FDA Grants Priority Review to Beti-Cel for β-thalassemia Requiring Transfusions

The FDA has granted a priority review designation to a biologics license application (BLA) for betibeglogene autotemcel (beti-cel) for the treatment of adult, adolescent, and pediatric patients with β-thalassemia across all genotypes who require regular red blood cell (RBC) transfusions.¹

The BLA for beti-cel is based on data from the phase 3 HGB-207 (Northstar-2; NCT02906202) and HGB-212 (Northstar-3; NCT03207009) trials, the phase 1/2 HGB-204 (Northstar; NCT01745120) and HGB-205 (NCT02151526) studies, and the long-term follow-up study LTF-303 (NCT02633943).

As of March 9, 2021, data have been collected on 63 pediatric, adolescent, and adult patients, including long-term efficacy and safety results in 2 patients with more than 7 years of follow-up.

If approved, beti-cel will be the first one-time treatment that targets the genetic cause of disease in the United States, providing an alternative to regular RBC transfusions and iron chelation therapy.

The regulatory agency is scheduled to decide on the BLA by May 20, 2022, under the Prescription Drug User Fee Act.

“The FDA’s acceptance of our BLA for beti-cel brings us one step closer to potentially providing a one-time treatment that can address the underlying cause of β-thalassemia and offer patients freedom from regular transfusions,” Andrew Obenshain, chief executive officer of bluebird bio, said in a press release.

At the 2021 European Hematology Association Virtual Congress, findings from the phase 3 HGB-207 and HGB-212 trials were presented alongside those of the 13-year long-term follow-up study LTF-303.²

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).

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.

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).

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).

No deaths were reported, and no vector-derived replication-competent lentivirus or insertional oncogenesis or malignancy events had been reported.

No drug-related adverse effects (AEs) had been reported either. Serious AEs during LTF-303 unrelated to beti-cel included gonadotropic insufficiency, ectopic pregnancy, gall bladder wall thickening/polyp, bacteremia, neutropenia, cholelithiasis, diabetic ketoacidosis, pulmonary embolism, fetal death, and major depression (n = 1 for each).

Northstar-2 and Northstar-3

As of March 9, 2021, 41 patients were treated in Northstar-2(n = 23) and Northstar-3(n = 18), with a median follow-up of 24.3 months (range, 13.0-27.5) and 23 months (range, 4.1-26.8), respectively.

Following treatment with beti-cel, 89% (n = 32/36) of evaluable patients achieved transfusion independence. As of March 9, 2021, patients 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).

Moreover, the median gene therapy-derived hemoglobin (HbAT87Q) was stable approximately 6 months after 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).

Grade 3 or greater veno-occlusive liver disease in 3 patients was attributed to busulfan conditioning and resolved with defibrotide treatment. One patient developed serious, grade 3 congestive heart failure unrelated to beti-cel, which was downgraded to grade 1 at 5 months, and resolved at 12 months.

AEs related or possibly related to beti-cel included thrombocytopenia (n = 3), abdominal pain (n = 3), leukopenia (n = 1), neutropenia (n = 1), pain in the extremity (n = 1), tachycardia (n = 1) and autoimmune disorder (n = 1).

Non-hematologic grade 3 or greater AEs in at least 3 patients following infusion that were unrelated to beti-cel included oropharyngeal inflammation (n = 29), febrile neutropenia (n = 20), epistaxis (n = 8), decreased appetite (n = 6), pyrexia (n = 5), alanine aminotransferase increase (n = 5) and veno-occlusive liver disease (n = 3). No deaths, graft failures or graft-vs-host disease (GVHD), or cases of replication-competent lentivirus, insertional oncogenesis, clonal predominance, or malignancy were reported.

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) were treated with a median follow-up of 25.5 months (range, 4.1-41.5 months).

Treatment with beti-cel led to a 91% (n = 20/22) rate of transfusion independence. 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).

AEs that were related or possibly related to beti-cel were non-serious and included tachycardia (grade 1, n = 1) and abdominal pain (grade 1, n = 2) on the day of infusion, and grade 3 thrombocytopenia in 1 patient following infusion.

No deaths, graft failures or GVHD, cases of replication-competent lentivirus or insertional oncogenesis, or clonal predominance were reported.

Grade 4 veno-occlusive liver disease was reported in 2 patients (age 12 to 18 years old) and 1 grade 2 event occurred in a patient under 12 years old; all events resolved after treatment with defibrotide.

Non-hematologic grade 3 or greater AEs that occurred in at least 2 patients following infusion unrelated to beti-cel included stomatitis (n = 15), febrile neutropenia (n = 15), epistaxis (n = 6), decreased appetite (n = 5), alanine aminotransferase increase (n = 3), hypoxia (n = 3), pyrexia (n = 3), pharyngeal inflammation (n = 3), mucosal inflammation (n = 3), veno-occlusive disease (n = 2), and dyspepsia (n = 2).

Additional data from the LTF-303, Northstar-2, and Northstar-3trials will be presented at the upcoming 2021 ASH Annual Meeting & Exposition, taking place December 11-14, 2021.

“For too long, people with β-thalassemia who rely on regular transfusions have had to live with extraordinary burdens associated with their disease. Beti-cel works uniquely to help patients produce adult hemoglobin at normal or near-normal levels, which can eliminate their need for chronic transfusions and chelation that only temporarily relieve the symptoms of anemia and are associated with serious health risks and reduced quality of life,” Anne-Virginie Eggimann, chief regulatory officer of bluebird bio said. “This BLA acceptance represents the culmination of contributions from many, including the patients involved in the clinical program, their caregivers, and the study investigators. We look forward to working closely with the FDA to bring this treatment to patients in need.”

References

1. bluebird bio announces FDA priority review of biologics license application for beti-cel gene therapy for patients with β-thalassemia who require regular red blood cell transfusions. News release. Bluebird bio. November 22, 2021. Accessed November 22, 2021. https://bit.ly/2ZczVGB
2. betibeglogene autotemcel (beti-cel) One-Time Gene Therapy for β-thalassemia Continues to Demonstrate Durable Efficacy Across Pediatric and Adult Patient Populations and All Genotypes in Data Presented at EHA2021 Virtual. News release. Bluebird bio. June 11, 2021. Accessed November 22, 2021. https://bit.ly/3xc8eua