Beti-cel Displays Long-Term Success in Adult and Pediatric Transfusion-Dependent β-Thalassemia


Bluebird bio’s gene therapy, marketed as Zynteglo, showed successful rates of transfusion independence up to 9 years with a reasonable safety profile in data presented at ASH 2023.

Alexis A. Thompson, MD, MPH, chief of the Division of Hematology and Elias Schwartz Endowed Chair in Hematology at Children's Hospital of Philadelphia

Alexis A. Thompson, MD, MPH

Long-term data from the clinical development of beti-cel (Zynteglo; bluebird bio) in adult and pediatric patients with transfusion-dependent β-thalassemia (TDT) suggest that the gene therapy is an effective treatment approach in this population, with up to 9-year follow-up suggesting high rates of transfusion independence (TI) and improved quality of life across age groups.1

All told, 90% (37 of 41) patients in the phase 3 studies—which notably utilized the updated commercial drug product manufacturing process—achieved TI and maintained it through the final follow-up, up to 6 years. Among those in the phase 1/2 studies—which utilized an older drug manufacturing process—68.2% (15 of 22) achieved TI, of whom 14 sustained TI through their final follow-up, up to 9 years. A single patient no longer met protocol-defined TI at year 6 (hemoglobin level <9g/dL) because of acute health events unrelated to TDT unattributed to loss of treatment effect.

“Beti-cel is a potentially curative gene therapy for patients with TDT across ages and genotypes through [the] achievement of TI and normal or near-normal [hemoglobin],” lead author Alexis A. Thompson, MD, MPH, chief of the Division of Hematology and Elias Schwartz Endowed Chair in Hematology at Children's Hospital of Philadelphia, and colleagues, wrote. “These data will inform real-world beti-cel treatment decisions for patients with TDT and providers.”

Thompson et al presented the data at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12, in San Diego, California. Patient data was analyzed from the phase 1/2 HGB-204 (NCT01745120) and HGB-205 (NCT02151526) studies, the phase 3 HGB-207 (NCT02906202) and HGB-212 (NCT03207009) studies, as well as the subsequent long-term, 13-year follow-up LTF-303 study (NCT02633943).1 All told, 63 patients had received the bluebird bio gene therapy and had enrolled in the LTF-303 study, with a median follow-up of 60.1 months (range, 23.8-109.5).

Genotypically, patient subgroups included ß0/ß0(n = 12) and non-ß0/ß0 (n = 29) showed similar rates of TI of 91.7% (n = 11; hemoglobin, 10.54 [range, 9.6-13.7]) and 89.7% (n = 26; hemoglobin, 11.92 [range, 9.8-13.4]), respectively. Specific to each phase 3 study, the rates of TI and the weighted average hemoglobin level during TI for patients in the analysis were as follows:

  • HGB-207
    • 23 patients
    • TI rate, 91.3% (n = 21)
    • Weighted average hemoglobin, 12.06 (range, 9.9-13.0)
  • HGB-212
    • 18 patients
    • TI rate, 88.9% (n = 16)
    • Weighted average hemoglobin, 10.47 (range, 9.6-13.7)

The investigators also noted that adult patients (n = 14) and pediatric patients (n = 27) additionally reported similar rates of TI and levels of hemoglobin. Of the adults included in the analysis, 85.7% (n = 12) reported TI, with an average weighted hemoglobin level of 12.65 (range, 9.6-13.7). Of the pediatric patients, 92.6% (n = 25) reported TI, with a hemoglobin level of 10.78 (range, 9.8-13.4).

READ MORE: After Elevidys: DMD Advocacy Past First Gene Therapy Approval

“Approximately 80% of pediatric and adult patients required only 1 mobilization cycle to achieve the drug product dose. The median percentage of drug product cells transduced with the BB305 [lentiviral vector] was comparable between adult and pediatric populations (at 78% and 80%, respectively), as were the month 6 median peripheral blood vector copy number (1.4 c/dg and 1.1 c/dg) and HbAT87Q (9.4 g/dL and 8.3 g/dL),” Thompson et al wrote.

