Betibeglogene autotemcel

Betibeglogene autotemcel adds functional copies of a modified β-globin gene into the patients' HSCs through transduction of autologous CD34+ cells with BB305 LVV, thereby addressing the underlying genetic cause of the disease. After betibeglogene autotemcel infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce RBCs containing biologically active β^A-T87Q-globin (a modified β-globin protein) that will combine with α-globin to produce functional Hb containing β^A-T87Q-globin (HbA^T87Q). β^A-T87Q-globin can be quantified relative to other globin species in peripheral blood using high performance liquid chromatography. β^A-T87Q-globin expression is designed to correct the β/α-globin imbalance in erythroid cells of patients with TDT and has the potential to increase total Hb to normal levels and eliminate dependence on chronic RBC transfusions. Following successful engraftment and achievement of transfusion independence, the effects of the product are expected to be life-long.

Pharmacodynamic effects

All patients with TDT with a non-β⁰/β⁰ genotype who received betibeglogene autotemcel with at least 3 months of follow-up produced HbA^T87Q (N=10, HGB-204; N=4, HGB-205; N=15, HGB-207; N=3, HGB-212). For patients with at least 6 months of follow-up, HbA^T87Q generally increased steadily after betibeglogene autotemcel infusion and stabilised by approximately Month 6. Patients had a Month 6 median (min, max) HbA^T87Q f 4.901 (1.03, 9.59) g/dL in the Phase ½ studies (N=14, HGB-204 and HGB-205) and 9.409 (3.35, 10.60) g/dL in ongoing Phase 3 studies (N=16, HGB-207 and HGB-212).

HbA^T87Q remained generally stable through Month 24 with a median (min, max) of 6.444 (1.10, 10.13) g/dL in the completed Phase ½ studies (N=14, HGB-204 and HGB-205) and 8.766 (0.89, 11.40) g/dL in the ongoing Phase 3 studies (N=3, HGB-207). HbA^T87Q continued to be stable at last follow-up through Month 60, demonstrating stable integration of the β^A-T87Q-globin gene into long-term HSCs and stable expression of the β^A-T87Q-globin gene in cells of the erythroid lineage.

Betibeglogene autotemcel is an autologous gene therapy medicinal product consisting of autologous cells that have been genetically modified ex vivo. The nature of betibeglogene autotemcel is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable.

Conventional mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have not been conducted.

The pharmacology, toxicology and genotoxicity of the BB305 LVV used for transduction in the manufacture of betibeglogene autotemcel were evaluated in vitro and in vivo. An in vitro immortalisation (IVIM) assay conducted with BB305 LVV-transduced mouse bone marrow cells (BMCs) showed minimal mutagenic potential (Fitness Score ≈ 0.1 × 10^-4). Insertion site analysis (ISA) of pre-transplantation transduced mouse BMCs and human CD34+ HSCs showed no enrichment for insertion in or near cancer-related genes. A pharmacology, biodistribution, toxicity and genotoxicity study was conducted in a mouse model of β-thalassaemia. In this study, there was no evidence of toxicity, genotoxicity or oncogenesis (tumorigenicity) related to BB305 LVV integration, and no toxicity related to production of β^A-T87Q-globin. ISA of post-transplantation BMCs demonstrated no preferred integration in the proximity of or within genes associated clinically (for gamma retroviral vectors) with either clonal dominance or leukaemia, and no evidence of clonal dominance was observed. Additional studies with human CD34+ HSCs administered to immunodeficient, myeloablated mice demonstrated no toxicity, tumorigenicity or genotoxicity.