Rare Daily Staff

The U.S. Food and Drug Administration lifted the clinical holds on Bluebird Bio’s gene therapy studies for the rare blood disorders sickle cell disease and transfusion-dependent beta-thalassemia.

Holds were lifted on the phase 1/2 HGB-206 and phase 3 HGB-210 studies of LentiGlobin as gene therapy for adult and pediatric patients with sickle cell disease, and the phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies of beti-cel gene therapy for adult, adolescent, and pediatric patients with transfusion-dependent β-thalassemia.

“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. “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-thalassemia.”

On March 10, 2021, Bluebird Bio reported that it is very unlikely the suspected unexpected serious adverse reaction of acute myeloid leukemia reported in the HGB-206 study of LentiGlobin for SCD was related to the BB305 lentiviral vector. No cases of hematologic 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 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 anemia.

Sickle cell disease (SCD) is a serious, progressive and debilitating genetic disease caused by a mutation in the β-globin gene that leads to the production of abnormal sickle hemoglobin, causing red blood cells to become sickled and fragile, resulting in chronic hemolytic anemia, vasculopathy and painful vaso-occlusive events. For adults and children living with SCD, this means unpredictable episodes of excruciating pain due to vaso-occlusion as well as other acute complications—such as acute chest syndrome, stroke, and infections, which can contribute to early mortality in these patients.

LentiGlobin for SCD is an experimental gene therapy 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 for people who have participated in bluebird bio sponsored clinical studies of LentiGlobin for SCD.

The FDA has granted Orphan Drug, Fast Track designation, Regenerative Medicine Advanced Therapy, and Rare Pediatric Disease designations for LentiGlobin for SCD. LentiGlobin has 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.

Transfusion-dependent β-thalassemia (TDT) is a rare genetic disease caused by mutations in the beta-globin gene that result in reduced or absent hemoglobin. To survive, people with TDT maintain hemoglobin levels through lifelong chronic blood transfusions. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload.

Beti-cel (betibeglogene autotemcel) is a one-time gene therapy that adds functional copies of a modified form of the beta-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic (blood) stem cells. Once a patient has the beta A-T87Q-globin gene, they have the potential to produce HbAT87Q, which is gene therapy-derived adult hemoglobin, at levels that may eliminate or significantly reduce the need for transfusions. In studies of beti-cel, transfusion independence 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.

The European Commission granted conditional marketing authorization (CMA) for beti-cel, marketed as ZYNTEGLO gene therapy, for patients 12 years and older with TDT who do not have a genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen-matched related HSC donor is not available. Non-serious adverse events observed during clinical studies that were attributed to beti-cel included abdominal pain, thrombocytopenia, leukopenia, neutropenia, hot flush, dyspnea, pain in extremity, tachycardia and non-cardiac chest pain. One serious adverse event (SAE) of thrombocytopenia was considered possibly related to beti-cel.

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 European Union, as well as the United Kingdom, Iceland, Liechtenstein, and Norway. In November 2020, Bluebird Bio submitted to the European Medicines Agency an application for the second renewal of the Conditional Marketing Authorization. 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 beta-thalassemia across all genotypes.

Beti-cel continues to be evaluated in the ongoing phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies. Bluebird Bio is conducting a long-term safety and efficacy follow-up study, LTF-303, for people who have participated in bluebird bio-sponsored clinical studies of beti-cel.

Photo: Andrew Obenshain, president, severe genetic diseases, Bluebird Bio

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