Oral presentation featured in the ASH press program includes long-term data through
beti-cel stabilized iron markers in patients who achieved TI and were able to stop iron chelation (n=20/34), with markers of iron management improving toward normal
Adult, adolescent and pediatric patients experienced early and sustained improvement in health-related quality-of-life measures from baseline across Phase 3 studies
“It is encouraging to see the results presented at ASH today showing that beti-cel is potentially curative for patients with β-thalassemia who require regular red blood cell transfusions, and which build on the strong evidence collected over seven years in this clinical program,” said
Transfusion-dependent beta-thal is a severe genetic disease caused by mutations in the β-globin gene, which may cause significantly reduced or absent adult hemoglobin (Hb) production. This can result in severe anemia and lifelong dependence on RBC transfusions, a lengthy process that patients typically undergo every 3-4 weeks. Despite advances in treatment and improved transfusion techniques, transfusions only temporarily address symptoms of anemia and people with beta-thal who require regular transfusions have an increased risk for morbidity and mortality due to treatment- and disease-related iron overload and its complications.
beti-cel is a one-time gene therapy that adds 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, the HSCs have the potential to produce gene therapy-derived adult Hb (HbAT87Q) at levels that can eliminate the need for transfusions. In studies of beti-cel, transfusion independence is defined as no longer needing RBC transfusions for at least 12 months while maintaining a weighted average Hb of at least 9 g/dL.
“These important new data build on a robust body of clinical evidence to reinforce the curative potential of beti-cel for patients and families living with β-thalassemia, a disease for which treatment advances are urgently needed,” said
As of the data cut-off of
“In the analysis published in NEJM, 91% of patients, including six of seven patients under the age of 12, achieved transfusion independence as well as improvement in erythropoiesis and liver iron concentrations,” said Professor
Adverse reactions considered related to beti-cel were few and consisted primarily of non-serious infusion-related reactions that occurred on the day of infusion (e.g., abdominal pain, hot flush, dyspnea, tachycardia and non-cardiac chest pain) and cytopenias (e.g. thrombocytopenia, leukopenia and neutropenia). Pain in extremity shortly after treatment was also documented. One of these adverse events (AE) was a serious adverse event (SAE) of thrombocytopenia considered possibly related to beti-cel and has resolved.
The majority of AEs and SAEs in the beti-cel clinical development program were unrelated to beti-cel and consistent with the known side effects of HSC collection and busulfan conditioning regimen (including several SAEs of veno-occlusive disease that resolved with treatment).
Updated Long-Term Efficacy & Safety Results (Long-term follow-up study, LTF-303)
After participating in and completing the two years of follow-up in any of the Phase 1/2 (HGB-204, HGB-205) or Phase 3 studies (HGB-207, HGB-212), patients treated with beti-cel were invited to enroll in a 13-year long-term follow-up study, LTF-303.
Transfusion Independence (TI)
Of the 57 patients enrolled in LTF-303, 46 patients achieved TI: 15/22 (68%) patients treated in Phase 1/2 and 31/35 (89%) patients treated in Phase 3. All 46 patients who achieved TI maintained it through last follow-up in LTF-303, demonstrating the long-term durability of beti-cel.
Phase 1/2 patients had a median duration of ongoing TI of 65.9 months (min-max: 19.8-84.5) and Phase 3 patients had a median ongoing TI duration of 32 months (min-max: 18.2-49.1).
Weighted average Hb in patients who achieved TI reached normal or near-normal levels in the Phase 1/2 studies (10.3 g/dL; min-max: 9.1-13.2) and in the Phase 3 studies (11.6 g/dL; min-max: 9.5-13.7).
Iron Marker Stabilization
Patients who require regular blood transfusions need to reduce excess iron caused by chronic blood transfusions. For people living with beta-thal, iron can be removed from the body in several ways, including chelation (pharmacological removal).
Prior to beti-cel infusion, all patients were on iron chelation. Importantly, the majority of patients who achieved TI (n=46/57) that restarted iron chelation after infusion have since stopped (59%, 20/34); and 24% of those who achieved TI (11/46) were able to receive phlebotomy (blood removal), which is another method for iron reduction that is only possible for patients who have sufficient hemoglobin levels without RBC transfusions. This supports the potential for beti-cel to reduce the treatment burden associated with iron management.
