ASH 2022 | Long-term outcomes of patients with TDT treated with beti-cel

One-time treatment with betibeglogene autotemcel (beti-cel) gene therapy adds functional copies of a modified HBB gene, βA-T87Q, to autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) through transduction with BB305 lentiviral vector (LVV). Franco Locatelli, MD, University of California San Francisco Benioff Children’s Hospital, Oakland, CA, outlines results across Phase I/II and Phase III studies investigating the efficacy, safety profile, and patient-reported outcomes of beti-cel gene therapy in patients with transfusion-dependent β-thalassemia (TDT). As of August 2021, 63 patients had received beti-cel and were followed for a median of 41.4 months across four parent studies: two completed Phase I/II studies, HGB-204 (NCT01745120) and HGB-205 (NCT02151526), and two ongoing Phase III studies, HGB-207 (NCT02906202) and HGB-212 (NCT03207009). Transfusion independence (TI) was the primary outcome and defined as weighted average hemoglobin (Hb) ≥ 9 g/dL without packed red blood cell transfusions for ≥ 12 months. Results demonstrated that beti-cel gene therapy was followed by durable TI across ages and genotypes with up to seven years follow up. Moreover, peripheral blood vector copy number (VCN) and Hb levels were stable and durable across all studies. An exploratory multivariate analysis in patients from phase III studies identified that the percentage of drug product cells transduced with the BB305 LVV was the best predictor of clinical outcomes. The most common adverse events (AEs) were abdominal pain and thrombocytopenia, but none were observed beyond two years post-infusion, supporting a favorable long-term safety profile.
Generic health related quality of life (HRQoL) over time was assessed using the Pediatric Quality of Life Inventory (PedsQL) for pediatric and adolescent patients. Whereas, Short Form-36 Health Survey Physical Component Summary (SF-36 PCS), Mental Component Summary (MCS) and the EuroQol (EQ-5D-3L) visual analog scale (VAS) composite index score was utilized for adult patients. Overall, the study reported that QoL improved from baseline in all measures. Among patients under 18 years who achieved Transfusion independence (TI), the mean PedsQL score increased from 77.4 (3.4) at baseline (n=19) to 92.1 (4.2) at month 36 (n=4). Among adult patients who achieved TI, the mean SF-36 PCS and MCS scores increased from 53.8 (1.4) and 50.9 (1.7) at baseline (n=12), respectively, to 55.7 (1.7) and 56.3 (1.4) at month 36 (n=9). There were also improvements in EuroQol (EQ-5D-3L) composite index and visual analog scale (VAS) scores.
Ultimately, this updated data indicates that beti-cel is a potentially curative gene therapy for patients with TDT through the achievement of TI and near normal Hb levels, and confirms the durability of QoL improvement through year three, showing the gene therapy has a positive impact on employment, school attendance, physical activity, and other aspects of life. This press briefing took place at the 64th ASH Annual Meeting and Exposition congress in New Orleans, LA.

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