Lovotibeglogene autotemcel (Monograph)

Brand name: Lyfgenia
Drug class: Gene Therapy

Introduction

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

Uses for Lovotibeglogene autotemcel

Lovotibeglogene autotemcel has the following uses:

Lovotibeglogene autotemcel is indicated for the treatment of patients 12 years of age or older with sickle cell disease (SCD) and a history of vaso-occlusive events (VOEs). Lovotibeglogene autotemcel has been designated an orphan drug by FDA for the treatment of SCD.

Following treatment with lovotibeglogene autotemcel, patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions. Lovotibeglogene autotemcel has not been studied in patients with more than two α-globin gene deletions.

Lovotibeglogene autotemcel is an autologous hematopoietic stem cell (HSC)-based gene therapy prepared from the patient's own HSCs, which are collected via apheresis procedure(s). The autologous cells are shipped to a manufacturing site where they are enriched with CD34+ cells, then transduced with a non-replicating lentiviral vector (BB305) containing the human β^A-T87Q-globin transgene sequence; BB305 lentiviral vector encodes β^A-T87Q-globin.

Efficacy of lovotibeglogene autotemcel was evaluated in a single-arm, 24-month, open-label multicenter phase 1/2 study (Study 1-C) in adults and adolescents (12 years of age and older) with SCD. Patients underwent mobilization and apheresis, followed by myeloablative conditioning and IV infusion of lovotibeglogene autotemcel. Efficacy outcomes assessed included complete resolution of VOEs and severe VOEs between 6 and 18 months after treatment. The transplant population for VOE efficacy outcomes included a total of 32 patients who had a history of at least 4 VOEs in the 24 months prior to study entry; among these patients, complete resolution of VOEs occurred in 88% and complete resolution of severe VOEs occurred in 94% of the patients. Four patients who achieved complete resolution of VOE during the primary evaluation period experienced VOEs after this period.

Related/similar drugs

Oxbryta, voxelotor, Casgevy, Lyfgenia, exagamglogene autotemcel

Lovotibeglogene autotemcel Dosage and Administration

General

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

Lovotibeglogene autotemcel is a cell suspension for IV infusion.

A single dose of lovotibeglogene autotemcel contains a minimum of 3 × 10⁶CD34+ cells/kg of body weight, in 1 to 4 infusion bags.

Dosage

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

For autologous use only. For IV use only.

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

Myeloablative conditioning must be administered before infusion of lovotibeglogene autotemcel. Following myeloablative conditioning, allow a minimum of 48 hours of washout before lovotibeglogene autotemcel infusion.

Verify that the patient’s identity matches the unique patient identification information on the lovotibeglogene autotemcel infusion bag(s) prior to infusion.

Do not sample, alter, irradiate, or refreeze lovotibeglogene autotemcel.

Do not use an in-line blood filter or an infusion pump.

Administer lovotibeglogene autotemcel within 4 hours after thawing.

Administer each infusion bag of lovotibeglogene autotemcel via IV infusion over a period of less than 30 minutes.

Pediatric Patients

Dosage and Administration

Dosing of lovotibeglogene autotemcel is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight. The minimum recommended dose in adolescents 12 years of age or older is 3 × 10⁶ CD34+ cells/kg.

Adults

Dosage and Administration

Dosing of lovotibeglogene autotemcel is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight. The minimum recommended dose is 3 × 10⁶ CD34+ cells/kg.

Cautions for Lovotibeglogene autotemcel

Contraindications

None.

Warnings/Precautions

Warnings

Hematologic Malignancy

Hematologic malignancy has occurred in patients treated with lovotibeglogene autotemcel (Study 1, Group A). At the time of initial product approval, two patients treated with an earlier version of lovotibeglogene autotemcel using a different manufacturing process and transplant procedure (Study 1, Group A) developed acute myeloid leukemia (AML). One patient with α-thalassemia trait (Study 1, Group C) has been diagnosed with myelodysplastic syndrome (MDS).

