Beti-Cel Withdrawn From Germany, bluebird Reduces Workforce

Betibeglogene autotemcel (beti-cel, Zynteglo), which is approved for transfusion-dependent β-thalassemia (TDT), is being withdrawn from the German market following a breakdown in reimbursement conversations. Following the decision, the company that manufactures the gene therapy, bluebird, noted that it planned to reduce and reshape its workforce as a result of less demand and to focus on other key markets.

The company noted that German discussion did not result in a price that reflected the benefits associated with the one-time gene therapy beti-cel, which enabled durable transfusion independence in most patients with TDT across 4 studies. The company continues to negotiate the price of the therapy across other countries in Europe and anticipates further updates in the second half of 2021.

"Through our continued engagement across Europe, we are optimistic that countries will reach pricing decisions that recognize the value of one-time gene therapies and provide the necessary access to the people who need them," said Andrew Obenshain, president, severe genetic diseases, bluebird bio. "In terms of operations, we have faced challenges over the last year that have resulted in the difficult decision to reduce our workforce and say goodbye to some valued bluebirds. We want to express our gratitude for their contributions and commitment to patients. As we move into the future, we look forward to bluebird bio advancing as a strong, thriving organization that is dedicated to developing treatments for rare genetic diseases."

Beti-cel adds functional copies of a modified form of the β-globin (βA-T87Q-globin) gene into a patient’s own hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells using a BB305 lentiviral vector. Following single-agent busulfan myeloablative conditioning, beti-cel is infused, after which the transduced HSCs engraft and reconstitute red blood cells containing functional adult hemoglobin derived from the gene therapy.

In the 4 studies, the median follow-up after beti-cel infusion has been 24.8 months (range, 1.1-71.8). Of 60 patients enrolled overall, 17 of 22 (77%) treated in the 2 phase 1/2 studies were able to stop packed red blood cell transfusions. In the 2 phase 3 studies, which used a refined manufacturing process resulting in improved beti-cel characteristics, 89% (n = 31/35) of patients with at least 6 months of follow-up achieved transfusion independence for more than 6 months, according to findings presented during the virtual 2021 Transplantation & Cellular Therapy Meetings.

Patients who achieved transfusion independence experienced a 38% median reduction in liver iron concentration (LIC) from baseline to month 48. The median reduction in LIC was 59% in patients with a baseline LIC more than 15 mg/g dw. A total of 21 of 37 (57%) patients who achieved transfusion independence have stopped iron chelation for 6 months or longer, with a median duration of 18.5 months from stopping iron chelation to last follow-up.

Persistent vector-positive hematopoietic cells and durable HbaT87Q levels supported stable total hemoglobin over time. In phase 3 trials, the median peripheral blood vector copy number was 1.2 c/dg at month 12 and 2.0 c/dg at month 24, and the median total hemoglobin was 11.5 g/dL at month 12 and 12.9 g/dL at month 24.

All patients were alive at the last follow-up (March 3, 2020). Eleven of 60 (18%) of patients experienced at least 1 adverse event (AE) considered related or possibly related to beti-cel, the most common being abdominal pain (8%) and thrombocytopenia (5%). Serious AEs were those expected after myeloablative conditioning: veno-occlusive liver disease (8%), neutropenia (5%), pyrexia (5%), thrombocytopenia (5%), and appendicitis, febrile neutropenia, major depression, and stomatitis (3% each).

Of the 7 patients experiencing veno-occlusive liver disease, 3 were of grade 4 and 2 were of grade 3. Two other patients had grade 2 veno-occlusive disease. There were no cases of insertional oncogenesis.

"We remain committed to our pioneering mission to deliver one-time gene therapies with life-long benefits to our patients," said Obenshain. "We are grateful for the clinical investigators and healthcare providers helping us better understand the recent safety events in our sickle cell disease studies. We are confident that working with the FDA and EMA, we will be able to determine a positive path forward as we seek to re-open our clinical studies."