FDA Approves Bluebird’s Zynteglo, First Gene Therapy for People with Beta Thalassemia Requiring Regular Red Blood Cell Transfusions

The U.S. Food and Drug Administration approved Bluebird Bio Zynteglo, also known as beti-cel, a one-time gene therapy custom-designed to treat the underlying genetic cause of beta thalassemia in adult and pediatric patients who require regular red blood cell transfusions.

Photo: Andrew Obenshain, CEO of Bluebird Bio

“The FDA approval of Zynteglo offers people with beta-thalassemia the possibility of freedom from burdensome regular red blood cell transfusions and iron chelation, and unlocks new possibilities in their daily lives,” said Andrew Obenshain, CEO of Bluebird Bio. “After more than a decade of research and clinical development, and through the perseverance of clinicians, patients, and their families, the approval of Zynteglo marks a watershed moment for the field of gene therapy. As the first ex vivo lentiviral vector gene therapy approved in the U.S. for the treatment of people with beta thalassemia, we are ushering in a new era in which gene therapy has the potential to transform existing treatment paradigms for diseases that currently carry a lifelong burden of care.”

Beta thalassemia is a rare, genetic blood disease caused by mutations in the beta globin gene and characterized by significantly reduced or absent adult hemoglobin production. Patients with the most severe form, sometimes called transfusion-dependent beta thalassemia or beta thalassemia major, experience severe anemia and lifelong dependence on regular red blood cell transfusions, a lengthy process that patients typically undergo every two to five weeks. Despite advances in treatment and improved transfusion techniques, transfusions only temporarily address symptoms of anemia and people with beta thalassemia who require regular transfusions have an increased risk for morbidity and mortality due to complications from treatment-related iron overload. Data from the Cooley’s Anemia Foundation indicate that the median age of death of patients with transfusion-dependent beta thalassemia in the U.S. who died during the last decade was just 37 years. Bluebird estimates that there are approximately 1,300 to 1,500 individuals with transfusion-dependent beta thalassemia in the U.S.

“The availability of a one-time gene therapy which offers the possibility of transfusion independence opens up new and exciting opportunities for those who are medically eligible to receive this treatment option,” said Craig Butler, national executive director, Cooley’s Anemia Foundation. “While advances in treatment have been of enormous benefit to those with beta thalassemia, a potentially curative therapy may offer a true life-changing experience.”

Zynteglo works by adding functional copies of a modified form of the beta-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic (blood) stem cells (HSCs) to allow them to make normal to near normal levels of total hemoglobin without regular red blood cell (RBC) transfusions. The functional beta-globin gene is added into a patient’s cells outside of the (ex vivo), and then infused into the patient. Though Zynteglo is designed to be administered to the patient once, the treatment process is comprised of several steps that may take place over the course of several months.

The approval of Zynteglo is based on data from bluebird bio’s phase 3 studies HGB-207 (Northstar-2) and HGB-212 (Northstar-3), and the long-term follow-up study LTF-303.

The single-arm, open-label, 24-month phase 3 studies of Zynteglo included 41 patients aged 4 to 34 years with both non-β0/β0 and β0/β0 genotypes, with longest follow up out to 4 years. Eighty-nine percent (32/36) of evaluable patients across ages and genotypes achieved transfusion independence (TI), which is defined as no longer needing red blood cell transfusions for at least 12 months while maintaining a weighted average total hemoglobin of at least 9 g/dL. Results in these patients were durable as of last follow-up.

The most common non-laboratory adverse reactions (≥20 percent) were mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus. The most common Grade 3 or 4 laboratory abnormalities (>50 percent) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia.

Enrollment is complete and all patients have been treated in the phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies evaluating ZYNTEGLO. Follow-up in HGB-212 is ongoing. Bluebird Bio is also conducting a long-term follow-up study, LTF-303, to monitor safety and efficacy for patients with TDT who have participated in bluebird bio-sponsored clinical studies of lentiviral vector (LVV) gene therapy through 15 years post-treatment.

Across all studies, all patients who achieved transfusion independence have remained transfusion-free.

Bluebird has set the wholesale acquisition cost of Zynteglo in the U.S. at $2.8 million, which it said is in recognition of its robust and sustained clinical benefit demonstrated in clinical studies and its potential to alleviate a lifetime of health care costs associated with regular red blood cell transfusions and iron management.

The company has devised a strategy to enable timely and quality access to Zynteglo that includes one upfront payment that can be paired with an outcomes-based agreement. As part of this agreement, bluebird will reimburse contracted commercial and government payers up to 80 percent of the cost of the therapy if a patient fails to achieve and maintain transfusion independence up to two years following infusion. All patients in Zynteglo phase 3 studies who achieved transfusion independence have remained transfusion free. This outcomes measure is recognized by payers and providers as clinically meaningful and straightforward to track through claims data.

Due to the complex nature of gene therapy, Zynteglo will be available exclusively at Qualified Treatment Centers, which are carefully selected based on their expertise in relevant areas such as stem cell transplantation, cell and gene therapy, and beta thalassemia; and receive specialized training to administer Zynteglo.

Zynteglo was reviewed under Priority Review, and the company received a Priority Review voucher upon approval. Zynteglo was previously granted Orphan Drug designation and Breakthrough Therapy designation.

Author: Rare Daily Staff