Betibeglogene Autotemcel (Monograph)

Brand name: Zynteglo
Drug class: Gene Therapy

Introduction

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

Uses for Betibeglogene Autotemcel

Betibeglogene autotemcel has the following uses:

Betibeglogene autotemcel is indicated for the treatment of adult and pediatric patients with β-thalassemia who require regular red blood cell (RBC) transfusions. Betibeglogene autotemcel has been designated an orphan drug by FDA for the treatment of β-thalassemia major and intermedia.

β-thalassemia is a group of inherited hemoglobinopathies caused by mutations in the β-globin gene leading to reduced or absent expression of -globin in erythropoietic cells.

Betibeglogene autotemcel is an autologous HSC-based gene therapy prepared from the patient's HSCs, which are collected via apheresis procedure(s). The collected cells are shipped to the manufacturing site where CD34+ cells are selected and then transduced with BB305 lentiviral vector (LVV) encoding a modified form of the β-globin gene.

Efficacy of betibeglogene autotemcel was evaluated in 2 ongoing phase 3 open-label, single-arm, 24-month, multicenter studies in patients 4–34 years of age with β-thalassemia requiring regular transfusions. Patients underwent hematopoietic cell mobilization and apheresis followed by full myeloablative conditioning prior to receiving betibeglogene autotemcel as an IV infusion. In both studies, efficacy of betibeglogene autotemcel was established based on achievement of transfusion independence (TI), defined as a weighted average hemoglobin (Hb) 9 g/dL without any packed RBC transfusions for a continuous period of 12 months at any time during the study, after infusion. Among 22 evaluable patients in the first study, 20 (91%) achieved TI with a median weighted average Hb during TI of 11.8 g/dL. Among 14 evaluable patients in the second study, 12 (86%) achieved TI with a median weighted average Hb during TI of 10.2 g/dL. All 32 patients in these studies who achieved TI with betibeglogene autotemcel maintained TI; these patients exhibited durable normal or near-normal total Hb levels with a median unsupported total Hb of 11.4 g/dL at last follow-up.

Betibeglogene Autotemcel Dosage and Administration

General

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

• Cell suspension for IV infusion.

• Supplied in up to 4 infusion bags; each bag contains approximately 20 mL. A single dose of betibeglogene autotemcel contains a minimum of 5.0 × 10⁶ CD34+ cells/kg of body weight, suspended in cryopreservation solution.

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 betibeglogene autotemcel manufacturing.

• Full myeloablative conditioning must be administered before infusion of betibeglogene autotemcel.

• Prophylaxis for hepatic veno-occlusive disease (VOD) is recommended. Prophylaxis for seizures should be considered.

• Verify that the patient's identity matches the unique patient identification information on the betibeglogene autotemcel infusion bag(s) prior to infusion.

• Do not sample, alter, or irradiate betibeglogene autotemcel.

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

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

• See Full Prescribing Information for additional details and preparation and administration.

Pediatric Patients

Dosage

Dosing of betibeglogene autotemcel is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight.

The minimum recommended dose is 5.0 × 10⁶ CD34+ cells/kg in pediatric patients older than 4 years of age. Safety and efficacy have not been established in pediatric patients younger than 4 years of age.

Adults

Dosage

Dosing of betibeglogene autotemcel is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight.

The minimum recommended dose is 5.0 × 10⁶ CD34+ cells/kg.

Cautions for Betibeglogene Autotemcel

Contraindications

None.

Warnings/Precautions

Delayed Platelet Engraftment

Delayed platelet engraftment has been observed with betibeglogene autotemcel treatment. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 15% of patients had ≥ Grade 3 decreased platelets on or after Day 100.

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.

Risk of Neutrophil Engraftment Failure

There is a potential risk of neutrophil engraftment failure after treatment with betibeglogene autotemcel. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 43 after infusion of betibeglogene autotemcel. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with betibeglogene autotemcel, provide rescue treatment with the back-up collection of CD34+ cells.

Risk of Insertional Oncogenesis

There is a potential risk of lentiviral vector (LVV)-mediated insertional oncogenesis after treatment with betibeglogene autotemcel.

Patients treated with betibeglogene autotemcel may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) at Month 6 and Month 12 and then at least annually for at least 15 years after treatment with betibeglogene 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.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of betibeglogene autotemcel. The dimethyl sulfoxide (DMSO) in betibeglogene autotemcel may cause hypersensitivity reactions, including anaphylaxis.

Anti-retroviral and Hydroxyurea Use

Patients should not take prophylactic HIV anti-retroviral medications or hydroxyurea for at least one month prior to mobilization, or for the expected duration for elimination of the medications, and until all cycles of apheresis are completed.

If a patient requires anti-retrovirals for HIV prophylaxis, then confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.

Interference with Serology Testing

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

Specific Populations

Pregnancy

There are no available data with betibeglogene 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 betibeglogene autotemcel to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known whether betibeglogene autotemcel has the potential to be transferred to the fetus. Therefore, betibeglogene autotemcel should not be administered to women who are pregnant, and pregnancy after betibeglogene autotemcel infusion should be discussed with the treating physician.

