On December 10, 2023 bluebird bio inc. (NASDAQ: BLUE) reported that data for gene therapy program in transfusion-dependent (TDT) beta-thalassemia were presented at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (Press release, bluebird bio, DEC 10, 2023, View Source [SID1234638368]). Updated follow-up data showed sustained treatment effect, reduced iron management burden and improved quality of life measures in patients with beta-thalassemia who require regular red blood cell transfusions following treatment with betibeglogene autotemcel (beti-cel) (FDA approved and marketed in the U.S. as ZYNTEGLO).
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"Long-term results presented at ASH (Free ASH Whitepaper) 2023 showed durable transfusion independence and a continued positive safety profile in patients with beta-thalassemia treated with our beti-cel gene therapy through up to nine years of follow-up," said Richard Colvin, M.D., Ph.D., chief medical officer, bluebird bio. "These data represent the longest follow-up with a gene therapy for patients with beta-thalassemia requiring regular transfusions and continue to show that beti-cel is a potentially curative therapy across ages and genotypes, through the achievement of durable transfusion independence and normal or near-normal hemoglobin levels."
As of January 30, 2023, 63 patients had received beti-cel across four clinical studies with a median follow-up of 5 years (60.1 months; range: 23.8-109.5). These include two Phase 3 studies (N=41) that led to the FDA approval of ZYNTEGLO in August 2022 as the first and only gene therapy for patients with beta-thalassemia who require regular red blood cell transfusions.
Sustained Efficacy and Safety Results, and Improved Quality of Life Measures in Adult and Pediatric Patients With Transfusion-Dependent β-Thalassemia Up to 9 Years Post Treatment With Betibeglogene Autotemcel (beti-cel) (poster #1102)
Among patients in the Phase 3 studies, 90.2% (37/41) achieved transfusion independence (TI). As of the data cutoff date, TI was maintained through last follow-up (up to 6 years) across ages and genotypes. Among patients in the Phase 1/2 studies, 68.2% (15/22) achieved TI, with 14 patients sustaining TI through the last follow-up (up to 9 years). One patient, with human immunodeficiency virus complicated by gastrointestinal infection and bleeding, no longer met protocol-defined TI as a result of a hemoglobin level <9 g/dL at year 6. The patient continued to benefit from beti-cell therapy and was not receiving chronic red blood cells transfusions as of the last follow-up.
Among 12 adult patients and 22 pediatric patients in the Phase 1/2 and Phase 3 studies, health-related quality of life (HRQOL) was assessed at baseline and every 6 months. Clinically meaningful improvements in quality of life assessments, including various quality of life assessments for mental, physical and psychosocial health, were demonstrated in both adult and pediatric patients up to 36 months.
As of the cutoff date, the safety results following beti-cel treatment largely reflected the known side effects of hematopoietic stem cell collection and the busulfan conditioning regimen. Overall, 19% of patients experienced ≥1 beti-cel-related AE. The most common beti-cel-related AEs (occurring in ≥3 patients) were abdominal pain (7.9% of patients) and thrombocytopenia (4.8% of patients). Five patients experienced serious veno-occlusive liver disease; all 5 received defibrotide and recovered. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported.
Improvement in Iron Burden in Patients With Transfusion-Dependent β-Thalassemia (TDT) Treated With Betibeglogene Autotemcel (beti-cel) Gene Therapy: Up to 9 Years of Follow-Up (poster #2480)
Additionally, iron management outcomes were presented from patients with transfusion-dependent beta-thalassemia who completed either a Phase 1/2 or Phase 3 beti-cel parent study and subsequently enrolled in the long-term follow-up study and were followed for up to 9 years. Across all studies, 37/51 patients restarted chelation, and 12 received phlebotomy post-infusion; however, 69% (35/51) were able to stop chelation therapy, demonstrating restoration of iron levels over time and reduced iron management burden in those patients.
About ZYNTEGLO (betibeglogene autotemcel) or beti-cel
ZYNTEGLO is a first-in-class, one-time ex-vivo LVV gene therapy. It is approved for the treatment of beta-thalassemia in adult and pediatric patients who require regular red blood cell transfusions and was launched commercially more than a year ago. ZYNTEGLO works by adding functional copies of a modified form of the beta-globin gene (βA-T87Q-globin gene) into a beta-thalassemia patient’s own hematopoietic (blood) stem cells to enable the production of a modified functional adult hemoglobin (HbAT87Q). Once a patient has the βA-T87Q-globin gene, they have the potential to increase ZYNTEGLO-derived adult hemoglobin (HbAT87Q) and total hemoglobin to normal or near normal levels that can eliminate the need for regular red blood cell (RBC) transfusions.
Indication
ZYNTEGLO is indicated for the treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell (RBC) transfusions.
Important Safety Information
Delayed Platelet Engraftment
Delayed platelet engraftment has been observed with ZYNTEGLO 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 ZYNTEGLO. 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 ZYNTEGLO. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with ZYNTEGLO, provide rescue treatment with the back-up collection of CD34+ cells.
Risk of Insertional Oncogenesis
There is a potential risk of LVV mediated insertional oncogenesis after treatment with ZYNTEGLO.
Patients treated with ZYNTEGLO 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 ZYNTEGLO, 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 ZYNTEGLO. The dimethyl sulfoxide (DMSO) in ZYNTEGLO 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 ZYNTEGLO 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 ZYNTEGLO should not be screened for HIV infection using a PCR-based assay.
Adverse Reactions
The most common non-laboratory adverse reactions (≥20%) were mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus. The most common Grade 3 or 4 laboratory abnormalities (>50%) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia.
Drug Interactions
Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of conditioning. The prescribing information for the iron chelator(s) and the myeloablative conditioning agent should be consulted for the recommendations regarding co-administration with CYP3A substrates.
Some iron chelators are myelosuppressive. After ZYNTEGLO infusion, avoid use of these iron chelators for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators. Phlebotomy can be used in lieu of iron chelation, when appropriate.
Pregnancy/Lactation
Advise patients of the risks associated with conditioning agents, including on pregnancy and fertility.
ZYNTEGLO should not be administered to women who are pregnant, and pregnancy after ZYNTEGLO infusion should be discussed with the treating physician.
ZYNTEGLO is not recommended for women who are breastfeeding, and breastfeeding after ZYNTEGLO 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 ZYNTEGLO administration.
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 ZYNTEGLO.
Advise patients of the option to cryopreserve semen or ova before treatment if appropriate.
Please see full Prescribing Information for ZYNTEGLO.