotemcel is an autologous HSC-based gene therapy prepared from the child's HSCs, which are collected via apheresis procedure(s). The collected cells are shipped to the manufacturing site where CD34+ cells are selected and then transduced ex vivo with a lentiviral vector (LVV) encoding the human ARSA gene. Atidarsagene autotemcel is intended for one-time administration to add functional copies of the ARSA gene into the child's own HSCs.

Efficacy and safety of atidarsagene autotemcel are based on data from 37 children in 2 single-arm, open-label clinical trials and an expanded access program. Patients underwent hematopoietic cell mobilization, apheresis, and myeloablative conditioning prior to receiving atidarsagene autotemcel as an IV infusion. Compared to an external untreated natural history cohort, treatment with atidarsagene autotemcel significantly improved severe motor impairment and increased overall survival in children with PSLI MLD. In the evaluable patients with PSEJ and ESEJ who were treated with atidarsagene autotemcel, favorable motor and cognitive function outcomes were observed.

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Lenmeldy

Atidarsagene Autotemcel Dosage and Administration

General

Atidarsagene autotemcel is available in the following dosage form(s) and strength(s):

• Atidarsagene autotemcel is a single-dose cell suspension for IV infusion.

• Atidarsagene autotemcel is composed of one to eight infusion bags which contain 2 to 11.8× 10⁶ cells/mL (1.8 to 11.8 x 10⁶CD34 ⁺cells/ml) suspended in cryopreservation solution.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Dosage and Administration

For autologous use only. For one-time single-dose IV use only.

• Children are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34+ cells for atidarsagene autotemcel manufacturing.

• Myeloablative conditioning must be administered before infusion of atidarsagene autotemcel.

• Confirm that the child’s identity matches the unique patient identification information on the atidarsagene autotemcel infusion bag(s) prior to infusion.

• Dosing of atidarsagene autotemcel 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 (see Table 1 below).

• Administer each infusion bag of atidarsagene autotemcel as an IV infusion via a central venous catheter within 30 minutes via gravity or infusion pump. An infusion flow rate should be calculated based on the volume in each infusion bag.

• Do not sample, alter, irradiate, or refreeze atidarsagene autotemcel.

• Do not use a leukodepleting filter.

• See Full Prescribing Information for additional details on preparation and administration.

Cautions for Atidarsagene Autotemcel

Contraindications

• None

Warnings/Precautions

Thrombosis and Thromboembolic Events

Treatment with atidarsagene autotemcel may increase the risk of thrombosis and thromboembolic events. A child with 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 atidarsagene autotemcel. 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 atidarsagene autotemcel cannot be ruled out. No other events related to cerebral infarction have been reported during the clinical development of atidarsagene autotemcel. Some children received anti-thrombotic prophylaxis. Evaluate the risk factors for thrombosis prior to and after atidarsagene autotemcel infusion according to best clinical practice.

Encephalitis

Treatment with atidarsagene autotemcel may increase the risk of encephalitis. A child with ESEJ MLD developed a serious event of encephalitis after treatment with atidarsagene autotemcel. At the time of treatment, GMFC-MLD (an assessment of motor and neurocognitive function) was Level 1 (able to walk independently with impaired gait). One month after treatment, the child experienced subacute neurological deterioration, with asthenia, hypotonia, cognitive and behavioral problems, vomiting, and swallowing disturbance. The child was afebrile, blood and CSF cultures were negative for bacterial infection, a large viral panel was negative and all routine laboratory tests were normal. The child was treated with plasmapheresis, immunoglobulin and rituximab leading to clinical improvement. Five months after onset of symptoms the child had reached GMFC-MLD Level 4 (walking not possible; able to sit without support and locomotion possible, or unable to sit without support but locomotion is possible). The child was subsequently treated with eculizumab and tocilizumab.

The etiology of this event is unclear but attribution to atidarsagene autotemcel cannot be ruled out. Treatment with atidarsagene autotemcel may trigger a relapsing-remitting pattern of disease progression. No other events related to encephalitis have been reported during the clinical development of atidarsagene autotemcel.

Monitor children for signs or symptoms of encephalitis after atidarsagene autotemcel treatment.

Serious Infection

In the period between start of conditioning and within one year after atidarsagene autotemcel 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%).

Grade 3 febrile neutropenia developed within 1 month after atidarsagene autotemcel infusion in 82% of children. In the event of febrile neutropenia, monitor for signs and symptoms of infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

Monitor children for signs and symptoms of infection after myeloablative conditioning and atidarsagene autotemcel infusion and treat appropriately. Administer prophylactic antimicrobials according to best clinical practice.

