Lovotibeglogene autotemcel is an intravenous autologous hematopoietic stem cell-based gene therapy indicated for the treatment of sickle cell disease in persons with a history of vaso-occlusive events (VOEs). Lovotibeglogene autotemcel adds functional copies of a modified betaA-globin gene into subjects' hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with BB305 lentiviral vector (LVV). After lovotibeglogene autotemcel infusion, the transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce functional hemoglobin. Efficacy and safety of lovotibeglogene autotemcel was evaluated in a single-arm, 24-month, open-label, multicenter phase 1/2 clinical trial and continued on a long-term follow-up clinical trial (n = 32). The efficacy outcomes were complete resolution of VOEs (VOE-CR) and severe VOEs (sVOE-CR) between 6 months and 18 months after infusion of lovotibeglogene autotemcel. VOE-CR and sVOE-CR occurred in 88% (95% CI 71% to 97%) and 94% (95% CI 79% to 99%) of lovotibeglogene autotemcel-treated subjects, respectively. Delayed platelet engraftment has been reported with lovotibeglogene autotemcel and there is a potential risk for neutrophil engraftment failure and new hematologic malignancy after treatment with lovotibeglogene autotemcel. Lovotibeglogene autotemcel has not been studied in persons with more than 2 alpha-globin gene deletions.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Lovotibeglogene autotemcel may carry the risk of transmitting infectious diseases to health care professionals handling the product. Follow universal precautions and biosafety guidelines for handling and disposal of lovotibeglogene autotemcel.
-Allow a minimum of 48 hours after completion of myeloablative conditioning before lovotibeglogene autotemcel infusion.
Route-Specific Administration
Injectable Administration
-Visually inspect each infusion bag for any breaches of integrity before thawing and infusion. If an infusion bag is compromised, follow local guidelines.
Intravenous Administration
Preparation
-Coordinate the timing of lovotibeglogene autotemcel thaw and infusion; confirm the infusion time in advance and adjust the start time for thaw so that the recipient and care team are ready.
-Remove each metal cassette from liquid nitrogen storage and each infusion bag from the metal cassette. Confirm that lovotibeglogene autotemcel is printed on the infusion bag(s).
-Confirm that recipient identity matches the unique personal identification information located on the lovotibeglogene autotemcel infusion bag(s). Do not infuse if the information on the recipient-specific label on the infusion bag does not match the intended recipient.
-Ensure the correct number of infusion bags are present. Use the accompanying Lot Information Sheet to confirm that each infusion bag is within the expiration date.
-Thaw the infusion bag(s) at 37 degrees C (98.6 degrees F) in a water bath or dry bath. Thawing of each infusion bag takes approximately 2 to 4 minutes. Do not leave unattended and do not submerge the infusion ports in a water bath. If more than 1 infusion bag is provided, thaw and administer each infusion completely before proceeding to thaw the next infusion bag. Maintain any additional infusion bag(s), if applicable, at -140 degrees C (-220 degrees F) or less until time to thaw.
-After thawing, mix the contents gently by massaging the infusion bag to disperse clumps of cellular material until all the contents are uniform. If visible cell clumps remain, continue to gently mix the contents of the bag; most small clumps of cellular material should disperse with gentle manual mixing.
-Do not filter, wash, spin down, and/or resuspend lovotibeglogene autotemcel in new media before infusion.
-Do not sample, alter, irradiate or refreeze lovotibeglogene autotemcel.
-Storage: Infuse lovotibeglogene autotemcel as soon as possible after thawing and complete the infusion within 4 hours.
Intravenous (IV) Infusion
-Confirm the recipient's identity with the personal identifiers on the infusion bag. Confirm the total number of infusion bags with the Lot Information Sheet.
-If more than 1 infusion bag is provided, thaw and administer each infusion completely before proceeding to thaw the next infusion bag.
-Do not use an in-line blood filter or an infusion pump.
-Administer each bag by IV infusion over a period of less than 30 minutes.
-Flush all lovotibeglogene autotemcel remaining in the infusion bag(s) and the tubing with at least 50 mL of 0.9% Sodium Chloride Injection to ensure as many cells as possible are infused into the patient.
-Repeat steps for each infusion bag.
Hypersensitivity or anaphylactoid reactions, including anaphylaxis, may occur with lovotibeglogene autotemcel infusion due to the dimethyl sulfoxide (DMSO) component. Infusion-related reactions, including flushing and decreased diastolic blood pressure (hypotension), were reported in 2 subjects on the day of lovotibeglogene autotemcel infusion. Both infusion-related reactions resolved and were grade 1. Pre-medication for infusion-related reactions was managed at physician discretion in lovotibeglogene autotemcel clinical trials.
