FDA-Approved Gene Therapy for Transfusion-Dependent Beta-Thalassemia Offers Potential Cure

Patients with transfusion-dependent beta-thal will soon be treated with lentiviral vector gene therapy Zynteglo to restore hemoglobin levels

María Carla Rosales Gerpe, MSc, PhD
Published:Oct 21, 2022
|Updated:Nov 08, 2022
|3 min read

Thalassemia patients face a lifetime of grueling challenges. Patient rights advocate Maria Hadjidemetriou explains that “growing up, thalassemia […] was just something to do with blood transfusions,” describing how little medical knowledge was available for the rare genetic blood disorder when she was diagnosed in the 1970s. 

Thalassemia is an umbrella medical term for heritable blood disorder types alpha and beta, where mutations in different globin genes drastically decrease or obliterate hemoglobin expression, resulting in mild to severe anemia and other complications from poor oxygen distribution and iron regulation throughout the body.

The form of beta-thalassemia (beta-thal) that Hadjidemetriou has is one of the most severe, while also one of the most common rare autosomal recessive disorders, affecting 1 in 100,000 people worldwide. In the US, between 1 in 1,300–1,500 people (0.08 percent of the population) live with the disease, and every two to five weeks, they must visit a hospital or clinic for red blood cell (RBC) transfusions and chelation therapy to reduce liver and serum iron levels that can result in heart and/or liver failure. “At this point of my life,” says Hadjidemetriou, “I wish I could get fewer transfusions.”

For many people with the disorder, this wish could soon to come true, as Zynteglo, a cell-based gene therapy developed by Bluebird Bio, Inc. to treat beta-thal in adults and children, was approved by the FDA in August. Bluebird bio will begin setting up treatment centers and training personnel this fall in anticipation for Zynteglo administration.

Zynteglo gene therapy offers potential cure for transfusion-dependent beta-thalassemia patients

The clinical data for Zynteglo show great promise. In a Phase 3 clinical trial, which began in 2016, a remarkable 89 percent of patients did not need to undergo blood transfusions after Zynteglo administration and continue to be transfusion-independent as of 2022. The Phase 3 results were published earlier this year in The New England Journal of Medicine

Zynteglo gene therapy introduces functional copies of the modified form of the beta-globin gene (βA-T87Q-globin gene) via a lentiviral vector (LVV) into the patient’s hematopoietic stem cells (HSCs), which produce all types of blood cells. Introducing the functional gene into the patient’s own HSCs eliminates the risk of transplant rejection. 

Before using Zynteglo, patients undergo apheresis, a process that separates the cellular and soluble compartments of the blood. At the lab, patient samples are enriched for CD34+ HSCs, then the LVV containing the functional gene is added to the cells during the manufacturing process to modify them prior to delivering them to the patient as Zynteglo gene therapy. 

Despite the potential for LVV to result in oncogenic events, there have been zero cases of insertional oncogenesis, and zero hematologic malignancies in patients treated with Zynteglo in clinical studies. In the longest clinical program evaluating gene therapy in transfusion-dependent beta?thal, Bluebird Bio also tested treatment protocols to obtain HSCs from both bone marrow and peripheral blood cells, showing similar efficacy. This effort expanded the treatment possibilities for folks living with beta-thal to benefit from safer and less invasive therapies.

A small price to pay for a lifetime of happiness?

At $2.8 million USD, the price for Zynteglo gene therapy has definitely raised a few eyebrows. “The price was based on the potentially curative benefit of Zynteglo as a one-time gene therapy that can replace years of burdensome, chronic RBC transfusions and iron management for patients with the most severe form of beta-thalassemia, who on average, require regular RBC transfusions every two to five weeks for life,” the company’s CEO Andrew Obenshain spoke of the regulatory news. “The lifetime cost for each of these patients can reach up to $6.4 million USD. A one-time therapy, Zynteglo has the potential to untether these patients from the health care system and offset these costs.”

The first thalassemia patient to be president of the Cooley’s Anemia (thalassemia) Foundation, Ralph Colasanti is eager to see gene therapy adapted to the larger thalassemia community. “It’s not just beta-thal,” he says. “Although we have focused on it because it’s one of the most severe forms, we hope that in the future there is treatment that can work for all the other types [of thalassemia].”

Note: Comments from Maria Hadjidemetriou and Ralph Colasanti represent their own views and not those of the organizations they represent.

Top Image:
The Bluebird Bio lentiviral vector gene therapy manufacturing process for Zynteglo.
Bluebird Bio, Inc.