The additional hematopoietic stress associated with mobilization, conditioning, and infusion of lovotibeglogene autotemcel, including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy.

Patients with sickle cell disease have an increased risk of hematologic malignancy as compared to the general population. Patients treated with lovotibeglogene autotemcel may develop hematologic malignancies and should have lifelong monitoring. Monitor for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment with lovotibeglogene autotemcel, and integration site analysis at Months 6, 12, and as warranted.

In the event that a malignancy occurs, contact bluebird bio at 1-833-999-6378 for reporting and to obtain instructions on collection of samples for testing.

Postmarketing long-term follow-up stduy: Patients who intend to receive treatment with lovotibeglogene autotemcel are encouraged to enroll in the study, as available, to assess the long-term safety of lovotibeglogene autotemcel and the risk of malignancies occurring after treatment with lovotibeglogene autotemcel by calling bluebird bio at 1-833-999-6378. The study includes monitoring (at pre-specified intervals) for clonal expansion.

Delayed Platelet Engraftment

Delayed platelet engraftment has been observed with lovotibeglogene autotemcel. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia. Two patients (4%) required more than 100 days post treatment with lovotibeglogene autotemcel to achieve platelet engraftment.

Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise.

Neutrophil Engraftment Failure

There is a potential risk of neutrophil engraftment failure after treatment with lovotibeglogene autotemcel. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 0.5 × 109 cells/L obtained on different days by Day 43 after infusion of lovotibeglogene autotemcel. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with lovotibeglogene autotemcel, provide rescue treatment with the back-up collection of CD34+ cells.

Insertional Oncogenesis

There is a potential risk of insertional oncogenesis after treatment with lovotibeglogene autotemcel.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of lovotibeglogene autotemcel. The dimethyl sulfoxide (DMSO) or dextran 40 in lovotibeglogene autotemcel may cause hypersensitivity reactions, including anaphylaxis. Monitor for hypersensitivity reactions during infusion.

Anti-retroviral Use

Patients should not take prophylactic HIV anti-retroviral medications for 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.

Hydroxyurea Use

Patients should not take hydroxyurea for at least 2 months prior to mobilization and until all cycles of apheresis are completed. If hydroxyurea is administered between mobilization and conditioning, discontinue 2 days prior to initiation of conditioning.

Iron Chelation

Do not administer myelosuppressive iron chelators for 6 months post-treatment with lovotibeglogene autotemcel.

Interference with PCR-based Testing

Patients who have received lovotibeglogene autotemcel are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a possible false-positive PCR assay test result for HIV. Therefore, patients who have received lovotibeglogene autotemcel should not be screened for HIV infection using a PCR-based assay.

Specific Populations

Pregnancy

There are no available data on lovotibeglogene autotemcel 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 lovotibeglogene autotemcel to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known whether lovotibeglogene autotemcel has the potential to be transferred to the fetus. Therefore, lovotibeglogene autotemcel should not be administered to women who are pregnant, and pregnancy after lovotibeglogene 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 is no information regarding the presence of lovotibeglogene autotemcel in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lovotibeglogene autotemcel and any potential adverse effects on the breastfed child from lovotibeglogene autotemcel. Therefore, lovotibeglogene autotemcel is not recommended for women who are breastfeeding, and breastfeeding after lovotibeglogene autotemcel infusion should be discussed with the treating physician.

Females and Males of Reproductive Potential

Pregnancy Testing: A negative serum pregnancy test must be confirmed prior to the start of mobilization and re‑confirmed prior to conditioning procedures and before lovotibeglogene autotemcel administration.

Contraception: There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with lovotibeglogene autotemcel. Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra-uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of lovotibeglogene autotemcel. Advise patients of the risks associated with conditioning agents.

Infertility: There are no data on the effects of lovotibeglogene autotemcel on fertility. Data are available on the risk of infertility with myeloablative conditioning. Advise patients of the risks and the options for fertility preservation.

