FDA Lifts Hold on bluebird BB305 Studies

Andrew Obenshain

The FDA has lifted clinical holds placed on several gene therapy programs from bluebird bio, following the demonstration that its lentiviral vector BB305 was not associated with cancer in patients enrolled in clinical trials for sickle cell disease (SCD).

The company is working closely with investigators and clinical sites to resume studies exploring therapies that use the BB305 vector, this includes the phase 1/2 HGB-206 and phase 3 HGB210 trials for LentiGlobin for SCD as well as the phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies of betibeglogene autotemcel (Zynteglo) for patients with transfusion-dependent β-thalassemia (TDT).

“Patient safety continues to be our utmost priority, and we are grateful for the close partnership with the FDA, investigators, scientists and most importantly, patients, who all contributed to the assessments of the adverse events in HGB-206 that ultimately led to today’s announcement,” Andrew Obenshain, president, severe genetic diseases, bluebird bio, said in a statement.

The company announced in February that the studies were halted, following the diagnosis of acute myeloid leukemia (AML) in a patient who received the BB305-based gene therapy bb1111 approximately 6 years ago in a phase 1/2 study. Another Suspected Unexpected Serious Adverse Reactions (SUSARs) of myelodysplastic syndrome (MDS) was also reported.

On March 10, bluebird indicated that BB305 was found in the AML blast cells but that further assessment by independent parties identified the vector solely in the VAMP4 gene, which is not associated with oncogenesis. Despite the vector inserting into the VAMP4 gene, investigators could not find any disruption in the gene expression or regulation, which further ruled out its role in the development of AML.

Early assessments of the patient with MDS suggested that the patient did not meet the classical definition of MDS, as there were not blasts or dysplastic cells found in the bone marrow. On April 20, the company announced this diagnosis had been revised by the treating investigator to transfusion-dependent anemia, which effectively cleared BB305 from both SUSAR cases.

“As pioneers in gene therapy, we remain committed to advancing the field through our learnings. Over the past four months, we have gained deeper knowledge and understanding of the pathophysiology of sickle cell disease that will allow us to better serve patients and the broader community," said Obenshain. "We look forward to resuming our clinical programs and continuing to advance toward major regulatory submissions for sickle cell disease and β-thalassemia.”

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 the BB305 lentiviral vector. The therapy used for SCD disease, BB1111, utilizes the same method and gene. In both cases, myeloablative conditioning with single agent busulfan is administered prior to the gene therapy infusion.

Beti-cel is approved in the European Union, United Kingdom, Iceland, Liechtenstein, and Norway for patients 12 years and older with TDT. In the United States, beti-cel has received an orphan drug designation but is not yet approved. Additionally, BB1111 has received several regulatory designations, including fast track, orphan, drug, regenerative medicine advanced therapy, and rare pediatric. The resumed, ongoing clinical trials will act as evidence for potential regulatory submissions, if the results are positive.