By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the first cell-based gene therapy to treat adult and pediatric patients with beta-thalassemia who require regular blood transfusions.1 It is a one-time (single-dose), custom-designed, autologous hematopoietic, stem cell-based gene therapy to correct the underlying genetic mutation in the hemoglobin subunit beta gene (HBB gene). Betibeglogene autotemcel received an accelerated priority review, breakthrough therapy designation, and orphan drug status.1 It is marketed as Zynteglo.
INDICATIONS
Betibeglogene autotemcel can be prescribed to treat pediatric and adult patients with beta-thalassemia who require regular red blood cell transfusions.2
DOSAGE
The minimum recommended dose is 5.0 × 106 CD34+ cells/kg.2 Prophylaxis for hepatic veno-occlusive disease (e.g., ursodeoxycholic acid or defibrotide) is recommended. Consider prophylaxis for seizures.2
POTENTIAL ADVANTAGES
This one-time treatment results in sustained hemoglobin levels and transfusion independence in most patients.3 Since this is autologous therapy, long-term immunosuppressive agents were not required in clinical studies.2
POTENTIAL DISADVANTAGES
The risks of using this solution include delayed platelet engraftment and possible neutrophil engraftment failure.2 Fifteen percent of patients exhibited grade 3 or higher decreased platelet counts on or after day 100. There also is a risk of lentiviral vector-mediated insertional oncogenesis. Patients should be monitored at least annually for hematologic malignancies for at least 15 years. The most frequently reported (> 30%) adverse reactions were febrile neutropenia, mucositis, vomiting, abdominal pain, pyrexia, epistaxis, cough, alopecia, and grade 3 or 4 hematologic abnormalities (thrombocytopenia, anemia, leukopenia, and lymphopenia).2 Hypersensitivity reactions may occur with infusion and the presence of dimethylsulfoxide in the formulation. Antiretrovirals and hydroxyurea should not be taken at least one month before mobilization or the expected duration for elimination (e.g., three elimination half-lives) of the medication until all cycles of apheresis are completed.2 Women of childbearing potential and men capable of fathering a child should use an effective method of contraception from the start of mobilization through at least six months after administration.2
COMMENTS
Beta-thalassemia is caused by a mutation of the HBB gene. This results in an absence or reduction in function of adult hemoglobin, which is a tetramer of 2 alpha and 2 beta-globulin units. There are three genetic variants: beta0, beta+, and betaE. Beta-thalassemia is categorized as two main genotypes: no copies of beta-globulin (beta0/beta0) or one or no copies of beta0 (non-beta0/beta0 genotype). The goal of gene therapy is to harvest CD34+ cells and transduce these cells in ex-vivo with third-generation lentivirus (LentiGlobin BB305) vector, which encodes the T87Q amino acid substitution, leading to restoration of expression and function of the beta-globin gene (betaAT87Q) and resultant functioning hemoglobin (HbAAT87Q). These are reinfused into the patient after busulfan myeloablation conditioning. This allows the patient to make normal or near-normal hemoglobin without the need for regular red blood cell transfusions.
Evidence supporting efficacy was based on two Phase III, single-arm, 24-month studies that included subjects requiring regular transfusions.2,4 Subjects presented with a history of at least 100 mL/kg/year of packed red blood cells (pRBCs) or with eight or more transfusions per year. Study 1 included only non-beta0/beta0 genotypes (n = 23), while study 2 included both non-beta0/beta0 (n = 6) and beta0/beta0 genotypes (n =12). The efficacy endpoint was transfusion independence (TI), defined as a weighted average Hb > 9 g/dL without any RBC transfusion for a continuous period of ≥ 12 months at any time during the study after transfusion. TI was achieved in 20 of 22 patients in study 1 and 12 of 14 patients in study 2. In both studies, subjects who did not achieve TI experienced significant reduction in transfusion volume and/or frequency.2 All subjects (n = 32) who achieved TI maintained TI with a median (min, max) unsupported total Hb of 11.4 g/dL (9.5, 14.8).2 Nineteen of the 23 subjects in study 1 have rolled over to a long-term follow-up study (NCT02633943).2
CLINICAL IMPLICATIONS
Beta-thalassemia is the most common autosomal recessive disorder in the world, most prevalent in the Mediterranean, Middle East, Africa, central Asia, the Indian subcontinent, and the Far East.5 These patients require regular transfusion to treat anemia and maintain a reasonable quality of life. However, one of the adverse effects of repeated transfusion is iron overload. Betibeglogene autotemcel eliminates the need for regular transfusions for these patients.6 Clinicians should monitor these patients’ blood for at least 15 years for any evidence of cancer.
The estimated cost is $2.8 million per treatment. The manufacturer estimates the lifetime cost for regular transfusions is $6.4 million.7 The Institute for Clinical and Economic Review reported this treatment meets accepted value (cost effectiveness) at $2.1 million, with an 80% payback option for patients who do not achieve and maintain transfusion independence over a five-year period.8 Betibeglogene autotemcel is available exclusively at selected qualified treatment centers.
REFERENCES
1. U.S. Food & Drug Administration. FDA approves first cell-based gene therapy to treat adult and pediatric patients with beta-thalassemia who require regular blood transfusions. Aug. 17, 2022.
2. Bluebird bio. Zynteglo prescribing information. August 2022.
3. Thompson AA, Walters MC, Kwiatkowski J, et al. Gene therapy in patients with transfusion-dependent beta-thalassemia. N Engl J Med 2018;378:1479-1493.
4. Locatelli F, Thompson AA, Kwiatkowski JL, et al. Betibeglogene autotemcel gene therapy for non-beta0/beta0 genotype beta-thalassemia. N Engl J Med 2022;386:415-427.
5. National Organization for Rare Disorders. Beta-thalassemia.
6. Evalueserve. Zynteglo (beti-cel) gene therapy – A potential gamechanger for bluebird bio. June 2022.
7. Bluebird bio. Bluebird bio announces U.S. commercial infrastructure to enable patient access to Zynteglo. Aug. 17, 2022.
8. Institute for Clinical and Economic Review. ICER publishes evidence report on gene therapy for beta-thalassemia. June 2, 2022.
The FDA has approved the first cell-based gene therapy to treat adult and pediatric patients with beta-thalassemia who require regular blood transfusions.
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