The gene therapy is currently under FDA review for the treatment of β-thalassemia across genotypes.
Betibeglogene autotemcel (beti-cel; LentiGlobin; bluebird bio) gene therapy yielded transfusion independence in most treated adult and pediatric patients with transfusion-dependent β-thalassemia and a non–β0/β0 genotype, according to results from a phase 3 study (HGB-207; NCT02906202) published in the New England Journal of Medicine.1
Investigators, including first author Franco Locatelli, MD, PhD, professor of pediatrics, University of Pavia, and head, department of pediatric hematology and oncology, IRCCS Ospedale Bambino Gesù, Rome, found that treatment with beti-cel produced transfusion independence in 20 of 22 evaluable patients (91%), including 6 of 7 patients (86%) younger than 12 years of age.
“In two phase 1–2 clinical studies (HGB-204 and HGB-205)… the weighted average hemoglobin levels after infusion... were often lower than normal levels... The vector copy number and the percentage of lentiviral vector–positive cells in beti-cel were shown to be associated with hemoglobin levels; therefore, the transduction process was refined to increase the vector copy number in beti-cel and, consequently, to increase the levels of gene therapy–derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q),” Locatelli and colleagues wrote.1
The investigators evaluated the safety and efficacy of beti-cel in 23 treated patients in 2 cohorts: 15 patients who were 12 to 50 years of age and 8 patients who were younger than 12. Patients had a median age of 15 years (range, 4–34), were 52% female, and 57% were Asian. Patients had the option to participate in a long-term follow-up study (LTF-303; NCT02633943) after the 2-year study period. Median follow-up was 29.5 months (range, 13.0-48.2).
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Neutrophil engraftment occurred at a median of 23 days (range, 13 to 32) after beti-cel infusion and vectors were detected in all treated patients. Transfusion independence occurred in 20 evaluable patients (91%) and was durable with a median duration of 20.4 months (range, 15.7-21.6). The average hemoglobin level during transfusion independence was 11.7 g/dL (range, 9.5-12.8).
Twelve months post-infusion, median gene therapy–derived HbAT87Q level was 8.7 g/dL (range, 5.2-10.6) in patients who had achieved transfusion independence. The 2 evaluable patients who did not have transfusion independence had 67.4% and 22.7% reductions in transfusion volume from 6 months to the last follow-up, at 48.2 and 27.2 months, respectively.
Ineffective erythropoiesis improved after transfusion independence. In these patients, the median ratio of myeloid to erythroid cells increased from 1:2.4 (range, 1:10 to 1:0.24) in 20 patients at baseline to 1:1.2 (range, 1:3.3 to 1:0.53) in 16 patients at 24 months but remained outside the normal reference range. Durable improvements were also seen in myocardial iron and median hepcidin levels.
“The limitations of our study include a small patient population and a short follow-up period. The phase 3 HGB-212 (Northstar-3) study (NCT03207009) is under way to evaluate patients with the β0/β0, β0/β+IVS-I-110, and β+IVS-I-110/β+IVS-I-110 genotypes. Additional follow-up is needed to fully characterize the long-term efficacy and safety of beti-cel,” Locatelli and colleagues wrote.1
The safety profile of beti-cel was consistent with that of busulfan-based myeloablation and 3 patients had grade 4 serious hepatic veno-occlusive disease while 1 patient had grade 2 nonserious hepatic veno-occlusive disease. All patients had at least 1 adverse event (AE) and 4 patients had a treatment-related or possibly treatment-related AE. All AEs were mild apart from thrombocytopenia in 1 patient. No cases of cancer were observed.
“Improvement in hematopoietic stem-cell transduction resulted in higher HbAT87Q levels in the current study than in the previous phase 1–2 studies. These data suggest that in most patients with transfusion-dependent β-thalassemia and a non–β0/β0 genotype, one-time infusion of beti-cel is potentially curative through transfusion independence and the attainment of near-normal hemoglobin levels,” Locatelli and colleagues concluded.1
The FDA previously extended the review date for beti-cel's biologics license application (BLA) in January 2022 along with that of another of bluebird’s gene therapies, elivaldogene autotemcel (eli-cel) for cerebral adrenoleukodystrophy, which remains on clinical hold after a report of persistent anemia.2
Both reviews were extended by 3 months, moving beti-cel's PDUFA date from May 20, 2022, to August 19, 2022, and eli-cel's from June 17, 2022, to September 16, 2022. The extension is intended to give the FDA time to review new clinical information received from bluebird in response to previous information requests.