FDA Lifts Hold on bluebird bio’s Sickle Cell and Beta-Thalassemia Gene Therapies

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The U.S. Food and Drug Administration (FDA) lifted the clinical holds on bluebird bio’s Phase I/II HGB-206 and Phase III HGB-210 studies of LentiGlobin for sickle number disease gene therapy for adults and children and the Phase III Northstar-2 and Northstar-3 trials of betibeglogene autotemcel gene therapy (Zynteglo in the EU and UK) for adults, adolescents and children with transfusion-dependent beta-thalassemia (TDT).

On February 16, bluebird bio placed its Phase I/II and Phase III trial of LentiGlobin for SCD on temporary suspensions because of a case of acute myeloid leukemia (AML). Another patient from Group C of HGB-206 was suspected of myelodysplastic syndrome (MDS). 

LentiGlobin is a gene therapy, which has been granted Orphan Drug Designation, Fast Track Designation, Regenerative Medicine Advanced Therapy (RMAT) Designation, and Rare Pediatric Disease Designation. The Suspected Unexpected Serious Adverse Reaction (SUSAR) was assumed to be linked to the viral vector used to deliver their genetic payloads in the gene therapies. 

On April 20, they revised a previously reported case of myelodysplastic syndrome (MDS) in its Phase I/II trial of LentiGlobin for SCD but have now decided it is not a case of MDS and revised it to transfusion-dependent anemia.

At the time, Philip Gregory, bluebird bio’s chief scientific officer, stated, “In addition to our earlier findings of several well-known genetic mutations and gross chromosomal abnormalities commonly observed in AML in this patient, our latest analyses identified the integration site for the vector within a gene called VAMP4. VAMP4 has no known association with the development of AML nor with processes such as cellular proliferation or genome stability."

"Moreover, we see no significant gene misregulation attributable to the insertion event. In totality, the data from our assessments provide important evidence demonstrating that it is very unlikely our BB305 lentiviral vector played a role in this case, and we have shared with the FDA that we believe these results support lifting the clinical holds on our beta-thalassemia and sickle cell disease programs,” Gregory said. 

Betibeglogene autotemcel (beti-cel) is a one-time gene therapy that adds function copies of a modified form of the beta-globin gene to a patient’s own hematopoietic stem cells. This has been granted conditional marketing authorization (CMA) under the brand name Zynteglo for patients 12 years and older with TDT in Europe and the UK. It is apparently on hold there while the European Medicines Agency (EMA)’s Pharmacovigilance Risk Assessment Committee (PRAC) reviews the therapy’s safety. The CMA remains valid while the renewal application review is ongoing.

“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," Obenshain continued. "We look forward to resuming our clinical programs and continuing to advance toward major regulatory submissions for sickle cell disease and beta-thalassemia.”

Bluebird plans to continue its rolling Biologics License Application (BLA) to the FDA for beti-cel in mid-2021 for adults, adolescents, and children with transfusion dependent beta-thalassemia across all genotypes.