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Lovotibeglogene Autotemcel

FDA Drug Information • Also known as: Lyfgenia

Brand Names
Lyfgenia
Route
INTRAVENOUS
Dosage Form
SUSPENSION
Product Type
CELLULAR THERAPY

⚠ Boxed Warning (Black Box)

WARNING: HEMATOLOGIC MALIGNANCY Hematologic malignancy has occurred in patients treated with LYFGENIA. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through integration site analysis at Months 6, 12, and as warranted [see Warnings and Precautions (5.1) ]. WARNING: HEMATOLOGIC MALIGNANCY See full prescribing information for complete boxed warning. Hematologic malignancy has occurred in patients treated with LYFGENIA. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through integration site analysis at Months 6, 12, and as warranted. ( 5.1 )

Description

11 DESCRIPTION LYFGENIA (lovotibeglogene autotemcel) is a β A-T87Q -globin gene therapy consisting of autologous CD34+ cells from patients with sickle cell disease containing hematopoietic stem cells (HSCs) transduced with BB305 LVV encoding β A-T87Q -globin, suspended in cryopreservation solution. LYFGENIA is intended for one-time administration to add functional copies of a modified form of the β-globin gene (β A-T87Q -globin gene) into the patient's own HSCs. LYFGENIA is prepared using the patient's own HSCs, which are collected via apheresis procedure(s). The autologous cells are enriched for CD34+ cells, then transduced ex vivo with BB305 LVV. The promoter, a regulatory element that controls the expression of the transgene selected for BB305 LVV, is a cellular (non-viral) promoter that controls gene expression specific to the erythroid lineage cells (red blood cells and their precursors). BB305 LVV encodes β A-T87Q -globin. The transduced CD34+ cells are washed, formulated into a suspension, and then cryopreserved. LYFGENIA is frozen in a patient-specific infusion bag(s) and is thawed prior to administration [see Dosage and Administration (2.2) , How Supplied/Storage and Handling (16) ] . The thawed product is colorless to white to red, including shades of white or pink, light yellow, and orange, and may contain small proteinaceous particles. Due to the presence of cells, the solution may be clear to slightly cloudy and may contain visible cell aggregates. The formulation contains 5% dimethyl sulfoxide (DMSO).

What Is Lovotibeglogene Autotemcel Used For?

