Drug product attributes predict clinical efficacy in betibeglogene autotemcel gene therapy for β-thalassemia

Dustin Whitney; Ilya Shestopalov; Maeva Fincker; Marc d'Anjou; Kelly Kral; Marisa Gayron; Francis J Pierciey; Richard A Colvin

doi:10.1016/j.omtm.2023.101155

Drug product attributes predict clinical efficacy in betibeglogene autotemcel gene therapy for β-thalassemia

Mol Ther Methods Clin Dev. 2023 Nov 10:31:101155. doi: 10.1016/j.omtm.2023.101155. eCollection 2023 Dec 14.

Authors

Dustin Whitney¹, Ilya Shestopalov¹, Maeva Fincker¹, Marc d'Anjou¹, Kelly Kral¹, Marisa Gayron¹, Francis J Pierciey¹, Richard A Colvin¹

Affiliation

¹ bluebird bio, Inc., Somerville, MA 02145, USA.

Abstract

Ex vivo autologous hematopoietic stem cell lentiviral-based gene therapy with betibeglogene autotemcel has been studied in patients with transfusion-dependent β-thalassemia in Phase III clinical trials (HGB-207 and HGB-212), with 90% of patients reaching transfusion independence (TI). Here, we explore manufacturing parameters, drug product quality attributes, and limited patient characteristics that had an impact on clinical efficacy in HGB-207 and HGB-212. Retrospective analysis revealed that the peripheral blood vector copy number (VCN) was related to TI, with a strong correlation between peripheral blood VCN at 6 months and gene therapy-derived therapeutic protein (HbA^T87Q) expression at 6 months (correlation coefficient, 0.8681; p < 0.0001; R² = 0.7536). A peripheral blood VCN threshold of ≥0.75 copies per diploid genome at 6 months post betibeglogene autotemcel infusion provided a stringent surrogate biomarker for TI and was used as the outcome variable for multivariate analysis using a random forest classifier. The top predictive feature of clinical efficacy was found to be the percentage of lentiviral vector-positive cells in the drug product. This retrospective analysis is critical to understanding the key product quality attributes that can predict clinical efficacy in lentiviral vector gene therapy within this clinical trial population.

Keywords: Zynteglo; beti-cel; betibeglogene autotemcel; drug product quality attributes; lentiviral-based gene therapy; multivariate analysis; transduction efficiency; transfusion-dependent thalassemia.