A sub-analysis of iron status in LTF-303 included 16 patients who achieved TI and stopped chelation, with at least nine months of follow-up after discontinuation of chelation. The sub-analysis showed iron reduction in response to chelation and stabilization of iron markers after chelation was discontinued.
There were no deaths, no vector-derived replication-competent lentivirus, and no events of insertional oncogenesis or malignancy in LTF-303.
No drug-related AEs were reported. Serious AEs unrelated to beti-cel included infertility issues (gonadotropic insufficiency, ectopic pregnancy, fetal death as a result of a miscarriage), gallbladder disease (gall bladder wall thickening/polyp), cholelithiasis, infection and low white blood cell count in the setting of a wild-type HIV (bacteremia, neutropenia), and individual events of diabetic ketoacidosis, pulmonary embolism, and major depression. Pulmonary embolism occurred concurrently with diabetic ketoacidosis in a patient with a history of thromboembolic events. Each event was reported once.
Health-Related Quality of Life (HRQoL)
“People with β-thalassemia live with increased morbidity and mortality and reduced health-related quality of life compared with the general population,” said
Measures of HRQoL were evaluated in adult (≥18 years of age) and pediatric/adolescent (<18 years of age) patients who achieved TI following treatment with beti-cel in the Phase 3 HGB-207 and HGB-212 studies and who completed baseline and one post-baseline self-reported HRQoL assessment. HRQoL was assessed at baseline and at Months 6, 12, 18, and 24 after beti-cel infusion, using multiple validated quality-of-life instruments.
Improvements in HRQoL outcomes were observed among patients across age groups and across multiple domains of physical and psychological health.
Clinically relevant improvements were observed, as measured by PedsQL and SF-36 scores at Month 24. Patients with scores below the population norm at baseline experienced the most improvement.
Additional HQRoL data will be presented at ASH in a poster titled, Improvement in Health-Related Quality of Life Following Treatment with Betibeglogene Autotemcel in Patients with Transfusion-Dependent β-Thalassemia Enrolled in Phase 3 Studies, on
About betibeglogene autotemcel (beti-cel)
betibeglogene autotemcel (beti-cel) (pronounced BEH tee cell) is a one-time gene therapy custom-designed to treat the underlying cause of β-thalassemia in patients who require regular red blood cell (RBC) transfusions. Beti-cel adds 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) in order to correct the deficiency of adult hemoglobin that is the hallmark of β-thalassemia. Once a patient has the modified β-globin gene, they have the potential to produce beti-cel-derived adult hemoglobin (HbAT87Q) at levels that may eliminate the need for transfusions. In Phase 3 beti-cel studies 89% (31/35) of evaluable patients across ages and genotypes, including pediatric patients as young as four years of age and those with the most severe β0/β0 genotypes, achieved transfusion independence, which is defined as no longer needing RBC transfusions for at least 12 months while maintaining a weighted average Hb of at least 9 g/dL.
beti-cel is manufactured using the BB305 lentiviral vector (LVV), a third-generation, self-inactivating LVV that has been studied for more than a decade across two therapeutic areas.
Adverse reactions considered related to beti-cel consisted primarily of non-serious infusion-related reactions that occurred on the day of the infusion and cytopenias. One serious adverse event (SAE) of thrombocytopenia considered possibly related to beti-cel was reported and has resolved.
The majority of AEs and SAEs in the beti-cel clinical development program were considered to be unrelated to beti-cel by the Investigator and were consistent with known side effects of HSC collection and the bulsufan conditioning regimen.
The Phase 3
A biologics license application (BLA) for beti-cel is under priority review by the FDA. The agency has set a Prescription Drug User Fee Act (PDUFA) goal date of
About bluebird bio, Inc.
bluebird bio is pursuing curative gene therapies to give patients and their families more bluebird days.
With a dedicated focus on severe genetic diseases, bluebird has industry-leading clinical and research programs for sickle cell disease, β-thalassemia and cerebral adrenoleukodystrophy and is advancing research to apply new technologies to these and other diseases. We custom design each of our therapies to address the underlying cause of disease and have developed in-depth and effective analytical methods to understand the safety of our lentiviral vector technologies and drive the field of gene therapy forward.
Founded in 2010, bluebird has the largest and deepest ex-vivo gene therapy data set in the world—setting the standard for industry. Today, bluebird continues to forge new paths, combining our real-world experience with a deep commitment to patient communities and a people-centric culture that attracts and grows a diverse flock of dedicated birds.
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Source: bluebird bio, Inc.