1 INDICATIONS AND USAGE LYFGENIA is indicated for the treatment of patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events. LYFGENIA is an autologous hematopoietic stem cell-based gene therapy indicated for the treatment of patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events. ( 1 ) Limitations of Use Following treatment with LYFGENIA, patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions. LYFGENIA has not been studied in patients with more than two α-globin gene deletions. ( 1 ) Limitations of Use Following treatment with LYFGENIA, patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions [see Adverse Reactions (6.1) ] . LYFGENIA has not been studied in patients with more than two α-globin gene deletions.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION For autologous use only. For one-time single-dose intravenous use only. For autologous use only. For intravenous use only. Patients are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34+ cells for LYFGENIA manufacturing. ( 2.2 ) Dosing of LYFGENIA is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight. ( 2.1 ) The minimum recommended dose is 3 × 10 6 CD34+ cells/kg. ( 2.1 ) Myeloablative conditioning must be administered before infusion of LYFGENIA. ( 2.2 ) Following myeloablative conditioning, allow a minimum of 48 hours of washout before LYFGENIA infusion. ( 2.2 ) Verify that the patient's identity matches the unique patient identification information on the LYFGENIA infusion bag(s) prior to infusion. ( 2.2 ) Do not sample, alter, irradiate, or refreeze LYFGENIA. ( 2.2 ) Do not use an in-line blood filter or an infusion pump. ( 2.3 ) Administer LYFGENIA within 4 hours after thawing. ( 2.3 ) Administer each infusion bag of LYFGENIA via intravenous infusion over a period of less than 30 minutes. ( 2.3 ) 2.1 Dose LYFGENIA is provided as a single dose for infusion containing a suspension of CD34+ cells in one to four infusion bags. The minimum recommended dose of LYFGENIA is 3 × 10 6 CD34+ cells/kg. See the Lot Information Sheet provided with the product shipment for additional information pertaining to dose. 2.2 Preparation Before LYFGENIA Infusion Confirm that autologous hematopoietic stem cell (HSC) transplantation is appropriate for the patient before mobilization and apheresis and before myeloablative conditioning are initiated. Perform screening for infectious diseases, specifically human immunodeficiency virus 1 & 2 (HIV-1/HIV-2), in accordance with clinical guidelines before collection of cells for manufacturing. There are no data on use of LYFGENIA in HIV-positive patients. Prepare for Mobilization and Apheresis Prepare patients for mobilization with at least 2 cycles of scheduled transfusions (one each month) with erythrocytapheresis being preferred. For at least 60 days prior to mobilization and through myeloablative conditioning, patients should undergo a transfusion regimen to reach a target Hb of 8-10 g/dL, not to exceed 12 g/dL, and HbS of less than 30% to reduce the risk of SCD-related complications. Perform erythrocytapheresis within a recommended 4 days preceding mobilization to reach the target of less than 30% HbS. Manage other concomitant medications (as applicable) as described below: Hydroxyurea: Discontinue at least 2 months prior to mobilization. Patients should not resume hydroxyurea until all cycles of apheresis are completed. Disease-modifying agents (e.g., L-glutamine, voxelotor and crizanlizumab): Discontinue at least 2 months prior to mobilization as the interaction between disease modifying agents and mobilization agents is unknown. Erythropoietin: Discontinue at least 2 months prior to mobilization. Iron...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: Hematologic Malignancy [see Warnings and Precautions (5.1) ] Delayed Platelet Engraftment [see Warnings and Precautions (5.2) ] Neutrophil Engraftment Failure [see Warnings and Precautions (5.3) ] Insertional Oncogenesis [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions ≥ Grade 3 (incidence ≥ 20%) were stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact bluebird bio at 1-833-999-6378 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety was based on patients with sickle cell disease in one open-label, single-arm clinical trial and one long-term follow-up study. Of the 54 patients who initiated stem cell collection, the median (min, max) age across the studies was 25 (12, 43) years, 63% were males, 89% were Black or African American, 2% were Asian, 2% White/Caucasian and 4% were not reported. The median (min, max) duration of follow-up was 42 (12, 87) months. Mobilization and apheresis triggered SAEs of sickle cell crisis in 6 (14%, 6/44) patients who initiated mobilization in the intent-to-treat population. All patients who initiated conditioning (100%, 45/45) experienced at least one adverse event attributed to conditioning. The majority of conditioning-attributed events were non-serious and were consistent with the known effects of alkylating agents. Thirty-three (73%, 33/45) patients who received LYFGENIA experienced at least one serious adverse event (SAE). Most SAEs were related to conditioning or underlying disease. Table 1 presents the adverse drug reactions following treatment with LYFGENIA (Day 1) to Month 24. Table 1: Adverse Reactions ≥ Grade 3 (> 5%) Following Treatment with LYFGENIA from Day 1 to Month 24 (N = 45) Includes adverse events associated with busulfan myeloablative conditioning and underlying sickle cell disease. Adverse Reaction Grade 3 or Higher n (%) Blood and lymphatic system disorders -- Thrombocytopenia 31 (69) Neutropenia 27 (60) Febrile neutropenia 20 (44) Anemia Includes a patient with α-thalassemia trait who was diagnosed with myelodysplastic syndrome after Month 24. 15 (33) Leukopenia 15 (33) Sickle cell anemia with crisis Includes events prior to Month 6 and non-adjudicated occurrences. 7 (16) Gastrointestinal disorders -- Stomatitis 32 (71) Nausea 4 (9) General disorders and administration site conditions -- Pyrexia 3 (7) Infections and infestations -- Bacteremia 3 (7) Investigations -- Aspartate aminotransferase increased 8 (18) Alanine aminotransferase increased 6 (13) Gamma-glutamyl transferase increased 6 (13) Blood bilirubin increased 3 (7) Metabolism and nutrition disorders -- Decreased appetite 5 (11) Respiratory, thoracic, and mediastinal disorders -- Pharyngeal inflammation 5 (11) Three patients died during LYFGENIA clinical trials; one from sudden cardiac death due to underlying disease and two from acute myeloid leukemia who were treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A). Anemia Two patients developed anemia following LYFGENIA treatment; one patient continues to require monthly packed red blood cell (pRBC) transfusions. The other patient has been diagnosed with MDS. Both subjects had α-thalassemia trait (-α3.7 /-α3.7) [see Limitations of Use (1) ]. Infusion-related reactions to LYFGENIA Pre-medication for infusion reactions was managed at physician discretion. Infusion-related reactions to LYFGENIA were observed in 2 patients on the day of...

