FDA Needs More Time to Assess Bluebird Bio Gene Therapy BLAs

Cell and Gene Therapy

The U.S. Food and Drug Administration (FDA) extended the review period for bluebird bio's Biologics License Applications (BLA) for two of its lentiviral vector gene therapies. The first is for betibeglogene autotemcel (beti-cel) for beta-thalassemia. The second is for elivaldogene autotemcel (eli-cel) for cerebral adrenoleukodystrophy (CALD). The BLA for beti-cel has been extended to August 19, 2022, and for eli-cel to September 16, 2022.

The extensions are due to the agency requiring more time to review additional clinical data it had requested from bluebird. The information was classified as major amendments, hence the extensions.

On December 21, 2021, the FDA placed a partial clinical hold on the company's lovotibeglogene autotemcel (lovo-cel) for participants under 18 years of age for sickle cell disease (SCD). The hold was placed after an adolescent patient was diagnosed with persistent, non-transfusion-dependent anemia after receiving the therapy. The patient had been receiving the gene therapy for 18 months.

Lovo-cel is designed as a one-time therapy that adds functional copies of a modified type of beta-globin gene into the patient's blood stem cells. Once the gene is incorporated into their stem cells, red blood cells can produce anti-sickling hemoglobin, decrease the amount of HbS and then reduce sickled RBCs, hemolysis, and related complications.

In today's announcement, bluebird also addressed the lovo-cel clinical hold, saying it had received a written question from the FDA and is still evaluating the impact the delay may have on the projected BLA submission expected in the first quarter of 2023.

Beti-cel is a one-time gene therapy to treat beta-thalassemia in patients who need regular RBC transfusions. The treatment inserts functional copies of a modified form of the beta-globulin gene into the patient's hematopoietic blood stem cells to correct the deficiency of adult hemoglobin. In Phase III trials of beti-cel, 89% of patients who could be evaluated achieved transfusion independence.

Enrollment is complete for the Phase III Northstar-2 (HGB-207) and Northstar-3 (HGB-212) trials of beti-cell, with completed enrollment and all patients having been treated. It is also running a long-term follow-up study, LTF-303, through 15 years post treatment.

Eli-cel leverages ex vivo transduction with the Lenti-D lentiviral vector (LVV) to insert functional copies of the ABCD1 gene into a patient's hematopoietic stem cells. This allows the patients to manufacture the ALD protein, which is believed to help break down very long-chain fatty acids (VLCFAs).

The company's development program for eli-cel includes the Phase II/III STARBEAM trial, which is completed, and the ongoing Phase III ALD-104 trial, which has completed enrollment. It is also running a long-term safety and efficacy follow-up trial (LTF-304) for patients who received the therapy for CALD and completed two years of follow-up in ALD-102 or ALD-104. But clinical trials of eli-cel are currently on hold with the FDA.

"Gene therapies are complex, potentially transformative treatment options for those living with severe genetic diseases, and we all share a responsibility to be diligent for patients as we progress this novel field," said Andrew Obenshain, Chief Executive Officer of bluebird bio. "We look forward to continuing to work with the FDA on its ongoing reviews of beti-cel and eli-cel, and to bringing these therapies to patients with beta-thalassemia and cerebral adrenoleukodystrophy in the U.S. later this year."

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