In February this year, the US Food and Drug Administration (FDA) converted the biotech’s voluntary pause of the studies to a regulator-demanded clinical hold for all LentiGlobin gene therapy trials, following an announcement that two enrolled sickle cell disease (SCD) patients developed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), respectively.
The trials paused included the Phase 1/2 HGB-206 and Phase 3 HGB-210 studies of LentiGlobin for SCD gene therapy (bb1111) for adult and pediatric patients with SCD, but also the Phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies of beti-cel for adult, adolescent and pediatric patients with TDT.
Investigations got underway to see if the blood cancers were related to the treatment, more specifically with the viral vector, BB305 lentiviral vector (LVV), that is used in both bluebird’s LentiGlobin for SCD and its beti-cel for TDT to deliver genetic information to patient cells.
On March 10, 2021, bluebird bio reported that it was very unlikely the suspected unexpected serious adverse reaction (SUSAR) of AML, reported in the HGB-206 study of LentiGlobin for SCD, was related to the BB305 LVV. No cases of hematologic malignancy had been reported in any patient who has received treatment with beti-cel, it added.
On April 20, 2021, bluebird bio announced a revised diagnosis for the previously reported case of MDS in its Phase 1/2 study of LentiGlobin for SCD. Upon further assessment, the treating investigator concluded this was not a case of MDS and revised the diagnosis to transfusion-dependent anemia.
The Massachusetts headquartered biotech said it is now is working with study investigators to resume all study activities as soon as possible.
Bluebird bio also reported today that, over the past four months, it has gained deeper knowledge and understanding of the pathophysiology of SCD, which will help it to better serve patients and the broader community.
A spokesperson for the gene therapy developer expanded on those learnings for us: “We have learned that people with SCD may have a higher risk for hematologic malignancies such as AML, likely due to the effect of SCD on the bone marrow. Additionally, our data and emerging data from other researchers suggest that suboptimal hematopoietic stem cell transplantation, which results in added proliferative stress in the bone marrow and/or ongoing hematopoietic stress, may further increase risk of hematologic malignancy in people with SCD.”
Regulatory status
LentiGlobin gene therapy for sickle cell disease (bb1111) is an investigational treatment being studied as a potential one-time therapy for SCD.
The therapy has not yet been approved in any geography.
The FDA has granted orphan drug designation, fast track designation, regenerative medicine advanced therapy (RMAT) designation and rare pediatric disease designation for that treatment.
LentiGlobin for SCD also 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.
Meanwhile, beti-cel, licensed as Zynteglo in the EU and the UK, is a one-time gene therapy that adds functional copies of a modified form of the β-globin gene into a patient’s own hematopoietic (blood) stem cells (HSCs). That gene therapy was granted conditional approval to treat TDT in Europe in June 2019, with Germany chosen as the launch country in January 2020. However, last month, the US firm abandoned the sale of that gene therapy Zynteglo in Germany after a pricing dispute with health authorities.
The FDA granted beti-cel Orphan Drug status and Breakthrough Therapy designation for the treatment of TDT. Bluebird said it is on track to complete its rolling Biologics License Application (BLA) submission to the FDA for beti-cel midway through this year.