bluebird bio’s Transfusion-Dependent β-Thalassemia Gene Therapy Beti-Cel Continues to Demonstrate Curative Potential in Long-Term Follow-Up Data

Alexis A. Thompson, MD, MPH

bluebird bio’s betibeglogene autotemcel (beti-cel; Zynteglo), a gene therapy approved by the FDA for the treatment of adult and pediatric patients with transfusion-dependent β-thalassemia (TDT) has continued to show curative potential in updated long-term follow-up data from multiple clinical trials.¹ The data were presented at the 66th American Society of Hematology (ASH) Annual Meeting, held December 7-10, 2024, in San Diego, California.

The data come from 63 participants in the long-term follow-up study LTF-303 (NCT02633943), which enrolled patients who were previously treated with beti-cel in phase 1/2 (HGB-204, NCT01745120; HGB-205, NCT02151526) or phase 3 (HGB-207, NCT02906202; HGB-212, NCT03207009) clinical trials for the gene therapy. Of these 63 patients, 2 patients have 10 years of follow-up and 51 patients (81.0%) have at least 5 years of follow-up. It was noted that 1 patient discontinued participation in LTF-303 for personal reasons at 39 months of follow-up.

Notably, protocol-defined transfusion independence (TI) was achieved by 52 of the 63 patients in LTF-303, and all but 1 of these patients had maintained TI through their most recent follow-up. Specifically, TI was achieved by 15 of 22 patients (68.2%) who had received beti-cel in the phase 1/2 trials and 37 of the 41 patients (90.2%) who had received beti-cel in the phase 3 trials. Thompson and colleagues noted that the 1 patient who lost TI status had lost it at 6 years posttreatment after having been diagnosed with HIV complicated by gastrointestinal infection and bleeding and no longer having an Hb level of less than 9 g/dL. Although, it was noted that this patient’s peripheral blood vector copy number maintained stability with continued production of Hb^AT87Q.

During her presentation, Thompson pointed out that ability to achieve TI was similar across genotypes and age cohorts for participants in LTF-303. With regard to markers of iron overload in patients who achieved TI, Thompson highlighted that maintenance of normalization for liver iron content and serum ferritin was observed, “which is really reflecting improved iron homeostasis.”

"When we look at long-term quality of life measures, we see an improvement in the mental component as well as physical component using the Short Form-36 Health Survey in adults, and using the Pediatric Quality of Life Inventory total scores we stability in patients with TDT,” Thompson added during the presentation.

With regard to safety, there were no fatal events reported in any of the treated patients, and no serious adverse events (SAEs) related to beti-cel occurred more than 2 years posttreatment. Notably, there were no cases of malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus observed. One of the 63 patients (1.6%) experienced a case of focal nodular hyperplasia that was deemed possibly related to beti-cel and 1 of the 63 participants experienced a case of immune thrombocytopenia that was also deemed possibly related to beti-cel. These 2 cases were noted to be reasonably related in time to treatment with beti-cel, but to potentially be explained equally well by other causes. For the case of immune thrombocytopenia, Thompson and colleagues noted that the event was reported between 24 and 36 months posttreatment and that hepatic nodules in this patient grew in size and number between 36 and 48 months posttreatment.

“Updated follow-up data of up to 10 years showed that patients treated with beti-cel in clinical trials experienced durable transfusion independence and normal or near-normal hemoglobin, regardless of genotype and age, and a continued favorable safety profile”, Richard Colvin, MD, PhD, the chief medical officer of bluebird bio, said in a December 7, 2024 press release.² “We are deeply grateful for the ongoing commitment of our investigators, patients, and study participants. Our collective efforts are not only advancing the field of gene therapy but also providing new hope and possibilities for individuals with severe genetic diseases."

For more coverage of ASH 2024, click here.

REFERENCES
1. Thompson A, M, Kwiatkowski JL, Schneiderman J, et al. Betibeglogene autotemcel (beti-cel) gene addition therapy results in durable hemoglobin A production with up to 10 years of follow-up with transfusion-dependent β-thalassemia. Presented at: ASH 2024 Annual Meeting. December 7-10, 2024; San Diego, CA. Abstract 2194
2. Long-term follow-up data continue to support beti-cel as a potentially curative gene therapy for β-thalassemia patients who require regular transfusions through achievement of durable transfusion independence and normal or near-normal adult Hb levels. News release. bluebird bio, Inc. December 7, 2024. Accessed December 8, 2024. https://investor.bluebirdbio.com/news-releases/news-release-details/long-term-follow-data-continue-support-beti-cel-potentially