Veno-occlusive Disease

Three children (8%) treated in clinical trials of atidarsagene autotemcel developed veno-occlusive disease (VOD), with one Grade 4 SAE and two Grade 3 AEs. None of these three events met Hy’s Law criteria.

Monitor children for signs and symptoms of VOD including liver function tests in all children during the first month after atidarsagene autotemcel infusion. Consider prophylaxis for VOD with anti-thrombotic agents based on risk factors for VOD and best clinical practice.

Delayed Platelet Engraftment

Delayed platelet engraftment has been observed with atidarsagene autotemcel treatment. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in children with prolonged thrombocytopenia. In clinical trials of atidarsagene autotemcel, 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 atidarsagene autotemcel received transfusion support with platelets according to best clinical practice.

Inform children of the risk of bleeding until platelet recovery has been achieved. Monitor children for thrombocytopenia and bleeding.

Neutrophil Engraftment Failure

There is a potential risk of neutrophil engraftment failure after treatment with atidarsagene autotemcel. In clinical trials of atidarsagene autotemcel, no cases of neutrophil engraftment failure have been reported. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 60 after infusion of atidarsagene autotemcel.

Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a child treated with atidarsagene autotemcel, provide rescue treatment with the unmanipulated back-up collection of CD34⁺cells.

Insertional Oncogenesis

There is a potential risk of lentiviral vector (LVV)-mediated insertional oncogenesis after treatment with atidarsagene autotemcel. In clinical trials of atidarsagene autotemcel, no cases of insertional oncogenesis have been reported. Children treated with atidarsagene autotemcel may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) annually and integration site analysis as warranted for at least 15 years after treatment with atidarsagene autotemcel.

In the event that a malignancy occurs, contact Orchard Therapeutics at 1-888-878-0185 for reporting and to obtain instructions on collection of samples for testing.

Hypersensitivity Reactions

There is a potential risk of allergic reactions in children treated with atidarsagene autotemcel. The dimethyl sulfoxide (DMSO) in atidarsagene autotemcel may cause hypersensitivity reactions, including anaphylaxis which is potentially life-threatening and requires immediate intervention. Hypersensitivity including anaphylaxis can occur in children with and without prior exposure to DSMO. In clinical trials of atidarsagene autotemcel, no cases of hypersensitivity reactions have been reported.

Antiretroviral Use

Children should not take prophylactic HIV antiretroviral medications for at least one month prior to mobilization, or for the expected duration of time needed for the elimination of the medications. Antiretroviral medications may interfere with the manufacturing of atidarsagene autotemcel.

If a child requires antiretrovirals for HIV prophylaxis, initiation of atidarsagene autotemcel treatment should be delayed until confirmation of a negative test for HIV.

Interference with Serology Testing

Children who have received atidarsagene autotemcel 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 atidarsagene autotemcel should not be screened for HIV infection using a PCR-based assay.

Specific Populations

Pregnancy

There are no clinical data from the use of atidarsagene autotemcel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with atidarsagene autotemcel to assess whether it can cause fetal harm when administered to a pregnant woman. Atidarsagene autotemcel must not be administered during pregnancy because of the risk associated with myeloablative conditioning. Pregnancy after atidarsagene autotemcel infusion should be discussed with the treating physician.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Lactation

There are no data on the presence of atidarsagene autotemcel in human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential risks associated with myeloablative conditioning, breast-feeding should be discontinued during conditioning. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for atidarsagene autotemcel and any potential adverse effects on the breastfed child from the treatment or from the underlying maternal condition. Breast-feeding after atidarsagene autotemcel infusion should be discussed with the treating physician. Children receiving breast milk may continue to do so throughout their treatment under the advice of their treating physician.

Females and Males of Reproductive Potential

As a precautionary measure, a negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before administration of atidarsagene autotemcel in females of childbearing potential.

Males capable of fathering a child and females of childbearing age should use an effective method of contraception from start of mobilization through at least 6 months after administration of atidarsagene autotemcel.

There are no data on the effects of atidarsagene autotemcel on fertility.

Data are available on the risk of infertility with myeloablative conditioning. In clinical trials of atidarsagene autotemcel, 7 children (50% of females) developed ovarian failure. Advise children of the option to cryopreserve semen or ova before treatment, if appropriate.

Pediatric Use

The safety and efficacy of atidarsagene autotemcel have been established in children with PSLI, PSEJ and ESEJ MLD. The clinical trials of atidarsagene autotemcel treated 20 PSLI, 7 PSEJ, and 10 ESEJ MLD children who received atidarsagene autotemcel between ages 8 – 19 months (median age of 12 months), 11 months – 5.56 years (median age of 2.57 years), and 2.54 – 11.64 years (median age of 5.84 years), respectively. The safety and efficacy of atidarsagene autotemcel have not yet been established in children with the late juvenile form of the disease.