Improvements in quality of life were reported by adult patients up to month 36, as assessed by the Short Form-36 Health Survey Questionnaire mental and physical component summary scores, Functional Assessment of Cancer Therapy (FACT), and EuroQol scores. These changes from baseline at month 36 were 3.29 (range, –5.70 to 21.46) and 1.85 (range, –3.75 to 8.37) on the SF-36 mental and physical components (n = 11 for both); 1.75 (range, –9.0 to 25) and 1.00 (range, –8.0 to 17.0) for the FACT-bone marrow transplantation and general total score domains; and 5.00 (–10.00 to 30.00) for the EuroQol health state today component.

As for safety, 19% (12 of 63) of patients experienced at least 1 beti-cel–related adverse event (AE), the most common (defined as occurring in ≥3 patients) being abdominal pain (5 of 63; 7.9%) and thrombocytopenia (3 of 63; 4.8%). In total, 5 patients experienced serious veno-occlusive liver disease, but all of them received defibrotide and recovered. There were no reported instances of malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus.

Beti-cel is an autologous, lentiviral gene therapy that delivers a modified form of the β-globin gene into patients’ hematopoietic stem cells ex vivo, which are then infused back into the patient to enable corrected levels of hemoglobin production without regular transfusions. It was approved by the FDA for the treatment of TDT in August 2022,2 after which Thompson spoke with CGTLive about the decision, calling it “an extraordinary day,” adding, “In my opinion, this is really a breakthrough and considerably transformational not only for thalassemia but also for the field.”

“This has been a collaboration that's been international, that has involved hematologists, general pediatricians, internists, researchers in the gene therapy field, and a remarkable commercial sponsor. My deepest gratitude is to the patients from the phase 1 trial all the way through the pivotal phase 3 trial that had the courage to be on this journey with us and to be able to pave the way for other patients with transfusion dependent beta thalassemia,” Thompson said at the time.

Bluebird bio is awaiting potentially another approval in the coming weeks, this time for its sickle cell disease (SCD) treatment, lovotibeglogene autotemcel (lovo-cel), which has a date with the FDA set for December 22, 2023.3 The company’s biologics license application is supported by efficacy data from 36 patients from the ongoing phase 1/2 HGB-206 clinical trial (NCT02140554) and 2 patients in the phase 3 HGB-210 clinical trial (NCT04293185). The patients treated in HGB-206 have a median of 32 months of follow-up while the 2 patients from HGB-210 both have 18 months of follow-up.

Julie Kanter, MD, the director of the Adult Sickle Cell Clinic and an associate professor of hematology and oncology at the University of Alabama Birmingham, as well as an investigator on multiple of lovo-cel's clinical trials, including HGB-206 and HGB-210, told CGTLive earlier this month, “I do support [lovo-cel's] approval. I think it's going to be very complicated, because we need to support sickle cell disease centers in delivering this product, as well as the product itself, which are sort of 2 different price streams. And I think it'll be a little bit complicated as we wander into this new territory of high-priced therapies. But I think the patients that I have taken care of would tell you it is absolutely worth it. It is truly a transformative therapy.”

Click here for more coverage of ASH 2023.

1. Thompson AA, Olson TS, Walters MC, et al. Sustained Efficacy, Safety, and Improved Quality of Life in Adult and Pediatric Patients with Transfusion-Dependent β-Thalassemia up to 9 Years Post Treatment with Betibeglogene Autotemcel (Beti-cel). Presented at: ASH 2023; December 9-12, 2023; San Diego, CA. Abstract 1102.
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. August 17, 2022. Accessed December 7, 2023.
3. bluebird bio confirms that FDA has communicated that advisory committee meeting will not be scheduled for lovo-cel gene therapy for sickle cell disease. News release. bluebird bio. August 16, 2023. Accessed December 7, 2023.
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