FDA Advisory Committee Supports Approval of Gene Therapy for Blood Disease


If approved, beti-cel will be the first potentially curative gene therapy for people with beta-thalassemia who require regular red blood cell transfusions. The PDUFA date is Aug. 19, 2022.

The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) voted in support of approval of Bluebird Bio’s betibeglogene autotemcel (beti-cel) for the treatment of people with beta-thalassemia who require regular red blood cell transfusions. The committee vote was unanimous with 13 yes votes and 0 no votes on the question of whether the benefits of beti-cel outweigh the risks.

Beta-thalassemia is a severe genetic blood disease caused by mutations in the beta-globin gene and is characterized by significantly reduced or absent adult hemoglobin production. This can result in severe anemia and lifelong dependence on red blood cell transfusions.

Patients who require regular transfusions to maintain hemoglobin levels typically undergo a four to seven-hour process every two to three weeks. While transfusions temporarily relieve symptoms associated with severe anemia, including fatigue, weakness, and shortness of breath, they can lead to iron overload and serious complications, including shortened survival.

“Despite advances in care, people living with the most severe form of beta-thalassemia still require frequent transfusions of healthy red blood cells to survive, tethering them to the healthcare system for life and increasing their risk for severe complications and early death,” Andrew Obenshain, chief executive officer, bluebird bio, said in a press release.

The biologic license application for beti-cel is currently under priority review by the FDA with a PDUFA goal date set for Aug. 19, 2022.

Beti-cel is a one-time gene therapy adds functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. Beti-cel uses the Lenti-D lentiviral vector (LVV)—HIV type 1 cells that have had their genetic information removed—to add beta-globin gene.

As of the data cutoff date of August 2021, 89% (34/38) of evaluable patients in phase 3 beti-cel studies achieved transfusion independence, which is defined as no longer needing red blood cell transfusions for at least 12 months.

In materials released by the FDA ahead of the meeting, FDA officials expressed concern about delayed platelet engraftment and slow platelet recovery. Delayed engraftment can lead to bleeding.

Additionally, one patient developed dysplastic megakaryocytes—the hematopoietic cells that are responsible for the production of blood platelets. These cells have lost their ability to undergo differentiation and have impaired nuclear development. Additionally, four patients developed sideroblastic anemia, which occurs when the bone marrow fails to produce a sufficient number of healthy red blood cells.

Lisa Butterfield, Ph.D.

Lisa Butterfield, Ph.D.

Lisa Butterfield, Ph.D., chair of the advisory committee, said after the vote that she voted yes because of the impressive efficacy data and minimal risk data as shown by the sponsor. Butterfield is vice president of research and development at Parker Institute for Cancer Immunotherapy and adjunct professor of microbiology and immunology at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

Bernard Fox, Jr., Ph.D. said after the vote 88.9% transfusion independence as remarkable. “I think the risk of delayed neutrophil and platelet engraftment are clear but they clearly outweigh the risks for the patients. Fox is chief, laboratory of molecular and tumor immunology, at Providence Portland Medical Center in Portland, Ore.

Both Fox and Butterfield support the monitoring proposals that have been put forward by Bluebird, which include long-term monitoring.

According to officials at the company, patients treated with beti-cel in the clinical trials will continue to be followed in ongoing clinical studies and in a long-term follow up study LTF-303. In addition, a voluntary registry study, REG-501, is planned that will follow patients treated in the post-marketing setting for 15 years after receiving beti-cel. In the post-marketing setting, beti-cel will only be distributed through a limited and targeted number of qualified treatment centers to manage administration and ensure quality.

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