bluebird bio, Inc. today announced that the U.S. Food and Drug Administration (FDA) has lifted the clinical holds on the Phase 1/2 HGB-206 and Phase 3 HGB-210 studies of LentiGlobin for sickle cell disease (SCD) gene therapy (bb1111) for adult and pediatric patients with SCD, and the Phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies of betibeglogene autotemcel gene therapy (beti-cel; licensed as ZYNTEGLO™ in the EU and the UK) for adult, adolescent and pediatric patients with transfusion-dependent β-thalassaemia (TDT). The company is working closely with study investigators and clinical trial sites to resume all study activities as soon as possible.
“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,” said Andrew Obenshain, President, Severe Genetic Diseases, bluebird bio. “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. We look forward to resuming our clinical programs and continuing to advance toward major regulatory submissions for sickle cell disease and β-thalassaemia.”
Previously Reported Safety Events
On March 10, 2021, bluebird bio reported that it is very unlikely the suspected unexpected serious adverse reaction (SUSAR) of acute myeloid leukemia (AML) reported in the HGB-206 study of LentiGlobin for SCD was related to the BB305 lentiviral vector (LVV). No cases of haematologic malignancy have been reported in any patient who has received treatment with beti-cel. On April 20, 2021, bluebird bio announced a revised diagnosis for the previously reported case of myelodysplastic syndrome (MDS) in its Phase 1/2 study of LentiGlobin for SCD. Upon further assessment, the treating investigator concluded this is not a case of MDS and revised the diagnosis to transfusion-dependent anaemia.
About betibeglogene autotemcel for TDT (beti-cel/ZYNTEGLO)
Betibeglogene autotemcel (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 a patient has the βA-T87Q-globin gene, they have the potential to produce HbAT87Q, which is gene therapy-derived adult hemoglobin (Hb), at levels that may eliminate or significantly reduce the need for transfusions. In studies of beti-cel, transfusion independence (TI) is defined as no longer needing red blood cell transfusions for at least 12 months while maintaining a weighted average Hb of at least 9 g/dL.
Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease. For details, please see the Summary of Product Characteristics (SmPC).
On April 28, 2020, the EMA renewed the CMA for beti-cel. The CMA for beti-cel is valid in the 27 member states of the EU as well as the UK, Iceland, Liechtenstein and Norway. In November 2020, bluebird bio submitted to the EMA an application for the second renewal of the CMA. This procedure is currently on hold while the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) reviews the safety of ZYNTEGLO. The CMA is valid while the renewal application review is ongoing by the regulatory agency.
The FDA granted beti-cel Orphan Drug status and Breakthrough Therapy designation for the treatment of TDT.
bluebird bio is on track to complete its rolling Biologics License Application (BLA) submission to the FDA for beti-cel in mid-2021. This submission is anticipated to include adult, adolescent and children with transfusion dependent β-thalassemia across all genotypes (including non-β0/β0 genotypes and β0/β0 genotypes). Beti-cel is not approved in the U.S.
About LentiGlobin for SCD (bb1111)
LentiGlobin gene therapy for sickle cell disease (bb1111) is an investigational treatment being studied as a potential one-time therapy for SCD. bluebird bio’s clinical development program for LentiGlobin for SCD includes the completed Phase 1/2 HGB-205 and the ongoing phase 1/2 HGB-206 and Phase 3 HGB-210 studies. In addition, bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-307) for people who have participated in bluebird bio sponsored clinical studies of LentiGlobin for SCD. For more information on the studies, visit: https://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov.
The FDA has granted orphan drug designation, fast track designation, regenerative medicine advanced therapy (RMAT) designation and rare pediatric disease designation for LentiGlobin for SCD.
LentiGlobin for SCD received orphan medicinal product designation from the European Commission for the treatment of SCD, and Priority Medicines (PRIME) eligibility by the European Medicines Agency (EMA) in September 2020.
LentiGlobin for SCD is investigational and has not been approved in any geography.