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An FDA advisory committee on Friday unanimously recommended betibeglogene autotemcel (beti-cel) for approval in patients with transfusion-dependent beta-thalassemia, a chronic inherited blood disorder.

With a 13-0 vote, FDA's Cellular, Tissue, and Gene Therapies Advisory Committee said the benefits of the one-time, first-in-class lentiviral vector (LVV) gene therapy outweigh any of the risks associated with the treatment, with most members agreeing that patients should be regularly monitored due to the potential risk of future hematological malignancies.

With nearly 90% of patients across two phase III trials achieving transfusion independence, with stable hemoglobin levels observed up to 7 years later, panel members enthusiastically backed the therapy despite some safety issues, such as delayed platelet engraftment.

"There is a clear benefit to the patient ... a therapeutic option that might be really paradigm shifting," said Jaroslaw Maciejewski, MD, PhD, of Taussig Cancer Center at the Cleveland Clinic in Ohio, explaining his vote. "I think this is a clear 'yes.'"

The efficacy was "outstanding," said Jeannette Yen Lee, PhD, of the University of Arkansas for Medical Sciences in Little Rock. "The opportunity to be transfusion independent is really life-changing for the patients, and I felt the safety risks were definitely outweighed by the benefits."

"The efficacy is great," echoed Melanie Ott, MD, PhD, of the University of California San Francisco. "I was impressed by the stable expression over 7 years that was provided, which is very reassuring that this is going to be a long-term benefit. And the safety data was very good in the absence of any clonality or malignancy."

Transfusion-dependent beta-thalassemia is a rare hemoglobinopathy associated with life-long anemia and frequent red blood cell transfusions, along with reduced quality of life and survival. While allogeneic hematopoietic stem cell transplantation (HSCT) using human leukocyte antigen (HLA)-matched related donors results in the best outcomes, few have such donors available.

A potentially curative option for beta-thalassemia "should allow patients to stop transfusions with a normal or near-normal hemoglobin," said panelist Alexis Thompson, MD, MPH, of the Ann & Robert H. Lurie Children's Hospital of Chicago. "It should prevent the life-shortening complications of beta-thalassemia, and reduce the need for lifelong thalassemia-specific or transfusions related to monitoring procedures."

"Beti-cel can potentially cure patients with beta-thalassemia who require regular transfusions, and has the potential to cure patients across a broad range of ages, genotypes, genders, race, and ethnicities," Thompson said.

Efficacy and Safety of Beti-Cel

Beti-cel is an LVV gene therapy that consists of a patient's own blood stem cells that have been genetically modified ex vivo with BB305 LVV. In vivo, these cells differentiate into red blood cells with sufficient functional beti-cel-derived hemoglobin A to eliminate the need for transfusions in most patients.

Primary evidence of effectiveness and safety supporting the application for beti-cel (developed by Bluebird Bio) was generated from two single-arm, open-label, phase III studies ( and ), with supportive safety data from a phase I/II study () as well.

Overall, 32 of 36 evaluable patients (88.9%) in the phase III beti-cel studies achieved transfusion independence, which is defined as no longer needing red blood cell transfusions for at least 12 months while maintaining a weighted average hemoglobin of at least 9 g/dL. These results were observed across all ages and genotypes, including pediatric patients as young as 4 years old and those with the most severe genotypes.

Beti-cel's safety profile is similar to that which is expected with autologous HSCT, FDA staff noted during Friday's meeting, though the gene therapy is also associated with a prevalent delay in platelet engraftment and prolonged thrombocytopenia. Ongoing concerns regarding insertional oncogenesis exist with these therapies as well, given the development of acute myeloid leukemia and myelodysplastic syndromes reported with LVV products for sickle cell disease and cerebral adrenoleukodystrophy (ALD).

"The pathways for developing these malignancies seem quite different," said committee member John DiPersio, MD, PhD, of Washington School of Medicine in St. Louis. "There is much more of a smoking gun with insertional oncogenesis with the [cerebral ALD] patients than for the sickle cell patients and for the [transfusion-dependent beta-thalassemia] patients, where there hasn't been any evidence of that."

While the FDA is not required to follow the advice of its advisory committees, it usually does.

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