On November 2, 2023 bluebird bio, Inc. (Nasdaq: BLUE) reported that new long-term efficacy, safety and health-related quality of life (HRQoL) follow-up data from its lentiviral vector (LVV) gene therapy programs in patients with sickle cell disease who have a history of vaso-occlusive events and patients with beta-thalassemia who require regular red blood cell transfusions will be presented at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, bluebird bio, NOV 2, 2023, View Source [SID1234636739]). The meeting will take place December 9-12, 2023 at the San Diego Convention Center and online.
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"The bluebird bio data to be presented at ASH (Free ASH Whitepaper) 2023 underscore the maturity of LVV gene therapies for hemoglobinopathies, with up to 9 years of follow-up data in transfusion-dependent beta-thalassemia and 5 years of follow-up in sickle cell disease," said Richard Colvin, M.D., Ph.D., chief medical officer, bluebird bio. "The robustness of this dataset is unparalleled, giving us continued confidence that the transformational impact these therapies may have for patients is sustained over time. We especially look forward to the first ever presentation of data from our long-term follow-up study of lovo-cel, the most deeply studied gene therapy in development for sickle cell disease."
bluebird bio will present updated follow-up data for lovotibeglogene autotemcel (lovo-cel) in patients from the HBG-206 Group C and HGB-210 studies with sickle cell disease followed for up to 60 months (median of 35.5 months), demonstrating sustained hemoglobin AT87Q production and near-complete resolution of vaso-occlusive events (VOEs) and severe VOEs, as well as sustained improvements in HRQoL. lovo-cel treatment regimen largely reflects known side effects of hematopoietic stem cell collection and busulfan conditioning regimen and underlying sickle cell disease.
Updated analyses of efficacy, safety, and HRQoL data from Phase 1/2 and Phase 3 studies of betibeglogene autotemcel (beti-cel) in patients with transfusion-dependent beta-thalassemia will also be presented, demonstrating sustained transfusion independence with up to nine years of follow-up and improvements in quality of life reported at Month 36. Updated iron management outcomes demonstrating sustained improvements in iron burden, with the majority of patients able to stop iron chelation therapy, will also be presented. Safety of beti-cel treatment largely reflects the known side effects of hematopoietic stem cell collection and busulfan conditioning regimen.
Sickle Cell Disease Data
Oral Presentation [#1051]: Efficacy, Safety, and Health-Related Quality of Life (HRQOL) in Patients with Sickle Cell Disease (SCD) Who Have Received lovotibeglogene autotemcel (lovo-cel) Gene Therapy: Up to 60 Months of Follow-up
Presenting Author: Julie Kanter, M.D., director of the UAB Adult Sickle Cell clinic, associate professor in the Division of Hematology and Oncology, and co-director of the UAB Comprehensive Sickle Cell Disease Center at the University of Alabama in Birmingham
Date/Time: Monday, December 11, 2023, 4:30 p.m. PT
Beta-Thalassemia Data
Poster Presentation [#1102]: Sustained, Efficacy, Safety, and Improved Quality of Life in Adult and Pediatric Patients with Transfusion-Dependent β-Thalassemia up to 9 Years Post Treatment with betibeglogene autotemcel (beti-cel)
Presenting Author: Alexis A. Thompson, M.D., M.P.H., professor of pediatrics (hematology), Perelman School of Medicine, University of Pennsylvania, Philadelphia, and chief, Division of Hematology, Children’s Hospital of Philadelphia
Date/Time: Saturday, December 9, 2023, 5:30 p.m. PT
Poster Presentation [#2480]: 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
Presenting Author: Janet L. Kwiatkowski, M.D., MSCE, professor of pediatrics (hematology), Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, and director, Thalassemia Center, Children’s Hospital of Philadelphia
Date/Time: Sunday, December 10, 2023, 6:00 p.m. PT
Abstracts outlining bluebird bio’s accepted data at ASH (Free ASH Whitepaper) 2023 are available on the ASH (Free ASH Whitepaper) conference website.
The U.S. Food and Drug Administration previously accepted the lovo-cel Biologics Licensing Application (BLA) for Priority Review and set a Prescription Drug User Fee Act (PDUFA) goal date of December 20, 2023. beti-cel was approved by the FDA in August 2022 and is commercially available in the United States as ZYNTEGLO.
About sickle cell disease (SCD)
Sickle cell disease (SCD) is a complex and progressive genetic disease associated with debilitating and unpredictable pain crises, anemia, irreversible damage to vital organs, and early death. In SCD, high concentrations of sickle hemoglobin (HbS) in red blood cells (RBCs) cause RBCs to become sickled, sticky, and rigid with a shorter life span, which manifests acutely as hemolytic anemia, vasculopathy, and vaso-occlusion. Pain onset can be sudden and unpredictable, often requiring hospitalization. Fifty to sixty percent of adults with SCD have end organ damage, with 24 percent experiencing damage in multiple organs, and one in four patients have a stroke by the age of 45. The impact of SCD is pervasive and affects every aspect of life for patients and their families and caregivers – from missed work and school, decreased quality of life and mental health, and ability to complete daily tasks. In the U.S., there are approximately 100,000 people living with SCD, and the median age of death is 45 years of age.
While SCD was the first disease to have a genetic cause identified, treatment advances have lagged – since that discovery in 1949,i only four therapies have been approved,ii none of which address the underlying genetic cause of disease.
About lovotibeglogene autotemcel (lovo-cel)
lovotibeglogene autotemcel (lovo-cel) gene therapy is an investigational one-time treatment being studied for sickle cell disease (SCD), that is designed to add functional copies of a modified form of the β-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic (blood) stem cells (HSCs). Once patients have the βA-T87Q-globin gene, their red blood cells (RBCs) can produce anti-sickling hemoglobin (HbAT87Q) that decreases the proportion of HbS, with the goal of reducing sickled RBCs, hemolysis, and other complications. bluebird bio’s clinical development program for lovo-cel includes the completed Phase 1/2 HGB-205 and ongoing Phase 1/2 HGB-206 and Phase 3 HGB-210 studies. bluebird bio is also conducting a long-term safety and efficacy follow-up study (LTF-307) for people who have been treated with lovo-cel in bluebird bio-sponsored clinical studies.
In the BLA submission, as of August 2022, the majority of adverse events in treated patients were attributed to underlying sickle cell disease or conditioning with busulfan. Nonserious adverse events related to lovo-cel included infusion reactions (hot flush and decreased blood pressure) in two patients (2% each). Serious adverse events related to lovo-cel included anemia in two patients (4%) with concurrent alpha-thalassemia trait. Three cases of hematologic malignancy have been reported, including one case of myelodysplastic syndrome that remains under investigation. No cases have been associated with insertional oncogenesis. Three of 50 patients (6%) died, one due to sudden cardiac death and two due to aforementioned hematologic malignancy.
The U.S. Food and Drug Administration accepted the lovo-cel Biologics Licensing Application (BLA) for Priority Review and set a Prescription Drug User Fee Act (PDUFA) goal date of December 20, 2023. The FDA previously granted lovo-cel orphan drug designation, fast track designation, regenerative medicine advanced therapy (RMAT) designation, and rare pediatric disease designation.
About ZYNTEGLO (betibeglogene autotemcel) or beti-cel
ZYNTEGLO is a first-in-class, one-time ex-vivo LVV gene therapy approved for the treatment of beta-thalassemia in adult and pediatric patients who require regular red blood cell 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 (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.