FDA Approves First Gene Therapy, Betibeglogene Autotemcel (Zynteglo), for Beta-Thalassemia

The US Food and Drug Administration (FDA) has approved the gene therapy betibeglogene autotemcel (Zynteglo) for adult and pediatric patients with beta-thalassemia who require regular red blood cell transfusions.

Beta-thalassemia causes a significant reduction of hemoglobin or the absence of hemoglobin altogether, owing to mutations in the beta-globin gene. Patients typically require transfusions every 2–5 weeks. The median age of death is 37 years.

Betibeglogene autotemcel, a one-time gene therapy, represents a potential cure in which functional copies of the mutated gene are inserted into patients' hematopoietic stem cells via a replication-defective lentivirus.

"Today's approval is an important advance in the treatment of beta-thalassemia, particularly in individuals who require ongoing red blood cell transfusions," Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research, said in an FDA press release. "Given the potential health complications associated with this serious disease, this action highlights the FDA's continued commitment to supporting development of innovative therapies for patients who have limited treatment options."

The approval was based on phase 3 trials, in which 89% of 41 patients aged 4 to 34 years who received the therapy maintained normal or near-normal hemoglobin levels and didn't need transfusions for at least a year. The patients were as young as age 4, maker Bluebird Bio said in a press release.

FDA's Cellular, Tissue, and Gene Therapies Advisory Committee unanimously recommended approval in June. The gene therapy had been approved in Europe, where it carried a price tag of about $1.8 million, but Bluebird pulled it from the market in 2021 because of problems with reimbursement.

"The decision to discontinue operations in Europe resulted from prolonged negotiations with European payers and challenges to achieving appropriate value recognition and market access," the company said in a Securities and Exchange Commission filing.

The company has set the therapy's cost at $2.8 million but is currently in negotiations with commercial payers as well as state Medicaid agencies to improve timely access to care. That includes reimbursing contracted payers up to 80% of the cost of therapy if a patient does not achieve or maintain transfusion independence up to 2 years following infusion.

The gene therapy will be available at bluebird Qualified Treatment Centers, which the company says include "preeminent transplant institutions" across the US.

"These Centers are critical partners in our mission for patients and were selected not only for their exceptional clinical expertise in treating patients with beta-thalassemia, but for their practical experience with the specialized manufacturing and novel reimbursement associated with one-time therapies," the company's chief medical officer, Richard Colvin, MD, said in a press release.

The company is planning an October 2022 launch and estimates the US market for betibeglogene autotemcel to be about 1500 patients.

Adverse events in studies were "infrequent and consisted primarily of nonserious infusion-related reactions," such as abdominal pain, hot flush, dyspnea, tachycardia, noncardiac chest pain, and cytopenias, including thrombocytopenia, leukopenia, and neutropenia. One case of thrombocytopenia was considered serious but resolved, according to the company.

Most of the serious adverse events were related to hematopoietic stem cell collection and the busulfan conditioning regimen. Insertional oncogenesis and/or cancer have been reported with Bluebird's other gene therapy products, but no cases have been associated with betibeglogene autotemcel.

M. Alexander Otto is a physician assistant with a master's degree in medical science. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape and is an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.

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Cite this: FDA Approves First Gene Therapy, Betibeglogene Autotemcel (Zynteglo), for Beta-Thalassemia - Medscape - Aug 17, 2022.