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Bluebird gene therapy approved by FDA for rare blood disease

Zynteglo is cleared for transfusion-dependent beta-thalassemia but will come at a cost of $2.8 million per patient.

The Food and Drug Administration on Wednesday approved a powerful new treatment for people with an inherited blood condition called beta thalassemia, clearing a personalized gene therapy developed by the biotechnology company Bluebird bio.

The therapy, which showed dramatic benefit in clinical testing, will come at a cost of $2.8 million per patient, making it one of the most expensive medicines sold.

Its approval is a milestone in a number of other respects, too. Beta thalassemia, a disease that in severe cases requires regular blood transfusions for life, has for years been marked as a target for gene therapy. Bluebird’s treatment, which will be sold as Zynteglo, is the first of several in development to reach the market in the U.S., giving patients an option that could free them from those transfusions and their associated side effects.

Prior to Wednesday’s decision on Zynteglo, the FDA has previously cleared only two other gene therapies for inherited diseases: one for a form of childhood blindness, the other for a rare and fatal neuromuscular disorder.

Zynteglo’s approval is also significant for Bluebird, a gene therapy pioneer that’s been beset by difficulties in recent years and now faces financial peril. Reaching this point with Zynteglo, and several other gene therapies Bluebird is developing has taken more than a decade of research and cost the company billions of dollars.

The FDA cleared Zynteglo for adults and children who have severe beta-thalassemia and depend on blood transfusions. Typically, these life-sustaining transfusions are needed every two to five weeks, requiring regular trips to health clinics and hospitals as well as medication to manage iron overload.

Clinical testing showed treatment with Zynteglo freed study participants from needing regular transfusions, with 89% of treated patients in Phase 3 studies meeting the criteria for transfusion independence.

In clearing Zynteglo, however, the FDA had to weigh the therapy’s clear benefit against concerns that it might cause cancer. While no cases of cancer were reported in studies of Zynteglo, a study volunteer in a trial of another Bluebird gene therapy for sickle cell disease developed a form of leukaemia. The two therapies are similarly designed, although there are differences in how they’re manufactured.

Three participants in a study of a third Bluebird gene therapy for a rare brain disease called CALD also developed a form of bone marrow cancer many months after their treatment.

But a panel of independent experts convened by the FDA in June agreed the therapies were distinct enough for Zynteglo’s otherwise relatively clean safety profile to be judged on its own. The advisers were also convinced by how effective the treatment was in clinical testing.

“The benefits clearly at this point outweigh the risks to the patients,” said Bernard Fox, one of the advisers and chief of Providence Portland Medical Center’s molecular and tumour immunology laboratory, at the meeting.

The FDA, in its statement on Zynteglo’s approval, noted the “potential risk” of blood cancer. The agency is requiring monitoring of the patient’s blood for any signs of cancer for at least 15 years.

Patients who attended the June meeting testified to the potential impact of transfusion independence.

“The promise of gene therapy is that of a life untethered and without limitations for those born with transfusion-dependent thalassemia,” said Radhika Sawh, who has beta-thalassemia and spoke at the meeting. “Being dependent on regular blood transfusions has shaped every aspect of my life.”

For some patients, the disease can be cured by a bone marrow transplant from a donor. But that procedure carries its own safety risks and is limited to roughly one-quarter of patients who have a matched sibling donor.

“Few people have access to bone marrow transplantation just simply because of lack of a match,” Ralph Colasanti, president of the Cooley’s Anemia Foundation, said at the meeting. “Even if they do have a match, some of the risks involved swaying our patients to do other things and just to live with thalassemia.”

The disease is caused by mutations in the gene responsible for encoding haemoglobin, a vital oxygen-carrying protein. People with the disease have lower levels of haemoglobin and red blood cells in their blood, leading to chronic anaemia, weakness and, over time, more serious health complications.

Zynteglo, which is constructed from a patient’s own stem cells, delivers a modified version of the mutated gene, allowing patients to produce functional haemoglobin.

Bluebird estimates between 1,300 and 1,500 patients are eligible for Zynteglo in the U.S., although it expects only a subset of that will seek treatment right away. Most are insured commercially, according to Tom Klima, the company’s chief commercial and operating officer.

While Zynteglo’s high price is likely to spark criticism, the company defends its value, noting that regular blood transfusions and associated care can cost millions of dollars over the course of a patient’s life.

“We looked at the burden of disease; we looked at potential cost savings and cost offsets to the system,” Klima said.

Alongside announcing Zynteglo’s approval Wednesday, Bluebird also revealed plans to reimburse insurers for up to 80% of its cost should patients not achieve transfusion independence up to two years after treatment.

Bluebird won the approval of Zynteglo in Europe three years ago but later withdrew the medicine from the market after difficulties securing reimbursement in Germany and other countries. The company has since shuttered its European operations as it cut back on spending.