Beti-cel gene therapy shows durable safety, efficacy for transfusion-dependent β-thalassaemia

Audrey Abella
12 Jan 2021
Beti-cel gene therapy shows durable safety, efficacy for transfusion-dependent β-thalassaemia

Long-term betibeglogene autotemcel (beti-cel) gene therapy led to durable, stable responses in patients with transfusion-dependent β-thalassaemia (TDT), according to two studies presented at ASH 2020.

Lifelong blood transfusions are the lifeline of TDT patients to improve haemoglobin (Hb) levels that drop due to β-globin gene mutations. However, transfusions inevitably lead to iron overload, which might subsequently progress to multi-organ damage. [Orphanet J Rare Dis 2010;5:11]

“The goal of beti-cel gene therapy in patients with TDT is lifelong, stable production of functional adult Hb sufficient for transfusion independence* (TI) and reduction in ineffective erythropoiesis,” said Dr Janet Kwiatkowski from the Children’s Hospital of Philadelphia, Pennsylvania, US, during the presentation of the LTF-303 results. “[Our findings] demonstrated the durability and stability of response after beti-cel gene therapy in [this patient setting].”


LTF-303 study

This 13-year follow-up analysis included data from four parent studies (two phase I/II [group 1] and two phase III studies [group 2]). After 2 years of follow-up, 32 patients (n=22 [group 1] and 10 [group 2) were enrolled. The results reported herein are based on those with follow-up data for up to 6 years. [ASH 2020, abstract 153]

Twenty-three patients achieved TI (n=14 [group 1] and 9 [group 2]) – two (from group 1) during follow-up and the rest during the parent studies. Weighted average Hb levels during TI were 10.4 and 12.5 g/dL in the respective groups 1 and 2. At last follow-up, all patients sustained TI for 39.4 months.

Gene therapy-derived Hb (HbAT87Q) in group 1 patients was stable at months 24, 36, 48, and 60 (6.4, 6.7, 6.6, and 7.1 g/dL, respectively). In group 2, median HbAT87Q was 9.5 g/dL at 24 months.

Pre-infusion, all participants were on iron chelation. Post-infusion, only 26 restarted iron chelation, but 11 discontinued. Seven patients (n=3 and 4 from groups 1 and 2, respectively) underwent phlebotomy for iron removal; three of whom were also on iron chelation.

“[The] sustained HbAT87Q levels and effective iron reduction with phlebotomy and/or iron chelation have resulted in improved haematologic parameters and iron burden,” said the researchers.

There were neither drug-product-related adverse events (AEs) >2 years post-infusion nor deaths, replication-competent lentivirus (RCL), or insertional oncogenesis. “The paucity of gene therapy-related AEs observed >2 years post-infusion study suggests a favourable long-term safety profile,” they added.


Similar responses in younger cohort

This interim evaluation focused on the expanded cohorts of the phase III Northstar 2 and 3 studies comprising 13 children (<12 years; n=8 [Northstar 2] and 5 [Northstar 3]) and 11 adolescents (≥12 to <18 years; n=6 and 5, respectively). [ASH 2020, abstract 154]

A total of 19 participants (n=12 and 7 from Northstar 2 and 3, respectively) with >3 months follow-up have stopped transfusions for ≥6 months.

In Northstar 2, three of four evaluable children and all adolescents achieved TI; at which point, weighted average Hb levels in these respective groups were 10.0 and 11.6 g/dL. At last visit, HbAT87Q were 5.1–7.1 and 8.4–10.5 g/dL, respectively.

In Northstar 3, one of two evaluable children and three evaluable adolescents achieved TI. Weighted average Hb levels during TI were 10.3 g/dL (children) and 9.6 g/dL (adolescents), and HbAT87Q at last visit were 9.2 and 8.0–10.9 g/dL, respectively.

“[These suggest] that, after treatment with beti-cel, paediatric patients <18 years achieved TI with comparable rates as in adults, suggesting that beti-cel gene therapy represents an effective treatment option across ages,” said Dr Alexis Thompson from the Ann & Robert H Lurie Children’s Hospital of Chicago, Illinois, US, who presented the findings.

The most frequent post-infusion nonhaematologic grade ≥3 AEs in either study were febrile neutropenia, stomatitis, and decreased appetite (children), and stomatitis, febrile neutropenia, and hypoxia (adolescents). Veno-occlusive disease occurred in one child (grade 2) and two adolescents (grade 4), which were successfully managed with defibrotide.

“Neither RCL, insertional oncogenesis, nor clonal dominance were observed … The safety profile of gene therapy with beti-cel was consistent with busulfan myeloablation,” added Thompson and colleagues.

In both LTF-303 and paediatric studies, autologous CD34+ cells were transduced with BB305 lentiviral vector containing a modified human β-globin gene to produce the beti-cel drug product, and infused after a single-agent, pharmacokinetic-adjusted busulfan myeloablation.


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