U.S. Food and Drug Administration (FDA)-Approved Indications

Zynteglo is indicated for the treatment of adult and pediatric patients with beta-thalassemia who require regular blood cell (RBC) transfusions.

Betibeglogene autotemcel, also known as beti-cel, is available as Zynteglo (Bluebird Bio, Inc.). Zynteglo is an autologous hematopoietic stem cell-based gene therapy (HSCT) indicated for the treatment of adult and pediatric patients with β-thalassemia who require regular red blood cell (RBC) transfusions. Zynteglo works by adding functional copies of a modified form of the beta-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic stem cells to allow them to make normal to near normal levels of total hemoglobin without regular RBC transfusions. The functional beta-globin gene is added into a patient’s cells outside of the body (ex-vivo), and then infused into the patient. Though Zynteglo is designed to be administered to the patient once, the treatment process is comprised of several steps that may take place over the course of several months.

Labeled warnings and precautions include delayed platelet engraftment, risk of neutrophil engraftment failure, risk of insertional oncogenesis, and hypersensitivity reactions.

The most common adverse reactions associated with Zynteglo included reduced platelet and other blood cell levels, as well as mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder and pruritus.

There is a potential risk of blood cancer associated with this treatment; however, no cases have been seen in studies of Zynteglo. Patients who receive Zynteglo should have their blood monitored for at least 15 years for any evidence of cancer. Patients should also be monitored for hypersensitivity reactions during Zynteglo administration and should be monitored for thrombocytopenia and bleeding (FDA, 2022).

Beta-Thalassemia

Beta-thalassemia, also called "Cooley’s anemia," is an inherited blood disorder that reduces the production of hemoglobin, an iron-containing protein in red blood cells that carries oxygen to cells throughout the body. In beta-thalassemia, low levels of hemoglobin lead to a lack of oxygen in many parts of the body and anemia, causing pale skin, weakness, fatigue and more serious complications. People with beta-thalassemia are also at an increased risk of developing abnormal blood clots. Supportive treatment for people with beta thalassemia often consists of lifelong regimens of chronic blood transfusions for survival and treatment for iron overload due to the transfusions.

On August 17, 2022, the U.S. Food and Drug Administration (FDA) announced the approval of Zynteglo (betibeglogene autotemcel), the first cell-based gene therapy for the treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell transfusions. Zynteglo is a one-time gene therapy product administered as a single dose. Each dose of Zynteglo is a customized treatment created using the patient’s own cells (bone marrow stem cells) that are genetically modified to produce functional beta-globin (a hemoglobin component).

The safety and effectiveness of Zynteglo were established in 2 ongoing Phase 3 open-label, single-arm, 24-month, multicenter clinical studies (Northstar-2, NCT02906202 and Northstar-3, NCT03207009) that included adult and pediatric patients (aged 4 to 34 years) with beta-thalassemia requiring regular transfusions. All patients (n = 41) were administered Zynteglo with a median (min, max) dose of 9.4 (5.0, 42.1) × 10

CD34+ cells/kg as an intravenous infusion. The primary endpoint for both studies was the proportion of patients who achieved transfusion independence, defined as a weighted average total hemoglobin (Hb) of at least 9 g/dL without any packed RBC (pRBC) transfusions for at least 12 months. Of 41 patients receiving Zynteglo, 89% achieved transfusion independence. Following completion of the 24-month parent studies, patients were invited to enroll in an ongoing long-term safety and efficacy follow-up study for an additional 13 years (Study 3). Patients were considered to be eligible for the Phase 3 studies if they had a history of transfusions of at least 100 mL/kg/year of pRBCs or with 8 or more transfusions of pRBCs per year in the 2 years preceding enrollment. Patients who had severely elevated iron in the heart (i.e., patients with cardiac T2* less than 10 msec by magnetic resonance imaging [MRI]) or advanced liver disease were not accepted into the studies. MRI of the liver was performed on all patients. Patients older than 18 years with MRI results demonstrating liver iron content greater than or equal to 15 mg/g underwent liver biopsy for further evaluation. Patients younger than 18 years with MRI results demonstrating liver iron content greater than or equal to 15 mg/g were excluded from the studies unless a liver biopsy could provide additional data to confirm eligibility. Patients with a liver biopsy demonstrating bridging fibrosis, cirrhosis, or active hepatitis, were also excluded (Bluebird Bio, 2022; FDA, 2022).

Study 1 (Northstar-2; NCT02906202) conducted by Locatelli et al (2022), evaluated the efficacy and safety of betibeglogene autotemcel (beti-cel) in adult and pediatric patients with transfusion-dependent β-thalassemia and a non-β0/β0 genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of greater than or equal to 9 g per deciliter without red-cell transfusions for 12 months or more). A total of 23 patients were enrolled and received treatment, with a median follow-up of 29.5 months. Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter. Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q) was 8.7 g per deciliter in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed. The authors concluded that treatment with beti-cel resulted in a sustained HbA

level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non-β0/β0 genotype, including those younger than 12 years of age.

Among 14 evaluable patients in Study 2 (Northstar-3; NCT03207009), 12 (86%) achieved transfusion independence (TI) with a median (min, max) weighted average Hb during TI of 10.20 g/dL. All patients who achieved TI were able to maintain TI with a min, max duration of ongoing TI of 12.5+, 32.8+ months. The median (min, max) time to last pRBC transfusion prior to TI was 0.8 (0.0, 1.9) months following Zynteglo infusion (Park, 2022).

Inclusion criteria for Study 1 and Study 2 required (not an all-inclusive list): weight of a minimum of 6 kilograms (kg) and are reasonably anticipated to be able to provide at least the minimum number of cells required to initiate the manufacturing process; a diagnosis of transfusion-dependent β-thalassemia (TDT) with a history of at least 100 milliliter per kilogram per year (mL/kg/year) of pRBCs in the 2 years preceding enrollment (all participants), or be managed under standard thalassemia guidelines with greater than or equal to 8 transfusions of pRBCs per year in the 2 years preceding enrollment (participants 12 years or older).

Exclusion criteria for Study 1 and Study 2 (not an all-inclusive list) were: presence of a mutation characterized as β0 mutation at both alleles of the β-globin gene (HBB) gene (Study 1); presence of a mutation characterized as other then β0 (e.g., β+, βE, βC) on at least one β-globin gene (HBB) allele (Study 2); positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 and HIV-2), hepatitis B virus (HBV), or hepatitis C (HCV); any prior or current malignancy; prior hematopoietic stem cell transplantation (HSCT); advanced liver disease; a cardiac T2* less than 10 ms by MRI; prior receipt of gene therapy; and a known and available human leukocyte antigen (HLA) matched family donor.

Appendix

Examples of non-β0/β0 OR β0/β0 genotypes:

: Requires Precertification:

Precertification of betibeglogene autotemcel (Zynteglo) is required of all Aetna participating providers and members in applicable plan designs. For precertification of betibeglogene autotemcel, call (866) 752-7021 (commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see

For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.

Site of Care Utilization Management Policy applies. For information on site of service for betibeglogene autotemcel (Zynteglo), see

.

Prescriber Specialties

This medication must be prescribed by or in consultation with a hematologist.

Criteria for Initial Approval

Aetna considers a one-time administration of betibeglogene autotemcel (Zynteglo) as medically necessary for the treatment of beta-thalassemia when

of the following criteria are met:

Member is 4 years of age or older and meets

of the following criteria:

Aetna considers all other indications as experimental and investigational.