Lenmeldy

Lenmeldy is a gene therapy used to treat types of metachromatic leukodystrophy in children. Lenmeldy works by helping the body make the ARSA enzyme to help stop the progression of MLD. It does this using the patient's own stem cells that have been modified. Lenmeldy is given as a one-time infusion.

Lenmeldy is FDA-approved 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).

Lenmeldy FDA approval was received on March 18, 2024.

Metachromatic leukodystrophy is a rare and severe genetic condition that affects the brain and nervous system. Metachromatic leukodystrophy is caused by a faulty gene, which means that the body does not make enough of an enzyme called arylsulfatase A (ARSA). That lack of ARSA causes fatty substances called sulfatides to build up in the brain and nerves, leading to problems with movement and thinking abilities, severe spasticity, seizures, and patients gradually losing the ability to move, talk, swallow, eat, and see. Lenmeldy therapy replaces the faulty gene in the stem cells with an effective gene so that the body is now able to make the ARSA enzyme, which helps break down the harmful build-up of sulfatides and may stop the progression of MLD.

Lenmeldy therapy starts with a treatment called hematopoietic stem cell (HSC) mobilization; this is when the patient is given a medication that helps move stem cells from the bone marrow to the blood so that they can be collected. The stem cells are then genetically modified to include working copies of the ARSA gene, and this is the Lenmeldy infusion. Before receiving the Lenmeldy infusion, the patient had chemotherapy (myeloablative conditioning) to remove cells from the bone marrow so there is space for the new modified stem cells. Lenmeldy is then given a one-time, single-dose infusion, and the newly modified stem cells attach and multiply in the bone marrow. The newly modified stem cells enable the body to make the ARSA enzyme, which helps break down the harmful build-up of sulfatides and may stop the progression of MLD.

Lenmeldy is given as a one-time single-dose intravenous infusion.

Before the infusion can be done, the patient will have treatments to prepare the Lenmeldy infusion and prepare the body for the infusion. First, the patient will have treatment to mobilize their stem cells, which will be collected. The patient will then have chemotherapy to prepare the bone marrow, and then the patient will have their own Lenmeldy infusion.

A collection of unmanipulated back-up stem cells is required in case of manufacturing failure. These cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning.

The child must only receive Lenmeldy that has been made from the child’s own stem cells.

For more detailed information on the administration process, see Prescribing Information: Administration and Dosage.

Thrombosis and Thromboembolic Events: A risk of blood clots may occur. Seek immediate medical attention if your child has 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.

Brain inflammation (Encephalitis): Children should be monitored for signs or symptoms of encephalitis after treatment, including neurological deterioration such as weakness, decreased muscle tone, cognitive deterioration, behavioral problems, vomiting, and swallowing difficulties.

Serious Infection: Monitor children for serious infection.

Small blood vessels that lead into and are inside the liver become blocked (veno-occlusive disease (VOD)): Monitor children for signs and symptoms of VOD, including liver function tests in all patients during the first month after treatment, and consider prophylaxis for VOD.

Delayed Platelet Engraftment: A risk of bleeding exists after myeloablative conditioning and before platelet engraftment. Seek immediate medical attention for new or worsening bleeding or bruising.

Risk of Neutrophil Engraftment Failure: Monitor absolute neutrophil counts (ANC) after infusion. If neutrophil engraftment does not occur, administer rescue cells.

Risk of Insertional Oncogenesis: There is a potential risk of insertional oncogenesis after treatment with Lenmeldy. Children should be monitored lifelong, including assessment for hematologic malignancies annually for at least 15 years after treatment.

Risk of Hypersensitivity Reactions: Monitor for hypersensitivity reactions during infusion.

Anti-retroviral Use: Children should not take prophylactic HIV anti-retroviral medications for at least one month prior to mobilization or for the expected duration of time needed for the elimination of the medications. Anti-retroviral medications may interfere with the manufacturing of Lenmeldy. If a child requires antiretrovirals for HIV prophylaxis, initiation of treatment should be delayed until confirmation of a negative test for HIV.

Interference with Serology Testing: Children who have received this stem cell infusion 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.

Before your child is given Lenmeldy, the doctor will:

• Check your child’s lungs, heart, kidney, liver, as well as blood pressure.
• Look for signs of infection; any infection will be treated before your child is given this medicine.
• Check for hepatitis B, hepatitis C, human T-cell lymphotropic virus (HTLV), cytomegalovirus (CMV), HIV, or mycoplasm infection.
• Check if your child had a vaccination in the previous 6 weeks or if one is planned in the next few months.

Lenmeldy is made from your child’s own stem cells and should only be given to your child.

Patients who have received Lenmeldy should not donate blood, organs, tissues, or cells at any time in the future.

The most common Lenmeldy side effects were fever with low neutrophil count (85%), inflammation inside of the mouth (77%), respiratory tract infections (54%), rash (33%), device-related infections (31%), other viral infections (28%), fever (21%), gastroenteritis (21%), and an enlarged liver(18%). These are the side effects that happened in 10% or more of all children within one year of treatment and do not include laboratory adverse reactions.

The most common Lenmeldy laboratory abnormalities were elevated D-dimer (67%), neutropenia (28%), and elevated liver enzymes (23%).

Other clinically significant side effects are listed in the Warnings section.

Dosing of Lenmeldy infusion is based on the child's MLD disease subtype and the child's weight.

Tell your doctor if your child is taking, has recently taken, or might take any other medicines or vaccines.

• Vaccinations are not recommended during the 6 weeks before the start of myeloablative conditioning and until hematological recovery following treatment with Lenmeldy.
• Your child should not take any anti-retroviral medications for at least one month before the mobilization medicines or the expected duration for elimination of the medications as the anti-retroviral medications may interfere with the manufacturing of Lenmeldy.

Manufactured for: Orchard Therapeutics North America Boston, MA 02210