Patients Seropositive for Human Immunodeficiency Virus (HIV) or Other Infectious Diseases

Atidarsagene autotemcel has not been studied in children with HIV-1, HIV-2, HTLV-1, HTLV-2, HBV, HVC, or mycoplasma infection. Negative serology tests for HIV-1/2, HTLV-1/2, HBV, HCV, and mycoplasma are necessary to ensure acceptance of apheresis material for atidarsagene autotemcel manufacturing.

Renal Impairment

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

Hepatic Impairment

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

Common Adverse Effects

• The most common non-laboratory adverse reactions (incidence ≥ 10%) were 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 were elevated D-dimer (67%), neutropenia (28%), and elevated liver enzymes (23%).

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Antiretrovirals: Do not take antiretroviral medications for at least 1 month prior to initiating medications for stem cell mobilization and for the expected duration of time needed for the elimination of the medications.

Actions

Mechanism of Action

Atidarsagene autotemcel inserts one or more functional copies of the human ARSA complementary deoxyribonucleic acid (cDNA) into the patients’ HSCs, through transduction of autologous CD34 ⁺ cells with ARSA LVV. After atidarsagene autotemcel infusion, transduced CD34⁺ HSCs engraft in bone marrow, repopulate the hematopoietic compartment and their progeny produce ARSA enzyme. Functional ARSA enzyme can breakdown or prevent the harmful accumulation of sulfatides.

Advice to Patients

• Ensure that patients and/or caregivers understand the risk of manufacturing failure. A collection of unmanipulated back-up CD34 ⁺cells is required in case of manufacturing failure. These cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning.

• Prior to treatment, advise patients and/or caregivers of the risks associated with mobilization and myeloablative conditioning agents.

• Prior to treatment, advise patients and/or caregivers of hypersensitivity reactions. Although no cases have been reported to date, allergic reactions may occur with the infusion of atidarsagene autotemcel. The dimethyl sulfoxide (DMSO) in atidarsagene autotemcel may cause hypersensitivity reactions, including anaphylaxis.

• After treatment, advise patients and/or caregivers of the risk of thrombosis and thrombotic events. A risk of blood clots may occur. Monitor patients for signs and symptoms of thrombosis.

• After treatment, advise patients and/or caregivers of the risk of encephalitis. Monitor patients for signs or symptoms of encephalitis, including neurological deterioration such as weakness, decreased muscle tone, cognitive deterioration, behavioral problems, vomiting, and swallowing difficulties.

• After treatment, advise patients and/or caregivers of the risk of serious infection. Life-threatening bacterial and viral infections may occur. Monitor patients for signs and symptoms of infection.

• After treatment, advise patients and/or caregivers of the risk of veno-occlusive disease. Blood sampling will occur before and after atidarsagene autotemcel infusion to monitor for liver problems including severe, life threatening, veno-occlusive disease.

• After treatment, advise patients and/or caregivers of the risk of delayed platelet engraftment. A risk of bleeding exists after myeloablative conditioning and before platelet engraftment and may continue after engraftment in patients who have continued thrombocytopenia.

• After treatment, advise patients and/or caregivers of the risk of neutrophil engraftment failure. There is a potential risk of neutrophil engraftment failure and the need for rescue treatment with their back-up collection of CD34⁺ cells.

• There is a potential risk of insertional oncogenesis after treatment with atidarsagene autotemcel. Patients should be monitored lifelong. Monitoring will include assessment for hematologic malignancies annually for at least 15 years after treatment with atidarsagene autotemcel. This will include integration site analysis as warranted.

• Advise patients and/or caregivers to seek immediate attention for signs of a blood clot, which may include pain, discoloration, or swelling of an arm, legs or feet, with warmth over the affected area, unexplained shortness of breath, acute chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body.

• Advise patients and/or caregivers to seek immediate attention for new or worsening bleeding or bruising. Platelet recovery following atidarsagene autotemcel infusion could be delayed, potentially resulting in an increased risk of bruising or bleeding until platelet recovery has been achieved.

• Advise patients and/or caregivers to monitor for signs and symptoms of bleeding and have frequent blood draws for platelet counts, until platelet recovery has been achieved.

• Advise patients and/or caregivers to have their treating physician contact Orchard Therapeutics at 1-888-878-0185 if they are diagnosed with a malignancy.

• Advise patients and/or caregivers that patients should not donate blood, organs, tissues, or cells at any time in the future.

• Advise patients and/or caregivers that treatment with atidarsagene autotemcel may cause a false-positive human immunodeficiency virus (HIV) test result if tested using a PCR assay.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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