No nonclinical germline transmission studies have been conducted with betibeglogene autotemcel.

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 betibeglogene 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 betibeglogene autotemcel and any potential adverse effects on the breastfed child from betibeglogene autotemcel. Therefore, betibeglogene autotemcel is not recommended for women who are breastfeeding, and breastfeeding after betibeglogene autotemcel infusion should be discussed with the treating physician.

Females and Males of Reproductive Potential

A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before betibeglogene autotemcel administration.

There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with betibeglogene 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 betibeglogene autotemcel. Advise patients of the risks associated with conditioning agents.

There are no data on the effects of betibeglogene autotemcel on fertility.

Data are available on the risk of infertility with myeloablative conditioning. Advise patients of the option to cryopreserve semen or ova before treatment, if appropriate.

Pediatric Use

The safety and efficacy of betibeglogene autotemcel have been established in pediatric patients with β-thalassemia requiring regular transfusions. Use of betibeglogene autotemcel is supported by two Phase 3 studies that included 27 pediatric patients in the following age groups: 16 children (less than 12 years of age) and 11 adolescents (12 years to less than 18 years of age).

No differences in efficacy or clinical safety were observed between the adult and pediatric subgroups. Engraftment times were longer in pediatric patients, but not associated with increases in infections or bleeding events. The median (min, max) time to neutrophil engraftment for patients less than 18 years was 26 (16, 39) days versus 21 (13, 27) days for patients 18 years or older. The median (min, max) time to platelet engraftment for patients less than 18 years was 50 (20, 94) days versus 43 (21, 58) days for patients 18 years or older. Longer engraftment time was associated with intact spleens.

The safety and efficacy of betibeglogene autotemcel in children less than 4 years of age have not been established. No data are available.

Geriatric Use

Betibeglogene autotemcel has not been studied in patients >65 years of age. Hematopoietic stem cell (HSC) transplantation must be appropriate for a patient to be treated with betibeglogene autotemcel.

Patients Seropositive for Human Immunodeficiency Virus (HIV)

Betibeglogene autotemcel has not been studied in patients with HIV-1, HIV-2, HTLV-1, or HTLV-2. A negative serology test for HIV is necessary to ensure acceptance of apheresis material for betibeglogene autotemcel manufacturing. Apheresis material from patients with a positive test for HIV will not be accepted for betibeglogene autotemcel manufacturing.

Renal Impairment

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

Hepatic Impairment

Betibeglogene autotemcel has not been studied in patients with hepatic impairment. Patients should be assessed for hepatic impairment to ensure HSC transplantation is appropriate.

Common Adverse Effects

The most common non-laboratory adverse reactions (incidence ≥ 20%) were mucositis, febrile neutropenia, vomiting, pyrexia (fever), alopecia (hair loss), epistaxis (nose bleed), abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus (itch).

The most common Grade 3 or 4 laboratory abnormalities (> 50%) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia.

Drug Interactions

Specific Drugs

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

• Anti-retrovirals and Hydroxyurea: Do not take anti-retroviral medications or hydroxyurea for one month prior to mobilization, or for the expected duration for elimination of the medications, and until all cycles of apheresis are completed.

• Iron Chelation: Discontinue iron chelators 7 days prior to initiation of myeloablative conditioning. Avoid use of myelosuppressive iron chelators for 6 months after betibeglogene autotemcel infusion.

Actions

Mechanism of Action

Betibeglogene autotemcel adds functional copies of a modified β-globin gene into patients' hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with BB305 lentiviral vector (LVV). After betibeglogene autotemcel infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce RBCs containing biologically active β^A-T87Q-globin (a modified β-globin protein) that will combine with α-globin to produce functional adult Hb containing β^A-T87Q-globin (HbA^T87Q). β^A-T87Q-globin can be quantified relative to other globin species in peripheral blood using high-performance liquid chromatography. β^A-T87Q-globin expression is designed to correct the β/α-globin imbalance in erythroid cells of patients with β-thalassemia and has the potential to increase functional adult HbA and total Hb to normal levels and eliminate dependence on regular packed RBC transfusions.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).

• 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 betibeglogene autotemcel would be needed.

• Advise patients of the risks associated with mobilization and myeloablative conditioning agents.

• Advise patients of the risk of delayed platelet engraftment; a risk of bleeding exists after myeloablative conditioning and before platelet engraftment and may continue after engraftment in patients who have continued thrombocytopenia.

• 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 risk of insertional oncogenesis after treatment with betibeglogene autotemcel. Patients should be monitored lifelong. Monitoring will include assessment for hematologic malignancies with a complete blood count at Month 6 and Month 12 and then at least annually for at least 15 years after treatment with betibeglogene autotemcel. This will include integration site analysis at Months 6, 12, and as warranted.

• Advise patients to seek immediate attention if worsening bleeding or bruising occurs. Platelet recovery following betibeglogene autotemcel infusion could be delayed, potentially resulting in an increased risk of bruising or bleeding until platelet recovery has been achieved.

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

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

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

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.

Reload page with references included

Medical Disclaimer