Drug Interactions

7 DRUG INTERACTIONS No formal drug interaction studies have been performed. LYFGENIA is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters. Anti-retrovirals : Discontinue anti-retroviral medications at least one month prior to mobilization and until all cycles of apheresis are completed. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication. ( 7.2 ) Hydroxyurea : Discontinue 2 months prior to mobilization and 2 days prior to conditioning. ( 7.3 ) Iron chelation : Discontinue at least 7 days prior to mobilization and conditioning. ( 7.4 ) 7.1 Live Vaccines Follow institutional guidelines for vaccine administration. The safety of immunization with live viral vaccines during or following LYFGENIA treatment has not been studied. Recommendations for vaccination schedules should be followed as per guidelines post-autologous hematopoietic stem cell transplant and functional asplenia. 7.2 Anti-retrovirals Patients should not take anti-retroviral medications for at least one month prior to mobilization for required and until all cycles of apheresis are completed [see Warnings and Precautions (5.6) ] . There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication. Anti-retroviral medications may interfere with manufacturing of LYFGENIA. 7.3 Hydroxyurea Patients should not take hydroxyurea for at least 2 months prior to mobilization and until all cycles of apheresis are completed and should discontinue 2 days prior to initiation of conditioning [see Warnings and Precautions (5.7) ]. 7.4 Iron Chelation Drug-drug interactions between iron chelators and the mobilization process and myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of mobilization or conditioning. Myelosuppressive iron chelators (e.g., deferiprone) should be restarted no sooner than 6 months after LYFGENIA infusion [see Warnings and Precautions (5.8) ] . Non-myelosuppressive iron chelation should be restarted no sooner than 3 months after LYFGENIA infusion. Phlebotomy can be used in lieu of iron chelation, when appropriate.

Contraindications

4 CONTRAINDICATIONS None. None. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary There are no available data on LYFGENIA administration in pregnant women. Consider the risks associated with myeloablative conditioning agents on pregnancy and fertility. No reproductive and developmental toxicity studies in animals have been conducted with LYFGENIA to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known whether LYFGENIA has the potential to be transferred to the fetus. Therefore, LYFGENIA should not be administered to women who are pregnant, and pregnancy after LYFGENIA 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING LYFGENIA is supplied in one to four infusion bags containing a frozen suspension of genetically modified autologous cells, enriched for CD34+ cells. Each bag contains approximately 20 mL. Each infusion bag is individually packed within an overwrap in a metal cassette. LYFGENIA is shipped from the manufacturing facility to the treatment center storage facility in a cryoshipper, which may contain multiple metal cassettes intended for a single patient. A Lot Information Sheet is affixed inside the shipper. 20 mL infusion bag, overwrap, and metal cassette (NDC 73554-1111-1) Match the identity of the patient with the patient identifiers on the metal cassette(s), infusion bag(s), and Lot Information Sheet upon receipt. Keep the infusion bag(s) in the metal cassette(s) and store in the vapor phase of liquid nitrogen at less than or equal to -140°C (≤ -220°F) until ready for thaw and administration. Thaw LYFGENIA prior to infusion [see Dosage and Administration (2.2) ]. Do not re-freeze after thawing. Do not irradiate LYFGENIA, as this could lead to inactivation.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.