Gastrointestinal adverse reactions, including nausea (grade 3 or more, 9%), stomatitis (grade 3 or more, 71%), and anorexia (grade 3 or more, 11%) were reported with lovotibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials.
In clinical trials, grade 3 or 4 hematologic laboratory abnormalities that occurred between the start of conditioning and 24 months after lovotibeglogene autotemcel treatment included anemia (33%), sickle cell anemia with sickle-cell crisis (16%), leukopenia (33%), neutropenia (60%), febrile neutropenia (44%), and thrombocytopenia (69%). Anemia was reported in 2 subjects after lovotibeglogene autotemcel treatment; 1 subject continues to require monthly packed red blood cell transfusions and the other subject has been diagnosed with myelodysplastic syndrome. Both subjects had alpha-thalassemia trait (-alpha3.7/-alpha 3.7). Platelet engraftment was achieved in all subjects; the median (range) time to platelet engraftment was 37 days (19 to 235 days) after lovotibeglogene autotemcel infusion. Delayed platelet engraftment after day 100 was observed in 2 subjects (4%) treated with lovotibeglogene autotemcel; 1 of these subjects was administered eltrombopag until day 234. Platelet engraftment is defined as 3 consecutive platelet counts of 50,000 cells/mm3 or more obtained on different days after the initial post-transplant nadir without receiving any platelet transfusions for 7 days immediately preceding and during the evaluation period. Monitor for thrombocytopenia and bleeding according to standard guidelines. Perform frequent platelet counts until platelet engraftment and platelet recovery are achieved. When clinical symptoms suggestive of bleeding are observed, perform blood cell count determination and other appropriate testing. Neutrophil engraftment failure, defined as failure to achieve 3 consecutive absolute neutrophil counts (ANC) of 500 cells/mm3 or more obtained on different days by day 43 after lovotibeglogene autotemcel infusion, is a potential risk with lovotibeglogene autotemcel. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a person treated with lovotibeglogene autotemcel, provide rescue treatment with the back-up collection of CD34+ cells. However, all subjects in clinical trials achieved neutrophil engraftment after treatment with lovotibeglogene autotemcel. The median (range) time to neutrophil engraftment was 20 (12 to 35) days after lovotibeglogene autotemcel infusion. New primary malignancy has occurred in subjects treated with lovotibeglogene autotemcel. At the time of initial product approval, 2 subjects treated with an earlier version of lovotibeglogene autotemcel using a different manufacturing process and transplant procedure developed acute myeloid leukemia; both of these subjects died during lovotibeglogene autotemcel clinical trials. A single subject with alpha-thalassemia trait (-alpha3.7/-alpha 3.7) who received lovotibeglogene autotemcel has been diagnosed with myelodysplastic syndrome.
Infection (bacteremia) (grade 3 or more, 7%) and pharyngeal inflammation (grade 3 or more, 11%) were reported with lovotibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials.
Elevated hepatic enzymes, including increased aspartate aminotransferase (grade 3 or more, 18%), increased alanine aminotransferase (grade 3 or more, 13%), and increased gamma-glutamyl transferase (grade 3 or more, 13%), and hyperbilirubinemia (grade 3 or more, 7%) were reported with lovotibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials.
Fever (grade 3 or more, 7%) was reported with lovotibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials.
Sudden cardiac death (cardiac arrest) was reported in 1 subject in lovotibeglogene autotemcel clinical trials.
Lovotibeglogene autotemcel has not been studied in persons with human immunodeficiency virus (HIV) infection (i.e., HIV-1, HIV-2). A negative serology test for HIV is necessary prior to apheresis. Persons with a positive test for HIV will not be accepted for lovotibeglogene autotemcel treatment. Do not screen persons treated with lovotibeglogene autotemcel for HIV infection using a polymerase chain reaction (PCR)-based assay due to laboratory test interference. Persons who have received lovotibeglogene autotemcel are likely to test positive by PCR assays for HIV due to integrated BB305 lentiviral vector (LVV) proviral DNA, resulting in a false-positive test for HIV.
The safety of immunization with live viral vaccines during or after lovotibeglogene autotemcel treatment has not been studied. Follow institutional guidelines for vaccination and recommendations for vaccination schedules as per guidelines post-autologous hematopoietic stem cell transplant and functional asplenia.
