FDA Approves Beti-cel for β-thalassemia Requiring Transfusions

The FDA has approved betibeglogene autotemcel (beti-cel; Zynteglo) for the treatment of adult and pediatric patients with β-thalassemia who require regular red blood cell (RBC) transfusions.^1,2

Beti-cel, which is the first gene therapy to be approved for this patient population, adds functional copies of a modified form of the beta-globin gene into a patient's hematopoietic stem cells to allow them to create normal to near-normal levels of total hemoglobin without regular RBC transfusions. The functional beta-globin gene is added into a patient's cells ex vivo, and subsequently, it is infused into the patient. The therapy was designed to be administered into the patient one time, but the process entails several steps that may take place over a few months.

The regulatory decision was supported by data from two phase 3 studies, HGB-207 (Northstar-2; NCT02906202) and HGB-212 (Northstar-3; NCT03207009), and findings from the long-term follow-up study, LTF-303 (NCT02633943).

The single-arm, open-label, 24-month, phase 3 studies examined the gene therapy in a total of 41 patients between the ages of 4 years and 34 years. Notably, 89% of 36 evaluable patients spanning ages and genotypes acheived transfusion independence, which was defined as no longer requiring RBC tranfusions for at least 1 year while maintaining a weighted average total hemoglobin of at least 9 g/dL. These findings were found to be durable as of the last follow-up.

“The FDA approval of Zynteglo offers people with β-thalassemia the possibility of freedom from burdensome regular RBC transfusions and iron chelation, and unlocks new possibilities in their daily lives,” Andrew Obenshain, chief executive officer of bluebird bio, stated in a press release. “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 United States for the treatment of people with β-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.”

Northstar-2 and Northstar-3

Forty-one patients received treatment with the gene therapy in Northstar-2 (n = 23) and Northstar-3 (n = 18); the median follow-up in these trials was 24.3 months (range, 13.0-27.5) and 23 months (range, 4.1-26.8), respectively.³

As of March 9, 2021, the 32 patients who achieved transfusion independence continued to be free of transfusions for a median duration of 25 months (range, 12.5-38.5), with median weighted average total hemoglobin levels during transfusion independence of 11.6 g/dL (range, 9.3-13.7).³

Additionally, the median gene therapy–derived hemoglobin (HbAT87Q) was stable approximately 6 months following infusion; 8.8 g/dL at month 6 (n = 33); 9.2 g/dL at month 9 (n = 34); 8.7 g/dL at month 12 (n = 36); 9.3 g/dL at month 18 (n = 29); and 8.9 g/dL at month 24 (n = 26).³

Pediatric Patients in Northstar-2 and Northstar-3

As of March 9, 2021, 27 pediatric patients (12 years or younger: n = 16; 12 to 18 years old: n = 11) received treatment with beti-cel, with a median follow-up of 25.5 months (range, 4.1-41.5 months).³

Treatment with the gene therapy resulted in a 91% (n = 20/22) rate of transfusion independence in this population. These patients continued to be free of transfusions through their last follow-up, with median weighted average hemoglobin levels during transfusion independence of 10.0 g/dL in patients under 12 years old (n = 10), and 11.7 g/dL in patients aged 12 to 18 years old (n = 10).³

LTF-303

Eligible patients in LTF-303 included those who had participated in and completed 2 years of follow-up in the 2 phase 1/2 or phase 3 studies. As of March 9, 2021, 51 of 63 beti-cel-treated patients had completed 2 years of follow-up––22 in the phase 1/2 studies, and 29 in the phase 3 studies, with a median post-infusion follow-up of 44.2 months (range, 22.9-86.5).³

Of the 51 patients enrolled in LTF-303, 40 patients achieved transfusion independence––15 of 22 (68%) patients treated in the phase 1/2 studies, and 25 of 29 (86%) patients treated in the phase 3 studies. All patients achieved transfusion independence in the parent studies and maintained it through the last follow-up in LTF-303.³

As of the cut-off date, all patients who achieved transfusion independence remained free from transfusions through their last follow-up (n = 40). Patients in the phase 1/2 study had a median duration of ongoing transfusion independence of 57.1 months (range, 15.8-84.1), and patients in the phase 3 study had a median ongoing transfusion independence duration of 26.3 months (range, 13.1-39.4).³

The weighted average hemoglobin in patients who achieved transfusion independence reached normal or near-normal levels in the phase 1/2 studies (10.3 g/dL; range, 9.1-13.2) and in the phase 3 studies (11.8 g/dL; range, 9.4-13.7).³

Safety

The most common toxicities linked with the gene therapy included reduced platelet and other blood cell levels, as well as mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus.¹

References

1. FDA approves first cell-based gene therapy to treat adult and pediatric patients with beta-thalassemia who require regular blood transfusions. News release. FDA. August 17, 2022. Accessed August 17, 2022. https://bit.ly/3C9Mpjh
2. bluebird bio announces FDA approval of Zynteglo the first gene therapy for people with beta-thalassemia who require regular red blood cell transfusions. News release. bluebird bio, Inc. August 17, 2022. Accessed August 17, 2022. https://bit.ly/3JZHSSx