Gene therapy shows durable efficacy for transfusion-dependent beta-thalassemia
Click Here to Manage Email Alerts
Long-term follow-up data showed betibeglogene autotemcel to be a safe and efficacious treatment for patients with transfusion-dependent beta-thalassemia, according to study results presented at TCT Meetings Digital Experience.
Most patients in both phase 1/phase 2 and phase 3 trials of the investigational gene therapy achieved transfusion independence for at least 1 year, results showed.
“Transfusion-dependent beta-thalassemia is a severe genetic disease caused by impaired beta-globin production that results in lifelong transfusion dependence and iron overload,” Suradej Hongeng, MD, professor of hematology-oncology at Mahidol University Ramathibodi Hospital in Bangkok, said during a presentation. “Beti-cel gene therapy aims to establish lifelong, functional adult hemoglobin, allowing for transfusion independence without the need for a donor.”
Betibeglogene autotemcel (bluebird bio) — also known as beti-cel — is an autologous gene therapy comprising CD34+ hematopoietic stem cells from mobilized peripheral blood that are harvested by apheresis after plerixafor mobilization and transduced with a BB305 lentiviral vector. The one-time therapy adds functional copies of a modified form of the beta-globin gene into a patient’s hematopoietic stem cells.
Four days after the presentation, bluebird bio announced it suspended marketing of beti-cel in Europe — where it is licensed as Zynteglo — after temporarily halting two clinical trials of a LentiGlobin-based gene therapy for sickle cell disease that uses the same BB305 lentiviral vector. The company stopped the trials of its bb1111 therapy after a report that a patient treated more than 5 years ago in HGB-206 was diagnosed with acute myeloid leukemia. Additionally, a patient treated in the same study developed myelodysplastic syndrome.
During TCT, Hongeng and colleagues presented data on 60 patients with transfusion-dependent beta-thalassemia who received beti-cel as part of four other clinical trials. Therapeutic cells for patients in the two phase 3 studies — HGB-207 and HGB-212 — were transduced with a refined manufacturing process not used in the two phase 1/phase 2 trials, HGB-204 and HGB-205.
Twenty-two patients (median age, 20 years; range, 12-35) received beti-cel in the phase 1/phase 2 studies, whereas 38 patients (median age, 15 years; range, 4-34) received the gene therapy in the phase 3 trials. The beti-cel used in the phase 3 studies had a higher vector copy number (median, 3 vs. 0.8 vector copies/diploid genome) and higher percentage of CD34+ cells (78% vs 32%) transduced in the final product compared with phase 1/phase 2 studies.
All patients received myeloablative conditioning with busulfan before infusion with beti-cel at a median dose of 8.9 × 106 CD34+ cells/kg in the phase 1/phase 2 studies and 9.3 × 106 CD34+ cells/kg in the phase 3 studies.
Median follow-up was 24.8 months (range, 1.1-71.8) as of data cutoff on March 2, 2020.
Analysis of the phase 1/phase 2 studies showed 77% of patients stopped receiving blood transfusions, with 64% of patients achieving transfusion independence of 1 year or longer. Eighty-nine percent of patients in the phase 3 trials stopped receiving blood transfusions, with 85% achieving transfusion independence.
All patients who achieved transfusion independence across trials maintained this status as of last follow-up, according to the researchers.
Results of the phase 3 studies showed a higher increase in peripheral blood vector copy number and gene therapy-derived adult hemoglobin (HbAT87Q) levels than in the phase 1/phase 2 studies. Researchers attributed this to refinements in beti-cel manufacturing.
Patients who achieved transfusion independence with 48 months of follow-up (n = 13) had a median 38% reduction in liver iron content compared with baseline values. Additionally, 57% of patients who achieved transfusion independence stopped receiving iron chelation for 6 months or longer.
Safety results showed 18% of patients had at least one adverse event related or potentially related to treatment. The most common of these included abdominal pain in five patients (8%) and thrombocytopenia in three patients (5%).
All treatment-related adverse events were grade 1 or grade 2 except for two cases of grade 3 thrombocytopenia. Seven patients had veno-occlusive liver disease attributed to myeloablative conditioning that was later resolved, including five patients with grade 3 or grade 4 disease and two patients with grade 2 disease.
No cases of insertional oncogenesis or vector-derived replication-competent lentivirus occurred, and no treatment-related adverse events were reported more than 2 years after beti-cel infusion, according to researchers.
All patients in the studies remained alive as of the last follow-up.
“With up to 6 years of follow-up, one-time beti-cel gene therapy enabled durable transfusion independence in the majority of patients,” Hongeng said. “Improved drug product characteristics in phase 3 studies compared with phase 1 and [phase] 2 studies resulted in increased levels of hemoglobin derived from genetically transduced hematopoietic stem cells.”
Collapse
Hongeng S, et al. Abstract 1. Presented at: The 2021 TCT Meetings Digital Experience (virtual meeting); Feb. 8-12, 2021.
Click Here to Manage Email Alerts