Lentiviral vector (LVV)-mediated insertional oncogenesis is a potential risk after treatment with lovotibeglogene autotemcel. New primary malignancy, such as hematologic malignancy, may develop after treatment with lovotibeglogene autotemcel. The additional hematopoietic stress associated with mobilization, conditioning, and lovotibeglogene autotemcel infusion, including the need to regenerate the hematopoietic system, may increase the risk of hematologic malignancy. Persons with sickle cell disease have an increased risk of hematologic malignancy compared to the general population. Persons treated with lovotibeglogene autotemcel have an increased risk of hematologic malignancy and lifelong monitoring is necessary. 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 through integration site analysis at 6 and 12 months and as warranted. If a malignancy occurs, contact the manufacturer at 1-833-999-6378 to report and obtain instructions on collection of samples for testing. Persons who plan to receive treatment with lovotibeglogene autotemcel are encouraged to enroll in a study to assess the long-term safety of lovotibeglogene autotemcel and the risk of malignancies occurring after treatment with lovotibeglogene autotemcel by contacting the manufacturer at 1-833-999-6378; the study includes monitoring at pre-specified intervals for clonal expansion.
Platelet engraftment is defined as 3 consecutive platelet counts of 50,000 cells/mm3 or more obtained on different days after the initial post-transplant nadir without receiving any platelet transfusions for 7 days immediately preceding and during the evaluation period. Delayed platelet engraftment has been reported with lovotibeglogene autotemcel. Bleeding risk is increased before platelet engraftment and may continue after engraftment in persons with prolonged thrombocytopenia. Monitor for thrombocytopenia and bleeding according to standard guidelines. Perform frequent platelet counts until platelet engraftment and platelet recovery are achieved. When clinical symptoms suggestive of bleeding are observed, perform blood cell count determination and other appropriate testing.
Advise persons to avoid cell, organ, tissue, and blood donation after receiving treatment with lovotibeglogene autotemcel. Irradiate any blood products required within the first 3 months after lovotibeglogene autotemcel infusion.
Persons with alpha thalassemia trait (-alpha3.7/-alpha3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions after treatment with lovotibeglogene autotemcel. Lovotibeglogene autotemcel has not been studied in persons with more than two alpha-globin gene deletions.
Do not administer lovotibeglogene autotemcel during pregnancy. Advise females of reproductive potential who wish to become pregnant or think that they may be pregnant after treatment with lovotibeglogene autotemcel to discuss pregnancy with their care team. There are no data on lovotibeglogene autotemcel administration in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with lovotibeglogene autotemcel to assess whether it can cause fetal harm when administered to a pregnant woman.
Lovotibeglogene autotemcel is not recommended for use during breast-feeding. Advise mothers who wish to breast-feed after lovotibeglogene autotemcel treatment to discuss breast-feeding with their care team. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for lovotibeglogene autotemcel and any potential adverse effects on the breast-fed child from lovotibeglogene autotemcel. There is no information on the presence of lovotibeglogene autotemcel in human milk, the effect on the breast-fed infant, or the effects on milk production.
Lovotibeglogene autotemcel may be associated with reproductive risk. Confirm the absence of pregnancy with serum pregnancy testing before the start of mobilization, and reconfirm with a negative serum pregnancy test before conditioning procedures and before lovotibeglogene autotemcel administration. Discuss contraception requirements with the patient. Advise persons of childbearing potential and their partners capable of fathering a child to use an effective method of contraception (i.e., intra-uterine device or combination of hormonal and barrier contraception) from start of mobilization though at least 6 months after lovotibeglogene autotemcel administration. There are insufficient data to provide a precise recommendation on duration of contraception after lovotibeglogene autotemcel treatment. There are no data on the effect of lovotibeglogene autotemcel on fertility; however, data are available on the risk of infertility with myeloablative conditioning. Advise persons of reproductive potential of the risks and the options for fertility preservation.
General dosing information
-Allow a minimum of 48 hours after completion of myeloablative conditioning before lovotibeglogene autotemcel infusion.
For the treatment of sickle cell disease in persons with a history of vaso-occlusive events:
NOTE: Lovotibeglogene autotemcel has been designated an orphan drug by the FDA for the treatment of sickle cell disease.
Intravenous dosage:
Adults: 3 x 10 to the 6th power CD34+ cells/kg IV as a single dose is the minimum recommended dose. In clinical trials, 6.4 x 10 to the 6th power CD34+ cells/kg IV was the median dose and 14 x 10 to the 6th power CD34+ cells/kg IV was the maximum dose.
