Analysis of Beti-Cel for Severe β-Thalassemia Shows Extensive, Long-term Patient Improvement

Patients with β-thalassemia benefited greatly after receiving a single infusion of their own altered blood-forming stem cells, betibeglogene autotemcel (beti-cel), to correct the genetic mutation causing their bodies to produce significantly inadequate levels of hemoglobin. Results from a pair of abstracts presented at this year’s 64th American Society of Hematology Annual Meeting and Exposition bear out the significant transfusion-free rate at 3 years and marked improvements in patient-reported outcomes, including the ability to work and be physically active.

The 63 patients discussed in these abstracts were enrolled in 4 consecutive studies—HGB-204 and HGB-205, a pair of phase 1/2 studies; and HGB-207 and HGB-212, both phase 3 studies. After 2 years of follow-up, patients were given the option of enrolling in the long-term follow-up study (LTF-303)¹ for up to 13 years.

Currently, beti-cel is approved for use in the United States,² but it has received only conditional marketing approval in Europe, its advancement stymied there by ongoing disagreements between bluebird bio (the sponsor of the HGB-207 study) and payment agencies that have lasted for more than 2 years after conditional marketing authorization.³

Long-term patient-reported outcomes⁴

In the original 4 studies, patient enrollment was 63.⁵ This long-term analysis reports outcomes from 57 patients enrolled as of August 18, 2021. The patient mix was 45.6% pediatric/adolescent patients (younger than 18 years) and 54.4% adult patients, with 22 from the original phase 1/2 studies and 35 from the phase 3 studies. The Pediatric Quality of Life Inventory (PedsQL) evaluated health-related quality of life (HRQOL) among the younger cohort, and the Short Form-36 Health Survey Physical Component Summary (SF-36 PCS), Mental Component Summary (MCS), and EuroQol (EQ-5D-3L) visual analog scale (VAS) were used for the adult cohort.

“HRQOL was assessed at baseline; months 6, 12, 18, 24 (in the parent HGB studies); and months 36, 48, and 60 (in LTF-303) after beti-cel infusion,” the authors wrote.

Noting a population norm score of 80.9, for those who achieved transfusion independence (TI), or a weighted average hemoglobin of at least 9 g/dL without packed red blood cell transfusions for 12 or more months, mean (SE) PedsQL increased 19% from baseline to month 36: from 77.4 (3.4) (n = 19) to 92.1 (4.2) (n = 4). Among the adult patient population that achieved TI—with the population norm being 50—mean scores for SF-36 PCS and MCS improved 3.5% (from 53.8 [1.4] to 55.7 [1.7]) and 10.6% (from 50.9 [1.7] to 56.3 [1.4]), respectively, over the same time period. In addition, mean EQ-5D-3L rose 3.2% (from 0.92 [0.04] to 0.95 [0.03]) and VAS, 7.3% (from 85.2 [3.0] to 91.4 [2.2]). A significant increase was seen, too, in the ability to seek employment, and physical activity improved in 80% of patients, both at month 36, while school absences decreased by close to 50%.

Long-term outcomes after 7 years⁶

Reporting outcomes from all 63 patients, this analysis also looked at data from the 4 original studies plus the follow-up, noting that patients underwent myeloablative busulfan conditioning and beti-cel infusion after hematopoietic stem and progenitor cells collection. The median (IQR) follow-up was 41.4 (9.0-87.5) months across the 5 studies, with median days to neutrophil engraftment being 23 (13-39) and to platelet engraftment, 45 (19-191).

“Peripheral blood vector copy number, levels of gene therapy–derived adult hemoglobin (HbA^T87Q), and total hemoglobin were stable and durable across studies and higher in phase 3 vs phase 1/2 studies following optimized beti-cel drug product manufacturing,” the researchers wrote. “HbAT87Q levels were stabilized by month 6 and contributed to stable levels of total hemoglobin.”

As of the data cutoff in March 2021, there was a significant association seen between TI and total unsupported hemoglobin levels of 9 g/dL or higher at month 6 (P < .0001). More patients achieved TI in the phase 3 studies compared with the phase 1/2 trials, 89.5% vs 68.2%, but all patients who achieved this end point were shown to be able to maintain it as of their last follow-up. In addition, they demonstrated reduced markers of ineffective erythropoiesis and iron overload. And of the 37 patients who restarted chelation, 21 ceased it at 24 months. Meanwhile, 25% (12 of 49 patients) used phlebotomy for iron removal.

Eighteen percent of patients experienced at least 1 adverse event, with the most common related to beti-cel being abdominal pain (8%) and thrombocytopenia (5%), but nothing was seen by the 2-year postinfusion mark. Further, of the 11% who experienced veno-occlusive liver disease, treatment resolved the condition.

The best predictor of clinical outcomes, evaluated via an exploratory analysis from the phase 3 studies, was shown to be beti-cel cells transduced with the BB305 LVV (%LVV+ cells) lentiviral vector.

“The main message from our findings is that therapy to add a healthy gene to the stem cells is a valid, safe, and potentially curative treatment option for many patients with beta thalassemia,” study author Franco Locatelli, MD, professor of pediatrics at IRCCS Bambino Gesù Children’s Hospital, Catholic University of the Sacred Heart, in Rome, Italy, said in a statement.5 “Gene therapy resulted not only in sustained transfusion independence, but also in improved quality of life.”

References

1. Longterm follow-up of subjects with transfusion-dependent β-thalassemia treated with ex vivo gene therapy. ClinicalTrials.gov. Updated February 21, 2022. Accessed December 15, 2022. https://clinicaltrials.gov/ct2/show/NCT02633943

2. 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 December 15, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-treat-adult-and-pediatric-patients-beta-thalassemia-who

3. Payen E. Efficacy and safety of gene therapy for β-thalassemia. N Engl J Med. 2022;386(5):488-490. doi:10.1056/NEJMe2118580

4. Locatelli F, Walters MC, Kwiatkowski JL, et al. Long-term patient-reported outcomes following treatment with betibeglogene autotemcel in patients with transfusion-dependent β-thalassemia. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 3665. Accessed December 16, 2022. https://ash.confex.com/ash/2022/webprogram/Paper163178.html

5. Research highlights cutting-edge new treatments for blood disorders. News release. American Society of Hematology. December 10, 2022. Accessed December 15, 2022. https://www.hematology.org/newsroom/press-releases/2022/research-highlights-cutting-edge-new-treatments-for-blood-disorders

6. Walters MC, Kwiatkowski JL, Porter JB, et al. Long term outcomes of 63 patients with transfusion-dependent β-thalassemia (TDT) followed up to 7 years post-treatment with betibeglogene autotemcel (beti-cel) gene therapy and exploratory analysis of predictors of successful treatment outcomes in phase 3 trials. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 2348. Accessed December 16, 2022. https://ash.confex.com/ash/2022/webprogram/Paper162400.html