FDA Approval Sought for Betibeglogene Autotemcel for Transfusion-Dependent Beta-Thalassemia

A rolling submission of a biologic license application to the FDA has been completed for betibeglogene autotemcel for use in adult, adolescent, and pediatric patients with beta-thalassemia who require regular red blood cell transfusions, across all genotypes.

A rolling submission of a biologic license application (BLA) to the FDA has been completed for betibeglogene autotemcel (beti-cel) for use in adult, adolescent, and pediatric patients with beta-thalassemia who require regular red blood cell (RBC) transfusions, across all genotypes.1

The submission for the gene therapy is supported by findings from the phase 3 HGB-207 (Northstar-2; EuraCT 2015-004122-33) and HGB-212 (Northstar-3; EuraCT 2016-003611-35) trials, as well as the phase 1/2 HGB-204 (Northstar) and HGB-205 (Eura CT 2012-000695-42) trials. Data from the Northstar-2 and Northstar-3 trials were presented at the 2021 EHA Congress.

After receiving treatment with the gene therapy, 89% (n = 32) of 36 evaluable patients achieved transfusion dependence; this was observed across ages and genotypes in both trials. Additionally, these patients continued to be free of transfusions for a median duration of 25 months (range, 12.5-38.5) at the time of data cutoff.2 The median weighted average total hemoglobin level during transfusion independence was 11.6 g/dL (range, 9.3-13.7).

“With this submission, we are one step closer to bringing a potentially transformative gene therapy to people living with transfusion-dependent beta-thalassemia and their families,” Andrew Obenshain, president of severe genetic diseases at bluebird bio, stated in a press release. “At bluebird bio, we have a deep understanding of gene therapies, built over a decade of research and development in severe genetic diseases. We look forward to working with the FDA on its review of this BLA as we realize the promise that one-time gene therapies hold for patients.”

As of March 9, 2021, a total of 41 patients received beti-cel; 23 received the therapy on Northstar-2 and 18 patients received it on Northstar-3. The median follow-up in these trials was 24.3 months (range, 13.0-27.5) and 23.0 months (range, 4.1-26.81), respectively.

Additional data from the trial showed that the median gene therapy–derived hemoglobin was stable at about 6 months following infusion with beti-cel. It was 8.8 g/dL (n = 33) at month 6, 9.2 g/dL at month 9 (n = 34), 8.7 g/dL at month 12 (n = 36), 9.3 g/dL at month 18 (n = 29), and 8.9 g/dL at month 24 (n = 26).

Findings from exploratory analyses demonstrated that biomarkers of ineffective erythropoiesis trended toward normal over time in those who experienced transfusion independence, which may underscore the disease-modifying potential of the gene therapy in this population. Moreover, in those who achieved transfusion independence, biomarkers of hemolysis were found to normalize.

The treatment regimen includes mobilization/apheresis, conditioning, and infusion of the gene therapy, and the toxicity profile of this approach proved to be consistent with known adverse effects that come with mobilization with granulocyte colony-stimulating factor and plerixafor (Mozobil), as well as myeloablation with busulfan monotherapy.

Three patients experienced veno-occlusive liver disease that was grade 3 or higher in severity; these cases were attributed to conditioning therapy with busulfan and were noted to have resolved with defibrotide (Defitelio). Another patient reported serious congestive heart failure that was grade 3, but determined to be unrelated to the study drug; this was downgraded to grade 1 at 5 months and resolved by 12 months.

Other toxicities that were considered to be related, or potentially related, to beti-cel were thrombocytopenia (n = 3), abdominal pain (n = 3), leukopenia (n = 1), neutropenia (n = 1), pain in extremity (n = 1), tachycardia (n = 1), and autoimmune disorder (n = 1).

Grade 3 or higher toxicities that were experienced by 3 or more patients following infusion with the therapy included oropharyngeal inflammation (n = 29), febrile neutropenia (n = 20), epistaxis (n = 8), decreased appetite (n = 6), pyrexia (n = 5), alanine aminotransferase increase (n = 5), and veno-occlusive liver disease (n = 3). All these effects were not determined to be related to beti-cel.

Notably, no deaths, graft failures, or graft-versus-host disease (GVHD) were reported, nor were any cases of replication-competent lentivirus, insertional oncogenesis, clonal predominance, or malignancy.

Additional data on pediatric patients enrolled to Northstar-2 (n = 16) and Northstar-3 (n = 11) were also shared during the meeting. The median follow-up in these patients was 25.5 months (range, 4.1-41.5).

Results indicated that 91% of the 22 pediatric patients who were aged 4 to 17 years achieved transfusion independence following treatment with beti-cel; this included 10 patients who were under 12 years of age. These patients continued to be free of transfusions through their last follow-up. The median weighted average hemoglobin level during transfusion independence was 10.0 g/dL in 10 patients under age 12, and 11.7 g/dL in 10 patients between the ages of 12 and 18 years.

Moreover, in the 18 patients who achieved transfusion independence, the median baseline score was 79.90 (range, 47.83-97.83) on the PedsQL-4.0, in which healthy children typically reach scores of about 84. At 2 years, it was shown that improved quality of life was about 3 times higher than the minimal clinically significant meaningful difference, as measured by PedsQL-4.0. These improvements were underscored in those who had more severe baseline scores; this subset experienced five-fold higher improvements.

In pediatric patients, the toxicities that were related or thought to be related to the gene therapy included tachycardia (n = 1) and abdominal pain (n = 2) on the day of infusion, both grade 1 in severity, and grade 3 thrombocytopenia (n = 1) following infusion with the product.

No deaths, graft failures, GVHD, replication-competent lentivirus or insertional oncogenesis cases were reported in this population.

Previously, beti-cel was granted orphan drug and breakthrough therapy designation for the treatment of transfusion-dependent beta-thalassemia.


  1. bluebird bio submits biologics license application (BLA) to FDA for betibeglogene autotemcel (beti-cel) gene therapy for patients with β-thalassemia who require regular red blood cell transfusions. News release. bluebird bio, Inc. September 21, 2021. Accessed September 22, 2021. https://bit.ly/2XHX5UL
  2. Betibeglogene autotemcel (beti-cel) one-time gene therapy for β-thalassemia continues to demonstrate durable efficacy across pediatric and adult patient populations and all genotypes in data presented at EHA2021 Virtual. News release. bluebird bio, Inc. June 11, 2021. Accessed September 22, 2021. https://bit.ly/2XI8dkw