Pediatric Use

The safety and efficacy of lovotibeglogene autotemcel have been established in pediatric patients 12 years of age and older with sickle cell disease, including 8 adolescents (age 12 years to less than 18). No clinically meaningful differences in efficacy or safety were observed between the adult and pediatric subgroups. The safety and efficacy of lovotibeglogene autotemcel in children less than 12 years of age have not been established. No data are available.

Geriatric Use

Lovotibeglogene autotemcel has not been studied in patients 65 years of age and older. Autologous hematopoietic stem cell (HSC) transplantation must be appropriate for a patient to be treated with lovotibeglogene autotemcel.

Hepatic Impairment

Lovotibeglogene autotemcel has not been studied in patients with advanced hepatic disease. Patients’ hepatic function should be assessed for hepatic impairment to ensure autologous HSC transplantation is appropriate.

Renal Impairment

Lovotibeglogene autotemcel has not been studied in patients with renal impairment (defined as creatinine clearance ≤ 70 mL/min/1.73 m²). Patients’ renal function should be assessed for renal impairment to ensure autologous HSC transplantation is appropriate.

Common Adverse Effects

Most common adverse reactions ≥ Grade 3 (incidence ≥ 20%) were stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia.

Drug Interactions

Specific Drugs

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

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.

Hydroxyurea: Discontinue 2 months prior to mobilization and 2 days prior to conditioning.

Iron chelation: Discontinue at least 7 days prior to mobilization andconditioning.

Actions

Mechanism of Action

Lovotibeglogene autotemcel adds functional copies of a modified βA-globin gene (threonine [T] replaced with glutamine [Q] at position 87, T87Q or βA-T87Q-globin) into patients’ hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with BB305 LVV. After lovotibeglogene autotemcel infusion, the transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce red blood cells containing biologically active βA-T87Q-globin that will combine with α-globin to produce functional Hb containing βA-T87Q-globin (HbAT87Q). βA-T87Q-globin can be distinguished from wildtype βA-globin and from βS -globin through reverse-phase high-performance liquid chromatography (RPHPLC) or ultra-high performance liquid chromatography (UPLC). HbAT87Q has similar oxygen-binding affinity and oxygen hemoglobin dissociation curve to wild type HbA, reduces intracellular and total hemoglobin S (HbS) levels, and is designed to sterically inhibit polymerization of HbS thereby limiting the sickling of red blood cells.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Ensure that patients understand the risk of manufacturing failure. In case of manufacturing failure or the need for additional cells, additional cell collection and manufacturing of lovotibeglogene autotemcel would be needed.

• Risks associated with mobilization and myeloablative conditioning agents.

• Advise patients that hematologic malignancy has occurred in patients treated with lovotibeglogene autotemcel. Patients with sickle cell disease have an increased risk of hematologic malignancy as compared to the general population. The additional hematopoietic stress associated with mobilization, conditioning, and infusion of lovotibeglogene autotemcel, including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy.

• Advise patients that delayed platelet engraftment has been observed with lovotibeglogene autotemcel. Patients should be made aware of the risk of bleeding until platelet recovery has been achieved.

• Advise patients of the risk of neutrophil engraftment failure. Patients who experience neutrophil engraftment failure will receive rescue treatment with their back-up collection of CD34+ cells.

• Advise patients of the potential risk of insertional oncogenesis after treatment with lovotibeglogene autotemcel.

• Advise patients that they should be monitored lifelong. Monitoring will include assessment for hematologic malignancies with a complete blood count at least every 6 months for at least 15 years after treatment with lovotibeglogene autotemcel. This will include integration site analysis at Months 6, 12, and as warranted.

• Advise patients to have their treating physician contact bluebird bio at 1-833-999-6378 if they are diagnosed with a malignancy.

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

• Advise patients that they may test positive for HIV if tested using a PCR assay after being treated with lovotibeglogene autotemcel.

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

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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