FDA Puts bluebird bio’s LentiGlobin on Clinical Hold

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The U.S. Food and Drug Administration (FDA) has pushed bluebird bio’s voluntary pause to a regulator-demanded clinical hold for all LentiGlobin gene therapy trials, following last week’s announcement that two enrolled sickle cell disease (SCD) patients developed acute myeloid leukemia (AML) and myelodysplastic syndrome, respectively.

The hold comes just after patient dosing began in HGB-210, the company’s Phase III single-arm open-label LentiGlobin trial for SCD patients between the ages of 2 and 50.

The company disappointed patients and investors in November when is said it was still two years away from FDA submission for LentiGlobin.

The European Medicines Agency (EMA) also paused an annual renewal procedure for bluebird bio’s Zynteglo, a conditionally licensed therapy in Europe for transfusion-dependent beta-thalassemia, as it is manufactured with the same BB305 lentiviral vector bluebird bio uses for LentiGlobin. Zynteglo was first conditionally approved in 2019 and is only marketed in Germany, and the first commercial infusion only took place this month.

Details were shared in bluebird bio’s year-end earnings report, which were below analyst estimates for both earnings per share and revenue.

The AML diagnosis was characterized as a Suspected Unexpected Serious Adverse Reaction, which by FDA definition means there is a “reasonable possibility” that LentiGlobin caused the acute myeloid leukemia. The patient was enrolled in the Group A cohort of HGB-206, an ongoing Phase I/II trial, and received treatment five years ago. The patient with myelodysplastic syndrome was in Group C. LentiGlobin was manufactured for patients in Group C with a unique process designed to increase vector copy number, and it was derived from hematopoietic (blood) stem cells (HSCs) collected from peripheral blood after mobilization with plerixafor. 

Patients in cohorts A and B received LentiGlobin manufactured from HSCs derived from bone marrow harvest.

In December, bluebird bio reported data from Group C in HGB-206, focused on 19 patients with a history of severe vaso-occlusive events, defined by the company as at least four in the two years prior to treatment. The patients showed no severe vaso-occlusive events following treatment with LentiGlobin, and that all patients had a complete resolution of vaso-occlusive events by six month following treatment.

LentiGlobin has been hailed as a potentially curative one-and-done gene therapy.

Leukemia has been reported before in patients receiving a gene therapy, most notably in 2003 when two children in a French trial for an X-linked severe combined immune deficiency therapy developed disease. The company had previously reported a separate occurrence of myelodysplastic syndrome in Group C, but published a paper last year in Blood Advances claiming it was unrelated to the lentiviral vector.

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