Lenmeldy

— THERAPEUTIC CATEGORIES —
  • Inborn errors of metabolism
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Lenmeldy Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Atidarsagene autotemcel (contains 2–11.8×10^6 cells/mL [1.8–11.8×10^6 CD34+ cells/mL]); per single dose; cell susp for IV infusion; contains 5% dimethyl sulfoxide (DMSO).

    Pharmacological Class

    Autologous hematopoietic stem cell-based gene therapy.

    How Supplied

    Infusion bag (10–20mL)—up to 8 (overwrap, each in a metal cassette)

    Storage

    Store Lenmeldy in the vapor phase of liquid nitrogen at less than -130°C (-202°F) until ready for thaw and administration. Thaw Lenmeldy prior to infusion. Do not re-freeze after thawing.

    Manufacturer

    Orchard Therapeutics

    Generic Availability

    NO

    Mechanism of Action

    Lenmeldy inserts 1 or more functional copies of the human arylsulfatase A (ARSA) complementary deoxyribonucleic acid (cDNA) into the patients’ hematopoietic stem cells (HSCs), through transduction of autologous CD34+ cells with ARSA lentiviral vector. After 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.

    Lenmeldy Indications

    Indications

    Pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ) or early symptomatic early juvenile (ESEJ) metachromatic leukodystrophy. 

    Lenmeldy Dosage and Administration

    Adult

    Not established.

    Children

    For autologous and IV use only. Confirm that hematopoietic stem cell (HSC) therapy is appropriate. Must undergo HSC mobilization followed by apheresis to obtain CD34+ cells for product manufacturing; the minimum number of CD34+ cells to be collected is 8.0×106 CD34+ cells/kg. A back-up collection is required for rescue treatment: CD34+ cells of ≥2.0×106 CD34+ cells/kg (collected via mobilized peripheral blood apheresis or bone marrow). Must administer myeloablative conditioning prior to Lenmeldy infusion; allow ≥24hrs washout prior to infusion. Infuse via central venous catheter within 30mins via gravity or infusion pump; flush remaining with sodium chloride. Do not give more than 1 bag of product per hour. PSLI: minimum 4.2×106 CD34+ cells/kg. PSEJ: minimum 9×106 CD34+ cells/kg. ESEJ: minimum 6.6×106 CD34+ cells/kg. For all: max 30×106 CD34+ cells/kg. Mobilization, apheresis, myeloablative conditioning, preparation and administration for infusion: see full labeling.

    Lenmeldy Contraindications

    Not Applicable

    Lenmeldy Boxed Warnings

    Not Applicable

    Lenmeldy Warnings/Precautions

    Warnings/Precautions

    Increased risk for thrombosis and thromboembolic events. Evaluate the risk factors for thrombosis prior to and post-infusion. Monitor for encephalitis, thrombocytopenia, and bleeding. Monitor for infection after myeloablative conditioning and infusion; give prophylactic antimicrobials accordingly. Monitor for veno-occlusive disease including LFTs during first month post-infusion. Consider antithrombotic prophylaxis based on risk factors. Monitor neutrophil counts until engraftment is achieved. Administer rescue treatment with back-up collection of CD34+ cells if neutrophil engraftment failure occurs. Risk for insertional oncogenesis. Monitor lifelong for hematologic malignancies with CBCs (with differential) annually and integration site analysis as warranted for ≥15yrs after treatment. DMSO hypersensitivity. Patients seropositive for HIV or other infectious diseases. Assess for renal or hepatic impairment to ensure HSC transplantation is appropriate. Exclude pregnancy status prior to iniation. Advise males and females of reproductive potential to use effective contraception from start of mobilization through ≥6 months after treatment. Pregnancy, nursing mothers: not recommended (due to risks associated with myeloablative conditioning).

    Lenmeldy Pharmacokinetics

    See Literature

    Lenmeldy Interactions

    Interactions

    Concomitant vaccines: not studied. Vaccination during the 6 weeks preceding the start of myeloablative conditioning and until hematological recovery after treatment: not recommended. If feasible, give childhood vaccinations prior to myeloablative conditioning. Avoid prophylactic antiretroviral drugs for at least 1 month prior to mobilization, or the expected duration for elimination of the drugs; if needed, confirm negative HIV test prior to initiation. Avoid screening for HIV infection using a PCR-based assay; may result in a false (+) test.

    Lenmeldy Adverse Reactions

    Adverse Reactions

    Febrile neutropenia, stomatitis, respiratory tract infections, rash, device-related infections, other viral infections, pyrexia, gastroenteritis, hepatomegaly, elevated D-dimer, elevated liver enzymes, neutropenia; delayed platelet engraftment, hypersensitivity reactions (eg, anaphylaxis).

    Lenmeldy Clinical Trials

    Clinical Trials

    The approval was based on data from 37 pediatric patients with MLD treated with Lenmeldy who were enrolled in 2 open-label clinical trials or treated under expanded access frameworks. Study participants were compared with natural history data from 49 untreated patients. 

    The composite 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 (Gross Motor Function Classification-MLD [GMFC-MLD] Level ≥5) or death.

    Findings showed treatment with Lenmeldy significantly extended severe motor impairment-free survival in children with PSLI MLD compared with untreated natural history children. At 5 years old, 100% of PSLI children treated with Lenmeldy remained event-free compared with none of the children in the natural history cohort. Additionally, 12 of the 17 children who were at least 5 years old at last follow-up retained independent ambulation (GMFC-MLD level ≤1).

    Treatment with Lenmeldy significantly extended overall survival compared with untreated natural history. At 6 years from birth, all 14 PSLI MLD children with sufficient follow-up who received Lenmeldy were alive. At this timepoint, 42% (n=10) of children in the natural history cohort had died. As for cognitive function, 85% of the PSLI MLD children treated with Lenmeldy had normal language and performance IQ scores, which contrasted with natural history children who demonstrated severe cognitive impairment early in their disease course. 

    Lenmeldy was also associated with preservation of motor function and cognitive skills in children with PSEJ and ESEJ MLD.

    Lenmeldy Note

    Not Applicable

    Lenmeldy Patient Counseling

    See Literature

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