Children and Adolescents 12 to 17 years: 3 x 10 to the 6th power CD34+ cells/kg IV as a single dose is the minimum recommended dose. In clinical trials, 6.4 x 10 to the 6th power CD34+ cells/kg IV was the median dose and 14 x 10 to the 6th power CD34+ cells/kg IV was the maximum dose.
Maximum Dosage Limits:
-Adults
14 x 106 CD34+ cells/kg IV as a single dose.
-Geriatric
14 x 106 CD34+ cells/kg IV as a single dose.
-Adolescents
14 x 106 CD34+ cells/kg IV as a single dose.
-Children
12 years: 14 x 106 CD34+ cells/kg IV as a single dose.
1 to 11 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Colony Stimulating Factors: (Major) Avoid administration of granulocyte-colony stimulating factors for 21 days after lovotibeglogene autotemcel infusion.
Deferasirox: (Major) Avoid use of deferasirox for 6 months after lovotibeglogene autotemcel infusion due to risk of myelosuppression. If iron chelation is needed, may consider administration of non-myelosuppressive iron chelators (i.e., deferoxamine) 3 months after lovotibeglogene autotemcel infusion. Phlebotomy can be used instead of iron chelation, when appropriate.
Deferiprone: (Major) Avoid use of deferiprone for 6 months after lovotibeglogene autotemcel infusion due to risk of myelosuppression. If iron chelation is needed, may consider administration of non-myelosuppressive iron chelators (i.e., deferoxamine) 3 months after lovotibeglogene autotemcel infusion. Phlebotomy can be used instead of iron chelation, when appropriate.
Deferoxamine: (Major) Avoid use of deferoxamine for 3 months after lovotibeglogene autotemcel infusion. Phlebotomy can be used instead of iron chelation, when appropriate.
Eflapegrastim: (Major) Avoid administration of granulocyte-colony stimulating factors for 21 days after lovotibeglogene autotemcel infusion.
Filgrastim, G-CSF: (Major) Avoid administration of granulocyte-colony stimulating factors for 21 days after lovotibeglogene autotemcel infusion.
Pegfilgrastim: (Major) Avoid administration of granulocyte-colony stimulating factors for 21 days after lovotibeglogene autotemcel infusion.
Tbo-Filgrastim: (Major) Avoid administration of granulocyte-colony stimulating factors for 21 days after lovotibeglogene autotemcel infusion.
Lovotibeglogene autotemcel is an autologous hematopoietic stem cell (HSC)-based gene therapy that adds functional copies of a modified betaA-globin gene (threonine [T] replaced with glutamine [Q] at position 87, T87Q or betaA-T87Q-globin) into subjects' HSCs through transduction of autologous CD34+ cells with BB305 lentiviral vector (LVV), a cellular non-viral promoter that controls gene expression for red blood cells (RBCs) and their precursors. BB305 LVV encodes betaA-T87Q-globin. After lovotibeglogene autotemcel infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce RBCs containing biologically active betaA-T87Q-globin that will combine with alpha-globin to produce functional hemoglobin containing betaA-T87Q-globin (HbAT87Q). BetaA-T87Q-globin can be distinguished from wildtype betaA-globin and from betaS-globin through reverse-phase high performance liquid chromatography (RPHPLC) or ultra-high performance liquid chromatography (UPLC). HbAT87Q has similar oxygen-binding capacity affinity and oxygen hemoglobin dissociation curve to wild type HbA, reduces intracellular and total hemoglobin S (HbS) concentrations, and is designed to sterically inhibit polymerization of HbS, limiting the sickling of RBCs.
Lovotibeglogene autotemcel is administered intravenously. Conventional pharmacokinetic parameters of absorption, distribution, metabolism, and elimination are not applicable to lovotibeglogene autotemcel as this medication is an autologous gene therapy which includes hematopoietic stem cells that have been genetically modified ex vivo.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Intravenous Route
BetaA-T87Q-globin (HbAT87Q) generally increased steadily after lovotibeglogene autotemcel infusion and stabilized by approximately month 6 after infusion. The median (minimum, maximum) HbAT87Q at month 6 was 5.2 (2.6, 8.8) g/dL in an ongoing phase 1/2 clinical trial (n = 33). HbAT87Q remained durable with a median (minimum, maximum) of 5.5 (2.4, 9.4) g/dL at month 24 (n = 34). Additionally, HbAT87Q comprised a median (minimum, maximum) of 45.7% (26.9%, 63.2%) of total non-transfused hemoglobin at month 24. Expression of HbAT87Q remained durable through month 48 (n = 10), demonstrating sustained expression of the betaA-T87Q protein derived from irreversible integration of the betaA-T87Q-globin gene into long-term hematopoietic stem cells.